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]

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

Pleomorphic rhabdomyosarcoma occurs predominantly in adults aged 30 to 50 years and is rarely seen in children.[4] In adults, pleomorphic rhabdomyosarcoma is associated with a worse prognosis. In children, the term anaplasia is preferred.[5] In a retrospective review of 546 pediatric patients, the presence of anaplasia was only associated in univariate analysis with inferior clinical outcome in patients with intermediate-risk rhabdomyosarcoma.[6]

The embryonal and alveolar histologies have distinctive molecular characteristics that have been used for diagnostic confirmation, and may be useful for assigning therapy and monitoring residual disease during treatment.[7-11]

• Alveolar histology: Unique translocations between the FKHR gene on chromosome 13 and either the PAX3 gene on chromosome 2 or the PAX7 gene on chromosome 1 are found in 70% to 80% of patients with alveolar histology tumors.[7,12] Translocations involving the PAX3 gene occur in approximately 59% of alveolar rhabdomyosarcoma cases, while the PAX7 gene appears to be involved in about 19% of cases.[7] Patients with solid-variant alveolar histology have a lower incidence of PAX-FKHR gene fusions than do patients showing classical alveolar histology.[13]

  Alveolar cases associated with the PAX7 gene, with or without metastases, appear to occur in patients at a younger age, and may be associated with longer event-free survival (EFS) rates than those associated with PAX3 gene rearrangements.[14-17] Alveolar cases associated with the PAX3 gene are older and have a higher incidence of invasive tumor (T2). Around 22% of cases showing alveolar histology have no detectable PAX gene translocation.[11,13]

• Embryonal histology: Embryonal tumors often show loss of specific genomic material from the short arm of chromosome 11.[12,18,19] The consistent loss of genomic material from the chromosome 11p15 region in embryonal tumors suggests the presence of a tumor suppressor gene, although no such gene has yet been identified. Breakpoints involving the 1p11-1q11 region are relatively common (36%) in embryonal rhabdomyosarcoma.[20]

These findings highlight the important differences between embryonal and alveolar tumors. There are data that alveolar tumors carrying either a t(1;13) or a t(2;13) translocation (translocation-positive) are biologically and clinically different from alveolar tumors that do not have a translocation (translocation-negative) and from embryonal tumors.[11,21-23] A study has shown that the clinical characteristics and gene profile of translocation-negative alveolar rhabdomyosarcoma is indistinguishable from that seen in embryonal rhabdomyosarcoma cases. In a study of Intergroup Rhabdomyosarcoma Study Group (IRSG) cases, the outcome for patients with translocation-negative alveolar rhabdomyosarcoma was better than that observed for translocation-positive cases and was similar to that seen in patients with embryonal rhabdomyosarcoma, suggesting that fusion status is a critical factor for risk stratification in pediatric rhabdomyosarcoma.[22] However, a German study of 121 patients with alveolar rhabdomyosarcoma found no significant difference in EFS at 5 years among patients who were PAX-FKHR–positive compared with those who were translocation-negative.[24]

A study suggests that metagene expression analyses can classify patients with rhabdomyosarcoma into the three distinct risk groups and may be particularly helpful in identifying intermediate-risk patients with poor-risk features. Further studies are needed to confirm these findings.[21]

References

1. Parham DM, Ellison DA: Rhabdomyosarcomas in adults and children: an update. Arch Pathol Lab Med 130 (10): 1454-65, 2006.  [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. Sultan I, Qaddoumi I, Yaser S, et al.: Comparing adult and pediatric rhabdomyosarcoma in the surveillance, epidemiology and end results program, 1973 to 2005: an analysis of 2,600 patients. J Clin Oncol 27 (20): 3391-7, 2009.  [PUBMED Abstract]
   
   
5. Kodet R, Newton WA Jr, Hamoudi AB, et al.: Childhood rhabdomyosarcoma with anaplastic (pleomorphic) features. A report of the Intergroup Rhabdomyosarcoma Study. Am J Surg Pathol 17 (5): 443-53, 1993.  [PUBMED Abstract]
   
   
6. Qualman S, Lynch J, Bridge J, et al.: Prevalence and clinical impact of anaplasia in childhood rhabdomyosarcoma : a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Cancer 113 (11): 3242-7, 2008.  [PUBMED Abstract]
   
   
7. Barr FG, Smith LM, Lynch JC, et al.: Examination of gene fusion status in archival samples of alveolar rhabdomyosarcoma entered on the Intergroup Rhabdomyosarcoma Study-III trial: a report from the Children's Oncology Group. J Mol Diagn 8 (2): 202-8, 2006.  [PUBMED Abstract]
   
   
8. Kelly KM, Womer RB, Barr FG: Minimal disease detection in patients with alveolar rhabdomyosarcoma using a reverse transcriptase-polymerase chain reaction method. Cancer 78 (6): 1320-7, 1996.  [PUBMED Abstract]
   
   
9. Edwards RH, Chatten J, Xiong QB, et al.: Detection of gene fusions in rhabdomyosarcoma by reverse transcriptase-polymerase chain reaction assay of archival samples. Diagn Mol Pathol 6 (2): 91-7, 1997.  [PUBMED Abstract]
   
   
10. Sartori F, Alaggio R, Zanazzo G, et al.: Results of a prospective minimal disseminated disease study in human rhabdomyosarcoma using three different molecular markers. Cancer 106 (8): 1766-75, 2006.  [PUBMED Abstract]
    
    
11. Davicioni E, Anderson MJ, Finckenstein FG, et al.: Molecular classification of rhabdomyosarcoma--genotypic and phenotypic determinants of diagnosis: a report from the Children's Oncology Group. Am J Pathol 174 (2): 550-64, 2009.  [PUBMED Abstract]
    
    
12. Merlino G, Helman LJ: Rhabdomyosarcoma--working out the pathways. Oncogene 18 (38): 5340-8, 1999.  [PUBMED Abstract]
    
    
13. Parham DM, Qualman SJ, Teot L, et al.: Correlation between histology and PAX/FKHR fusion status in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group. Am J Surg Pathol 31 (6): 895-901, 2007.  [PUBMED Abstract]
    
    
14. Sorensen PH, Lynch JC, Qualman SJ, et al.: PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 20 (11): 2672-9, 2002.  [PUBMED Abstract]
    
    
15. Krsková L, Mrhalová M, Sumerauer D, et al.: Rhabdomyosarcoma: molecular diagnostics of patients classified by morphology and immunohistochemistry with emphasis on bone marrow and purged peripheral blood progenitor cells involvement. Virchows Arch 448 (4): 449-58, 2006.  [PUBMED Abstract]
    
    
16. Kelly KM, Womer RB, Sorensen PH, et al.: Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J Clin Oncol 15 (5): 1831-6, 1997.  [PUBMED Abstract]
    
    
17. Barr FG, Qualman SJ, Macris MH, et al.: Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Cancer Res 62 (16): 4704-10, 2002.  [PUBMED Abstract]
    
    
18. Koufos A, Hansen MF, Copeland NG, et al.: Loss of heterozygosity in three embryonal tumours suggests a common pathogenetic mechanism. Nature 316 (6026): 330-4, 1985 Jul 25-31.  [PUBMED Abstract]
    
    
19. Scrable H, Witte D, Shimada H, et al.: Molecular differential pathology of rhabdomyosarcoma. Genes Chromosomes Cancer 1 (1): 23-35, 1989.  [PUBMED Abstract]
    
    
20. Gordon T, McManus A, Anderson J, et al.: Cytogenetic abnormalities in 42 rhabdomyosarcoma: a United Kingdom Cancer Cytogenetics Group Study. Med Pediatr Oncol 36 (2): 259-67, 2001.  [PUBMED Abstract]
    
    
21. Davicioni E, Anderson JR, Buckley JD, et al.: Gene expression profiling for survival prediction in pediatric rhabdomyosarcomas: a report from the children's oncology group. J Clin Oncol 28 (7): 1240-6, 2010.  [PUBMED Abstract]
    
    
22. Williamson D, Missiaglia E, de Reyniès A, et al.: Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol 28 (13): 2151-8, 2010.  [PUBMED Abstract]
    
    
23. Davicioni E, Finckenstein FG, Shahbazian V, et al.: Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas. Cancer Res 66 (14): 6936-46, 2006.  [PUBMED Abstract]
    
    
24. Stegmaier S, Poremba C, Schaefer KL, et al.: Prognostic value of PAX-FKHR fusion status in alveolar rhabdomyosarcoma: a report from the cooperative soft tissue sarcoma study group (CWS). Pediatr Blood Cancer 57 (3): 406-14, 2011.  [PUBMED Abstract]
    
    

Stage Information

Before a biopsy of a suspected tumor mass is performed, imaging studies of the mass and baseline laboratory studies should be obtained. After the diagnosis of rhabdomyosarcoma has been made, an extensive evaluation to determine the extent of the disease should be done prior to instituting therapy. This evaluation should include a chest x-ray, computed tomography (CT) scan of the chest, bilateral bone marrow aspirates and biopsies, bone scan, magnetic resonance imaging (MRI) of the base of the skull and brain (for parameningeal primary tumors only), and CT scan of the abdomen and pelvis (for lower extremity or genitourinary primary tumors).

A CT or MRI scan of regional lymph nodes should be obtained. Abnormal-appearing lymph nodes should be biopsied when possible. One study has demonstrated that sentinel lymph node biopsies can be safely performed in children with rhabdomyosarcoma, and tumor-positive biopsies may alter the treatment plan.[1] Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose (FDG) scans can identify areas of possible metastatic disease not seen by other imaging modalities.[2-4] However, the efficacy of these two procedures for identifying involved lymph nodes or other sites is currently under investigation, and these procedures are not required by current treatment protocols.

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

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

1. Assigning a Stage (consider primary site, tumor's widest diameter, Surgical-pathologic Group, and presence or absence of metastases).

2. Assigning a local tumor Surgical-pathologic Group (status postsurgical resection/biopsy, with pathologic assessment of the tumor margin).

3. Assigning a Risk Group (classified by Stage, Group, and histology).

As noted previously, prognosis for children with rhabdomyosarcoma depends on the primary site, tumor size, Group, and histologic subtype. Favorable prognostic groups were identified in previous Intergroup Rhabdomyosarcoma Study Group (IRSG) studies, and treatment plans were designed on the basis of assignment of patients to different treatment groups according to prognosis. Several years ago, the IRSG merged with the National Wilms Tumor Study Group and two large cooperative pediatric cancer treatment groups to form the Children's Oncology Group (COG). New protocols for children with soft tissue sarcoma are developed by the Soft Tissue Sarcoma Committee of the COG (COG-STS).

Current COG-STS protocols for rhabdomyosarcoma use a TNM-based pretreatment staging system that incorporates the Surgical-pathologic Group, primary tumor site, regional lymph node status, and the presence or absence of metastases. This staging system is described in Table 2 below.[5,6]

The IRS-I, IRS-II, and IRS-III studies prescribed treatment plans based on the Surgical-pathologic Group system. In this system, Groups are defined by the extent of disease and by the extent of initial surgical resection after pathologic review of the tumor specimen(s). The definitions for these Groups are shown in Table 3 below.[7,8]

After patients are categorized by Stage and Surgical-pathologic Group, a Risk Group is assigned. This takes into account Stage, Group, and histology. Patients are classified for protocol purposes as having a low risk, intermediate risk, or high risk of disease recurrence.[9,10] Treatment assignment is based on Risk Group, as shown in Table 4. To be designated as alveolar, the tumor must have greater than 50% alveolar elements; if the alveolar component is 50% or less, the tumor is considered embryonal.

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

References

1. Kayton ML, Delgado R, Busam K, et al.: Experience with 31 sentinel lymph node biopsies for sarcomas and carcinomas in pediatric patients. Cancer 112 (9): 2052-9, 2008.  [PUBMED Abstract]
   
   
2. Völker T, Denecke T, Steffen I, et al.: Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 25 (34): 5435-41, 2007.  [PUBMED Abstract]
   
   
3. Tateishi U, Hosono A, Makimoto A, et al.: Comparative study of FDG PET/CT and conventional imaging in the staging of rhabdomyosarcoma. Ann Nucl Med 23 (2): 155-61, 2009.  [PUBMED Abstract]
   
   
4. Baum SH, Frühwald M, Rahbar K, et al.: Contribution of PET/CT to prediction of outcome in children and young adults with rhabdomyosarcoma. J Nucl Med 52 (10): 1535-40, 2011.  [PUBMED Abstract]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995.  [PUBMED Abstract]
   
   
9. 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]
   
   
10. 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] Surgical resection may be performed prior to chemotherapy, if feasible without major functional/cosmetic impairment. In most cases, this is not possible. Therefore, a biopsy is performed, followed by chemotherapy and radiation therapy unless the tumor is completely resected with negative margins. Some patients with initially unresected tumors may undergo second-look surgery to remove residual tumor. This is most appropriate if the delayed surgical procedure will entail a complete resection with acceptable functional/cosmetic outcome, and the resulting modest reduction in radiation dose is expected to significantly reduce the risk of long-term adverse effects. Radiation therapy is given to clinically suspicious lymph nodes (detected by palpation or imaging) unless the suspicious lymph nodes are biopsied and shown to be free of rhabdomyosarcoma.

The discussion of treatment options for children with rhabdomyosarcoma is therefore divided into separate sections describing the following local control options:

• Surgery.
• Radiation therapy.
• Chemotherapy.

The treatment of rhabdomyosarcoma by the Children's Oncology Group (COG) and in Europe—as exemplified by trials from the Intergroup Rhabdomyosarcoma Study Group (IRSG), the Soft Tissue Sarcoma Committee of the COG (COG-STS), and the International Society of Pediatric Oncology Malignant Mesenchymal Tumor (MMT) Group—differ in management and overall treatment philosophy.[2] In the MMT trials, the main objective is to reduce the use of local therapies using initial front-line chemotherapy followed by second-line therapy in the presence of poor response. Subsequent surgical resection is preferred over radiation therapy, which is used only after incomplete resection, documented regional lymph node involvement, or a poor clinical response to initial chemotherapy. This approach is designed to avoid major surgical procedures and long-term damaging effects from radiation therapy. The MMT Group approach led to an overall survival (OS) rate of 71% in the European MMT89 study compared with an OS rate of 84% in the IRS-IV study. Similarly, event-free survival rates at 5 years were 57% in the MMT89 study versus 78% in the IRS-IV study. Differences in outcome are most striking for patients with extremity and head and neck nonparameningeal tumors, whereas results are similar for patients with genitourinary tumors. Nevertheless, the overall impression is that survival for most patient subsets is superior with the use of early local therapy, including radiation therapy. 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]

Patients with undifferentiated sarcomas were treated in trials coordinated by the IRSG from 1972 until 2006,[4] but they are currently eligible for the nonrhabdomyosarcoma soft tissue sarcoma protocol using agents active in adult soft tissue sarcoma, ifosfamide and doxorubicin (COG-ARST0332). (Refer to the PDQ summary on Childhood Soft Tissue Sarcoma for more information.)

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]
   
   
4. 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]
   
   

Previously Untreated Childhood Rhabdomyosarcoma

In recent years, the predominant site of treatment failure in patients with initially localized rhabdomyosarcoma has been local recurrence. Both surgery and radiation therapy are primarily measures taken to produce local control, but each has risks, as well as benefits. Surgical removal of the entire tumor should be considered initially, but only if major functional/cosmetic impairment will not result.[1] With that proviso, complete resection of the primary tumor with a surrounding margin of normal tissue and sampling possibly involved lymph nodes in the draining nodal basin is recommended. Important exceptions to the rule of normal margins exist (e.g., tumors of the orbit and of the genitourinary region).[2,3] The principle of wide and complete resection of the primary tumor is less applicable to patients known to have metastatic disease at the initial operation, but it is a reasonable concept if easily accomplished. Patients with microscopic residual tumor following their initial excisional procedure appear to have improved prognoses if a second operative procedure (primary re-excision) to resect the primary tumor bed before beginning chemotherapy can achieve complete removal of tumor.[4] There is little evidence that debulking surgery with macroscopic residual tumor improves outcome, compared with biopsy alone.[5][Level of evidence: 2A] Second-look procedures (delayed primary excision) can identify viable tumor that remains after initial chemotherapy; patients with viable tumor had shorter event-free survival (EFS) rates than did those without viable tumor, but there was no effect on overall survival (OS).[6] The exact role of delayed primary excision remains undefined in rhabdomyosarcoma and is most appropriate if it is anticipated that a complete resection is possible and that the modest reduction in radiation dose will substantially decrease the risk for late effects.

Because rhabdomyosarcoma can arise from multiple sites, surgical care decisions and radiotherapeutic options must be tailored to the unique aspects of each site, and should be discussed with a multidisciplinary team including representatives of those specialties, as well as pediatric oncologists. Surgical management of the more common primary sites is provided in the Local Control Management with Surgery and RT By Primary Sites of Disease section of this summary.

Only 15% of patients present with Group I, completely resected disease, so RT is used in the majority of cases.

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) do well without RT.[7,8] In over 50% of Group II rhabdomyosarcoma patients, local recurrence was due to noncompliance with guidelines or omission of RT.[9] A review of European trials conducted by the German Cooperative Weichteilsarkom Studien (CWS) Group between 1981 and 1998 in which RT was omitted for some Group II patients demonstrated a benefit to using RT as a component of local tumor control for all Group II patient subsets, as defined by tumor histology, tumor size, and tumor site.[10]

The predominant type of relapse for patients with Group III disease is local failure. Patients with tumor-involved regional lymph nodes at diagnosis also have a higher risk of local and distant failure compared with patients whose lymph nodes are negative.[11] As with the surgical management of patients with rhabdomyosarcoma, recommendations for RT depend on the site of primary tumor and on the amount of residual disease, if any, following surgical resection.

For optimal care of pediatric patients undergoing radiation treatments, it is imperative to have available a radiation oncologist, radiation technicians, and nurses who are experienced in treating children. An anesthesiologist may be necessary to help sedate and immobilize young patients. Computerized treatment planning with a three-dimensional planning system should be available. Techniques to deliver radiation specifically to the tumor while sparing normal tissue (e.g., conformal radiation therapy, intensity-modulated radiation therapy [IMRT], proton-beam therapy [charged-particle radiation therapy], or brachytherapy) should be considered.[12-14]

The standard treatment of children with rhabdomyosarcoma with RT includes the following:

• The RT dose depends predominantly on the amount of residual disease, if any, following the primary surgical resection. In general, patients with microscopic residual disease (Group II) receive RT to approximately 41 Gy,[15,16] although doses from 30 Gy to 40 Gy may be adequate in patients receiving effective multiagent chemotherapy.[17] 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) were associated with unacceptable long-term toxic effects.[18,19] Group III patients on the IRS-IV standard treatment arm received 50.4 Gy.[20]

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

• The timing of RT generally allows for chemotherapy to be given for 1 to 3 months before RT is initiated. RT is usually given over 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 IRS-IV trial included a randomized study that reported giving RT twice a day, 6 to 8 hours apart, at 1.1 Gy per dose (hyperfractionated schedule), 5 days per week was feasible, but difficult to accomplish in small children who required sedation twice daily. Patients with localized, gross residual tumors were randomly assigned to receive conventional, once-daily RT (50.4 Gy) versus the twice-daily (59.4 Gy) hyperfractionated schedule. There was no demonstrated advantage in terms of local control.[21] Conventional RT remains the standard for treating patients who have rhabdomyosarcoma with gross residual disease.[22]

Brachytherapy, using either intracavitary or interstitial implants, is another method of local control and has been used in selected situations for children with rhabdomyosarcoma, especially those with primary tumors at vaginal or vulvar sites [23-27] and selected bladder/prostate sites.[28][Level of evidence: 3iiiA] In small series from one or two institutions, this treatment approach was associated with a high survival rate and with retention of a functional organ or tissue in most patients.[24,29] Other sites, especially head and neck, have also been treated with brachytherapy.[30] Patients with initial Group III disease who later have microscopic residual disease after chemotherapy with or without delayed surgery are likely to achieve local control with RT at doses of 40 Gy or more.[31]

Very young children (aged ≤36 months) diagnosed with rhabdomyosarcoma pose a therapeutic challenge because of their increased risk for treatment-related morbidity. Recent experience supports using a somewhat reduced dose of RT in settings where surgery alone is insufficient to provide a high likelihood of local control.[32] For children with initially unresectable tumors, delayed gross total resection followed by 36 Gy external-beam RT provides an excellent likelihood of local control. For infants with unresectable tumors, higher doses of RT remain appropriate. Radiation techniques are designed to maximize normal tissue sparing, and should include conformal approaches, often with intensity-modulated techniques.

Rhabdomyosarcomas of the orbit should not undergo exenteration, but biopsy is needed for diagnosis.[33,34] Biopsy is followed by chemotherapy and RT, with orbital exenteration reserved for the small number of patients with locally persistent or recurrent disease.[35,36] RT and chemotherapy are the standard of care, with survival in excess of 90% to 95%. For patients with orbital tumors, precautions should be taken to limit the RT dose to the lens, cornea, lacrimal gland, and optic chiasm.

If the tumors are nonorbital and cranial parameningeal (arising in the middle ear/mastoid, nasopharynx/nasal cavity, paranasal sinus, parapharyngeal region, or pterygopalatine/infratemporal fossa), a magnetic resonance imaging (MRI) scan with contrast of the primary site and brain should be obtained to check for presence of base-of-skull erosion and possible extension onto or through the dura.[37-39] If skull erosion and/or transdural extension is equivocal, a computed tomography (CT) scan with contrast of the same regions 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.

Nonorbital cranial parameningeal tumors are optimally managed by conformal RT and chemotherapy. Patients with parameningeal disease with intracranial extension in contiguity with the primary tumor, and/or cranial base bone erosion, and/or cranial nerve palsy do not require whole-brain irradiation or intrathecal therapy, unless tumor cells are present in the CSF at diagnosis.[37] Patients should receive RT to the site of primary tumor with a 1.5 cm margin to include the meninges adjacent to the primary tumor and the region of intracranial extension, if present, with a 1.5 cm margin.[38] Patients with intracranial extension should begin receiving RT within 2 weeks after diagnosis.[38] Children who present with tumor cells in the CSF may or may not have other evidence of diffuse meningeal disease and/or distant metastases. In a review of experience from IRSG Protocols II though IV, eight patients had tumor cells in the CSF at diagnosis; three of four without other distant metastases were alive at 6 to 16 years after diagnosis, as was one of four who had concomitant metastases elsewhere.[40] Patients may also have multiple intraparenchymal brain metastases from a distant primary tumor. They may be treated with central nervous system–directed RT in addition to treatment with chemotherapy/RT for the primary tumor. Spinal RT may also be indicated.

For nonparameningeal and nonorbital head and neck tumors, wide excision of the primary tumor (when feasible) and ipsilateral neck lymph node sampling of clinically involved nodes are appropriate.[41] Narrow resection margins (<1 mm) are acceptable because of anatomic restrictions. Cosmetic and functional factors should always be considered, but with modern techniques, complete resection in patients with superficial tumors need not be inconsistent with good cosmetic and functional results. Specialized, multidisciplinary surgical teams also have performed resections of anterior skull-based tumors in areas previously considered inaccessible to definitive surgical management, including the nasal areas, paranasal sinuses, and temporal fossa. These procedures should only be considered, however, in children with recurrent locoregional disease or residual disease following chemotherapy and RT.

For patients with head and neck primary tumors that are considered unresectable, chemotherapy and RT with organ preservation are the mainstay of primary management.[35,39,42-45] Four studies reported excellent local control in patients with rhabdomyosarcoma of the head and neck treated with 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.[46-48]; [49][Level of evidence: 3iiiA]

Intensity-modulated radiation therapy (IMRT) can be used to spare the bone, yet provide optimal soft tissue coverage, and is used for the management of extremity rhabdomyosarcoma. Complete primary tumor removal from the hand or foot is not feasible in most cases because of functional impairment.[50][Level of evidence: 3iiA] For children presenting with a primary tumor of the hands or feet, Children's Oncology Group (COG) studies have shown 100% 10-year local control using RT along with chemotherapy, avoiding amputation in these children.[51][Level of evidence: 3iiiA]

The Soft Tissue Sarcoma Committee of the COG (COG-STS) recommends systematic aggressive axillary node sampling for patients with upper-extremity primary tumors, even with clinically and radiographically negative nodes. The COG-STS also recommends inguinal and femoral triangle node sampling for patients with lower-extremity primary tumors, even with clinically and radiographically negative nodes. If clinically positive nodes are present, biopsy of more proximal nodes is recommended prior to sampling of the involved nodal region. Sentinel lymph node (SLN) mapping is employed at some centers to identify the regional nodes that are the most likely to be involved.[52-55] However, the contribution of SLN mapping is not yet clearly defined in pediatric patients.

Because of the significant incidence of regional nodal spread in patients with extremity primary tumors (often without clinical evidence of involvement) and because of the prognostic and therapeutic implications of nodal involvement, extensive pretreatment assessment of regional (and possibly in-transit) nodes is warranted.[52,56-59]; [60][Level of evidence: 3iiDi] In-transit nodes are defined as epitrochlear and brachial for upper-extremity tumors and popliteal for lower-extremity tumors. Regional lymph nodes for those tumor sites are axillary/infraclavicular nodes and inguinal/femoral nodes, respectively. In a review of 226 patients with primary extremity rhabdomyosarcoma, 5% had tumor-involved in-transit nodes, and over 5 years, the rate of in-transit node recurrence was 12%. Very few patients (n = 11) underwent in-transit node examination at diagnosis, but five of them, all with alveolar rhabdomyosarcoma, had tumor-involved nodes. However, the EFS rates were not significantly different among those evaluated initially and those not evaluated initially for in-transit nodal disease.[60]

The surgical management of patients with lesions of the chest wall or abdominal wall should follow the same guidelines as those used for lesions of the extremities (i.e., wide local excision and an attempt to achieve negative microscopic margins). These resections may require use of prosthetic materials. Very large truncal masses should be biopsied initially. Chemotherapy, with or without RT, is then given. Initial surgery is performed if there is a realistic expectation of achieving negative margins. However, most patients who present with large tumors in these sites have localized disease that becomes amenable to complete resection with negative margins after preoperative chemoradiotherapy and those patients may have excellent long-term survival.[61-64]

Intrathoracic or intraabdominal sarcomas may not be resectable at diagnosis because of the massive size of the tumor and extension into vital organs or vessels.[65] For patients with initially unresectable retroperitoneal/pelvic tumors, complete surgical removal following chemotherapy, with or without RT, offers a significant survival advantage (73% vs. 34%–44% without removal).[65]

With rhabdomyosarcoma of the biliary tree, total resection is rarely feasible and standard treatment includes chemotherapy and RT. Outcome for patients with this primary site is good despite residual disease after surgery. External biliary drains significantly increase the risk of postoperative infectious complications. Thus, external biliary drainage is not warranted.[66]

Patients with rhabdomyosarcoma arising from tissue around the perineum or anus usually have advanced disease. These patients have a high likelihood of regional lymph node involvement, and about half of the tumors have alveolar histology. The current recommendation is to sample the regional lymph nodes. When feasible and without unacceptable morbidity, removing all gross tumor prior to chemotherapy improves the likelihood of cure. In Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols I through IV, the OS after aggressive therapy for 71 patients with tumors in this location was 49%, best for patients in Stage 2, intermediate for those in Stage 3, and worst for those in Stage 4 at diagnosis.[67] However, with a goal of organ preservation, patients with tumors of the perineum/anus are preferentially managed with chemotherapy and RT without aggressive surgery, which may result in loss of sphincter control.

Primary sites for childhood rhabdomyosarcoma within the genitourinary system include the paratesticular area, bladder, prostate, kidney, vulva, vagina, and uterus. Specific considerations for the surgical and radiotherapeutic management of tumors arising at each of these sites are discussed in the paragraphs below.[68]

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).[69] Resection of hemiscrotal skin is required when there is tumor fixation or invasion, or when a previous transscrotal biopsy has been performed. For patients with incompletely removed paratesticular tumors that require RT, temporarily repositioning the contralateral testicle into the adjacent thigh prior to scrotal radiation therapy may preserve hormone production.[70][Level of evidence: 3iiiC]

Paratesticular tumors have a relatively high incidence of lymphatic spread (26% in IRS-I and IRS-II),[56] and all patients with paratesticular primary tumors should have thin-cut abdominal and pelvic CT scans with contrast to evaluate nodal involvement. For patients who have Group I disease, are younger than 10 years, and 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.[71,72] 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.[3,22,73] A staging ipsilateral retroperitoneal lymph node dissection is currently required for all children 10 years and older with paratesticular rhabdomyosarcoma on IRSG and COG-STS studies. However, node dissection is not routine in Europe for adolescents with resected paratesticular rhabdomyosarcoma. Many European investigators have relied on radiographic rather than surgical-pathologic assessment of retroperitoneal lymph node involvement.[69,71] It appears, however, that the ability of the CT scan to predict the presence of lymph node involvement needs further study.[74]

Bladder preservation is a major goal of therapy for patients with tumors arising in the prostate and bladder. An important review providing information about historical, current, and future treatment approaches for prostate and bladder rhabdomyosarcomas has been published.[75]

In rare cases, the tumor is confined to the dome of the bladder and can be completely resected. Otherwise, to preserve a functional bladder in patients with gross residual disease, chemotherapy and RT have been used to reduce tumor bulk,[76,77] followed, when necessary, by a more limited surgical procedure such as partial cystectomy.[78] 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).[78,79] The later experience from IRS-III and IRS-IV, which used more intensive chemotherapy and RT, showed 55% of patients alive with functional bladders at 3 years postdiagnosis, with 3-year OS exceeding 80%.[77,80,81] Patients with a primary tumor of the bladder/prostate who present with a large pelvic mass resulting from a distended bladder caused by outlet obstruction at diagnosis receive RT to a volume defined by imaging studies following initial chemotherapy to relieve outlet obstruction. This approach to therapy remains generally accepted, with the belief that more effective chemotherapy and RT will continue to increase the frequency of bladder salvage.

The initial surgical procedure in most patients consists of a biopsy, which often can be performed using ultrasound guidance or cystoscopy, or by a direct-vision transanal route. In selected cases in one series, bladder-conserving surgery plus brachytherapy for boys with prostate or bladder-neck rhabdomyosarcoma led to excellent survival, bladder preservation, and short-term functional results.[28][Level of evidence: 3iiiB] For patients with biopsy-proven, residual malignant tumor following chemotherapy and RT, appropriate surgical management may include partial cystectomy, prostatectomy, or exenteration (usually approached anteriorly with preservation of the rectum). Very few studies have objective long-term assessments of bladder function, and urodynamic studies are important to obtain accurate evaluation of bladder function.[82]

In patients who have been treated with chemotherapy and RT for rhabdomyosarcoma arising in the bladder/prostate region, the presence of well-differentiated rhabdomyoblasts in surgical specimens or biopsies obtained after treatment does not appear to be associated with a high risk of recurrence and is not an indication for a major surgical procedure such as total cystectomy.[80,83,84] One study suggested that in patients with residual bladder tumors with histologic evidence of maturation, additional courses of chemotherapy should be given before cystectomy is considered.[80] Surgery should be considered only if malignant tumor cells do not disappear over time following initial chemotherapy and RT. Because of very limited data, it is unclear whether this situation is analogous for patients with rhabdomyosarcoma arising in other parts of the body.

The kidney is occasionally the primary site for rhabdomyosarcoma; six cases were identified from among 5,746 eligible patients enrolled on IRSG protocols. The tumors were large (mean widest diameter, 12.7 cm), and anaplasia was present in 67% of patients. Three patients with grossly complete tumor removal at diagnosis survived; the three with incomplete removal and gross or metastatic disease died of infection or metastatic tumor.[85]

For patients with genitourinary primary tumors of the vulva/vagina/uterus, the initial surgical procedure is usually a vulvar or transvaginal biopsy. Initial radical surgery is not indicated for rhabdomyosarcoma of the vulva/vagina/uterus.[3] Conservative surgical intervention for vaginal rhabdomyosarcoma, with primary chemotherapy and adjunctive radiation (often brachytherapy) for residual disease (Group IIA or III), results in excellent disease-free survival.[86,87]

Girls with genitourinary primary tumors should have their ovaries shielded or possibly moved, in an effort to preserve fertility when they are receiving RT to the lower abdomen and pelvis. In the COG-ARST0331 study, there was an unacceptably high rate of local recurrences in girls with Group III vaginal tumors who did not receive RT.[87][Level of evidence: 3iiiDiii] The COG-STS is now recommending that RT be administered to patients with residual viable vaginal tumor, beginning at week 24.

Because of the smaller number of patients with uterine rhabdomyosarcoma, it is difficult to make a definitive treatment decision, but chemotherapy with or without RT is also effective.[86,88] Exenteration is usually not required for primary tumors at these sites, but if needed, it may be done, with rectal preservation possible in most cases.

Rhabdomyosarcoma occasionally arises in sites other than those discussed above. Patients with localized primary rhabdomyosarcoma of the brain can occasionally be cured using a combination of tumor excision, RT, and chemotherapy.[89][Level of evidence: 3iiiDiii]

Patients with laryngeal rhabdomyosarcoma will usually be treated with chemotherapy and RT after biopsy in an attempt to preserve the larynx.[90]

Patients with diaphragm tumors often have locally advanced disease that is not grossly resectable initially because of fixation to adjacent vital structures such as the lung, great vessels, pericardium, and/or liver. In such circumstances, chemotherapy and RT should be initiated after diagnostic biopsy, with the intent to consider removal of residual tumor at a later date if feasible.[91]

Two well-documented cases of primary ovarian rhabdomyosarcoma (one Stage III and one Stage IV) have been reported to supplement the eight previously reported patients. These two patients were alive at 20 and 8 months after diagnosis. Six of the previously reported eight patients had died of their disease.[92][Level of evidence: 3iiiDiii] Treatment with combination chemotherapy followed by removal of the residual mass or masses can sometimes be successful.[92]

Primary resection of metastatic disease at diagnosis (M1, Group IV) is rarely indicated.

The CWS Group reviewed four consecutive trials and identified 29 patients with M1 embryonal rhabdomyosarcoma and metastasis limited to the lung at diagnosis. They reported approximately 38% 5-year EFS for the cohort and did not identify any benefit for local control of pulmonary metastasis, whether by lung irradiation (n = 9), pulmonary metastasectomy (n = 3), or no targeted pulmonary therapy (n = 19).[93][Level of evidence: 3iiiA]

The IRSG IRS-IV (1991–1997) study reviewed 46 patients with metastatic disease at diagnosis confined to the lungs. Only 11 (24%) had a biopsy of the lung, including six at the time of primary diagnosis. They were compared to 234 patients with single nonlung metastatic sites or multiple other sites of metastases. The lung-only patients were more likely to have embryonal rhabdomyosarcoma and parameningeal primary tumors than the larger group of 234 patients, and were less likely to have regional lymph node disease at diagnosis. Failure-free survival (FFS) and OS rates at 4 years were 35% and 42%, respectively, better than for those with two or more sites of metastases (P = .005 and .002, respectively). Being younger than 10 years at diagnosis was also a favorable prognostic factor. Lung irradiation was recommended by the protocols for the lung-only group, but many did not receive it. Those who did receive lung irradiation had better FFS and OS at 4 years than those who did not (P = .01 and P = .039, respectively).[94][Level of evidence: 3iiiB]

All children with rhabdomyosarcoma should receive chemotherapy. The intensity and duration of the chemotherapy are dependent on the Risk Group assignment.[95] See Table 4 in the Stage Information section for more information on Risk Groups.

Standard treatment options

• Low-risk patients have localized (nonmetastatic) embryonal histology tumors in favorable sites that have been grossly resected (Groups I and II), embryonal tumors in the orbit that have not been completely resected (Group III), and localized tumors in an unfavorable site that have been grossly resected (Groups I and II). (See Table 3 in the Stage Information section of this summary.) Certain subgroups of low-risk patients have achieved survival rates higher than 90% when treated with a two-drug chemotherapy regimen that includes vincristine and dactinomycin (VA) plus RT for residual tumor. See Table 5 below.

The COG-D9602 study of the Children's Oncology Group stratified 388 patients with low-risk embryonal rhabdomyosarcoma into two groups.[96] Treatment for subgroup A patients (n = 264; Stage 1 Group I/IIA, Stage 2 Group I, and Stage 1 Group III orbit) consisted of VA with or without RT for 48 weeks. Patients with subgroup B disease (n = 78; Stage 1 Group IIB/C, Stage I Group III nonorbit, Stage 2 Group II, and Stage 3 Group I/II disease) received VA plus cyclophosphamide (total cumulative dose of 28.6 g/m²). Radiation doses were reduced from 41.4 Gy to 36 Gy for Stage 1 Group IIA patients and from 50 Gy or 59 Gy to 45 Gy for Group III orbit patients. For subgroup A patients, the 5-year overall FFS rate was 88% and the OS rate was 97%. For subgroup B patients, the 5-year FFS rate was 85% and the OS rate was 93%.

Other subgroups of low-risk patients have achieved survival rates of at least 90% with three-drug chemotherapy with VA and cyclophosphamide ([VAC], total cyclophosphamide dose of 28.6 g/m²) plus RT for residual tumor. See Table 6 below.

Standard treatment options

• In IRS-IV, intermediate-risk patients had survival rates at 3 years from 84% to 88%. This category includes patients with embryonal rhabdomyosarcoma at unfavorable sites (Stages 2 and 3) with gross residual disease (i.e., Group III), and patients with nonmetastatic alveolar rhabdomyosarcoma (Stages 2 and 3) at any site (Groups I, II, and III). The IRS-IV study randomly assigned intermediate-risk patients to receive either standard VAC therapy or one of two other chemotherapy regimens using ifosfamide as the alkylating agent. Outcomes with VAC were as good as the other two regimens and easier to administer. Because there was no difference in outcome between these three treatments, VAC remains the standard chemotherapy combination for children with intermediate-risk rhabdomyosarcoma.[22]

  A comparison of survival in patients with tumors of embryonal histology treated on IRS-IV (who received higher doses of alkylating agents) compared with similar patients treated on IRS-III (who received lower doses of alkylating agents) suggested a benefit with the use of higher doses of cyclophosphamide for certain groups of intermediate-risk patients. These included patients with tumors at favorable sites and positive lymph nodes, patients with gross residual disease, or patients with tumors at unfavorable sites who underwent grossly complete resections, but not patients with unresected embryonal rhabdomyosarcoma at unfavorable sites.[97] For other groups of intermediate-risk patients, an intensification of cyclophosphamide was feasible but did not improve outcome.[98]

• The COG has also evaluated whether the addition of topotecan and cyclophosphamide to standard VAC therapy improved outcome for children with intermediate-risk rhabdomyosarcoma. Topotecan was prioritized for evaluation on the basis of its preclinical activity in rhabdomyosarcoma xenograft models as well as its single-agent activity in previously untreated children with rhabdomyosarcoma, particularly those with alveolar rhabdomyosarcoma.[99,100] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity both in patients with recurrent disease and in newly diagnosed patients with metastatic disease.[101,102] The COG-D9803 clinical trial for newly diagnosed patients with intermediate-risk disease randomly assigned patients to receive either VAC therapy or VAC therapy with additional courses of topotecan and cyclophosphamide. However, patients who received topotecan and cyclophosphamide fared no better than those treated with VAC alone; 4-year FFS was 73% with VAC and 68% with VAC/VTC.[101][Level of evidence: 1iiA] Thus, VAC is still the standard form of multiagent chemotherapy for intermediate-risk patients.

• In a limited-institution pilot study, a combination of vincristine/doxorubicin/cyclophosphamide (VDC) alternating with ifosfamide/etoposide (IE) was used to treat patients with intermediate-risk rhabdomyosarcoma. The relative efficacy of this approach versus the standard approach would require further investigation.[103][Level of evidence: 3iiiA]

• Approximately 20% of Group III patients will have a residual mass at the completion of therapy. The presence of a residual mass had no adverse prognostic significance.[104,105] Aggressive alternative therapy may not be warranted for rhabdomyosarcoma patients with a residual mass at the end of planned therapy. For Group III patients, best response to initial chemotherapy had no impact on overall outcome.[105] While induction chemotherapy is commonly administered for 9 to 12 weeks, 2.2% of patients with intermediate-risk rhabdomyosarcoma on the IRS-IV and COG-D9803 studies were found to have early disease progression and did not receive their planned course of RT.[106] COG investigators are now studying the value of early administration of RT in patients of intermediate risk.

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

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

Standard treatment options

• High-risk patients have metastatic disease in one or more sites at diagnosis (Stage IV). These patients continue to have a relatively poor prognosis (5-year survival rate of 50% or lower) with current therapy, and new approaches to treatment are needed to improve survival in this group.[94,107,108] Two retrospective studies have looked at patients who present with metastases limited to the lungs;[93,94] results are summarized in the Metastatic sites section of this summary.

  A pooled analysis of 788 high-risk rhabdomyosarcoma patients treated with multiagent chemotherapy (all regimens used cyclophosphamide or ifosfamide plus dactinomycin and vincristine with or without additional chemotherapeutic agents), followed by local therapy (surgery with or without RT) within 3 to 5 months of starting chemotherapy, identified several adverse prognostic factors. These were age younger than 1 year, age 10 years or older, unfavorable primary site, bone and/or bone marrow involvement, and three or more different metastatic sites. The EFS rate at 3 years was 50% for patients without any of these adverse prognostic factors. The EFS rates were 42% for patients with one adverse prognostic factor, 18% for patients with two adverse prognostic factors, 12% for patients three adverse prognostic factors, and 5% for patients with four adverse prognostic factors (P < .0001).[109][Level of evidence: 3iiiA]

  The standard systemic therapy for children with metastatic rhabdomyosarcoma is the three-drug combination of VAC. Despite many clinical trials attempting to improve outcome by adding additional agents to standard VAC chemotherapy (or substituting new agents for one or more components of VAC chemotherapy), to date, no chemotherapy regimens have been shown to be more effective than VAC, including the following:

  • In the IRS-IV study, three combinations of drug pairs were studied in an up-front window—IE, vincristine/melphalan (VM),[110] and ifosfamide/doxorubicin (ID).[111] These patients received VAC after the up-front window agents were evaluated at weeks 6 and 12. OS rates for patients treated with IE and ID were comparable (31% and 34%, respectively) and better than for those treated with VM (22%).[111] However, results with VAC chemotherapy for Stage IV rhabdomyosarcoma in the North American experience are similar.

  • Results from a phase II window trial of patients with metastatic disease at presentation and treated with topotecan and cyclophosphamide showed activity for this two-drug combination, but survival was not different from that seen with previous regimens.[101,102] An up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma gave similar results.[100]

  • Irinotecan and irinotecan with vincristine [112] have also been evaluated as up-front windows by the COG-STS; the response rates were better when irinotecan was administered with vincristine than without it, but again, survival in a preliminary analysis was not improved over prior experience.[112]

  • In a French study, 20 patients with metastatic disease at diagnosis received window therapy with doxorubicin for two courses. Thirteen of 20 patients responded to therapy, and four patients had progressive disease.[113]

  • A study from the International Society of Pediatric Oncology (SIOP) demonstrated continued poor outcome for patients with high-risk features such as age 10 years and older or bone/bone marrow involvement. This study compared a standard six-drug combination followed by vincristine, doxorubicin, cyclophosphamide (VAC) maintenance versus an arm that evaluated a window of single-agent doxorubicin or carboplatin followed by sequential high-dose monotherapy courses including cyclophosphamide, etoposide, and carboplatin followed by maintenance VAC. No benefit was seen for the high-dose therapy arm.[114]

• High-dose chemotherapy with stem cell rescue has been evaluated in a limited number of patients with rhabdomyosarcoma.[115,116]; [117][Level of evidence: 3iiiA] The use of high-dose chemotherapy with stem cell rescue has failed to improve the outcome of patients with newly diagnosed or recurrent rhabdomyosarcoma.

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

• COG-ARST08P1 (Temozolomide, Cixutumumab [IMC-A12], and Combination Chemotherapy in Treating Patients With Metastatic Rhabdomyosarcoma): COG-ARST08P1 evaluates the addition of novel therapeutic agents to the intensive chemotherapy used in the COG study COG-ARST0431. Newly diagnosed patients with metastatic rhabdomyosarcoma (excluding patients younger than 10 years with embryonal rhabdomyosarcoma) who have an expected FFS of less than 20% are eligible. The study consists of the following three sequential pilots:
  • Pilot 1 assesses the feasibility of adding IMC-A12, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor-1 receptor (IGF-1R), to most known effective chemotherapy agents in rhabdomyosarcoma.

  • Pilot 2 assesses the feasibility of adding temozolomide, an alkylating agent, to vincristine/irinotecan cycles, based on synergistic activity of temozolomide when added to irinotecan.

  • Pilot 3 will assess the feasibility of adding both agents to the COG-ARST0431 backbone, provided that pilot studies 1 and 2 have not shown unexpected toxicity.

• The NCI's intramural Pediatric Oncology Branch conducted a study of consolidative immunotherapy incorporating T-cell reconstitution followed by a dendritic-cell plus tumor-peptide vaccine that was given with little toxicity to patients with translocation-positive metastatic or recurrent Ewing sarcoma and alveolar rhabdomyosarcoma.[118][Level of evidence: 3iiiA]

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

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

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33. 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]
    
    
34. 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]
    
    
35. 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]
    
    
36. Mannor GE, Rose GE, Plowman PN, et al.: Multidisciplinary management of refractory orbital rhabdomyosarcoma. Ophthalmology 104 (7): 1198-201, 1997.  [PUBMED Abstract]
    
    
37. 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]
    
    
38. 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]
    
    
39. 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]
    
    
40. Raney B, Anderson J, Breneman J, et al.: Results in patients with cranial parameningeal sarcoma and metastases (Stage 4) treated on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols II-IV, 1978-1997: report from the Children's Oncology Group. Pediatr Blood Cancer 51 (1): 17-22, 2008.  [PUBMED Abstract]
    
    
41. Raney RB, Chintagumpala M, Anderson J, et al.: Results of treatment of patients with superficial facial rhabdomyosarcomas on protocols of the Intergroup Rhabdomyosarcoma Study Group (IRSG), 1984-1997. Pediatr Blood Cancer 50 (5): 958-64, 2008.  [PUBMED Abstract]
    
    
42. 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]
    
    
43. 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]
    
    
44. 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]
    
    
45. Defachelles AS, Rey A, Oberlin O, et al.: Treatment of nonmetastatic cranial parameningeal rhabdomyosarcoma in children younger than 3 years old: results from international society of pediatric oncology studies MMT 89 and 95. J Clin Oncol 27 (8): 1310-5, 2009.  [PUBMED Abstract]
    
    
46. 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]
    
    
47. 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]
    
    
48. McDonald MW, Esiashvili N, George BA, et al.: Intensity-modulated radiotherapy with use of cone-down boost for pediatric head-and-neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 72 (3): 884-91, 2008.  [PUBMED Abstract]
    
    
49. Curtis AE, Okcu MF, Chintagumpala M, et al.: Local control after intensity-modulated radiotherapy for head-and-neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 73 (1): 173-7, 2009.  [PUBMED Abstract]
    
    
50. Casanova M, Meazza C, Favini F, et al.: Rhabdomyosarcoma of the extremities: a focus on tumors arising in the hand and foot. Pediatr Hematol Oncol 26 (5): 321-31, 2009 Jul-Aug.  [PUBMED Abstract]
    
    
51. La TH, Wolden SL, Su Z, et al.: Local therapy for rhabdomyosarcoma of the hands and feet: is amputation necessary? A report from the Children's Oncology Group. Int J Radiat Oncol Biol Phys 80 (1): 206-12, 2011.  [PUBMED Abstract]
    
    
52. 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]
    
    
53. 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]
    
    
54. 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]
    
    
55. Kayton ML, Delgado R, Busam K, et al.: Experience with 31 sentinel lymph node biopsies for sarcomas and carcinomas in pediatric patients. Cancer 112 (9): 2052-9, 2008.  [PUBMED Abstract]
    
    
56. 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]
    
    
57. 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]
    
    
58. 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]
    
    
59. Rodeberg DA, Garcia-Henriquez N, Lyden ER, et al.: Prognostic significance and tumor biology of regional lymph node disease in patients with rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 29 (10): 1304-11, 2011.  [PUBMED Abstract]
    
    
60. La TH, Wolden SL, Rodeberg DA, et al.: Regional nodal involvement and patterns of spread along in-transit pathways in children with rhabdomyosarcoma of the extremity: a report from the Children's Oncology Group. Int J Radiat Oncol Biol Phys 80 (4): 1151-7, 2011.  [PUBMED Abstract]
    
    
61. Saenz NC, Ghavimi F, Gerald W, et al.: Chest wall rhabdomyosarcoma. Cancer 80 (8): 1513-7, 1997.  [PUBMED Abstract]
    
    
62. 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]
    
    
63. 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]
    
    
64. Hayes-Jordan A, Stoner JA, Anderson JR, et al.: The impact of surgical excision in chest wall rhabdomyosarcoma: a report from the Children's Oncology Group. J Pediatr Surg 43 (5): 831-6, 2008.  [PUBMED Abstract]
    
    
65. Cecchetto G, Bisogno G, Treuner J, et al.: Role of surgery for nonmetastatic abdominal rhabdomyosarcomas: a report from the Italian and German Soft Tissue Cooperative Groups Studies. Cancer 97 (8): 1974-80, 2003.  [PUBMED Abstract]
    
    
66. 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]
    
    
67. 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]
    
    
68. Wu HY, Snyder HM 3rd, Womer RB: Genitourinary rhabdomyosarcoma: which treatment, how much, and when? J Pediatr Urol 5 (6): 501-6, 2009.  [PUBMED Abstract]
    
    
69. 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]
    
    
70. 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]
    
    
71. 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]
    
    
72. 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]
    
    
73. 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]
    
    
74. 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]
    
    
75. Ferrer FA, Isakoff M, Koyle MA: Bladder/prostate rhabdomyosarcoma: past, present and future. J Urol 176 (4 Pt 1): 1283-91, 2006.  [PUBMED Abstract]
    
    
76. 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]
    
    
77. 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]
    
    
78. Pappo AS, Shapiro DN, Crist WM, et al.: Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 13 (8): 2123-39, 1995.  [PUBMED Abstract]
    
    
79. 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]
    
    
80. 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]
    
    
81. 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]
    
    
82. Raney B, Anderson J, Jenney M, et al.: Late effects in 164 patients with rhabdomyosarcoma of the bladder/prostate region: a report from the international workshop. J Urol 176 (5): 2190-4; discussion 2194-5, 2006.  [PUBMED Abstract]
    
    
83. 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]
    
    
84. Arndt CA, Hammond S, Rodeberg D, et al.: Significance of persistent mature rhabdomyoblasts in bladder/prostate rhabdomyosarcoma: Results from IRS IV. J Pediatr Hematol Oncol 28 (9): 563-7, 2006.  [PUBMED Abstract]
    
    
85. Raney B, Anderson J, Arndt C, et al.: Primary renal sarcomas in the Intergroup Rhabdomyosarcoma Study Group (IRSG) experience, 1972-2005: A report from the Children's Oncology Group. Pediatr Blood Cancer 51 (3): 339-43, 2008.  [PUBMED Abstract]
    
    
86. 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]
    
    
87. Walterhouse DO, Meza JL, Breneman JC, et al.: Local control and outcome in children with localized vaginal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma committee of the Children's Oncology Group. Pediatr Blood Cancer 57 (1): 76-83, 2011.  [PUBMED Abstract]
    
    
88. Corpron CA, Andrassy RJ, Hays DM, et al.: Conservative management of uterine pediatric rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study III and IV pilot. J Pediatr Surg 30 (7): 942-4, 1995.  [PUBMED Abstract]
    
    
89. Guilcher GM, Hendson G, Goddard K, et al.: Successful treatment of a child with a primary intracranial rhabdomyosarcoma with chemotherapy and radiation therapy. J Neurooncol 86 (1): 79-82, 2008.  [PUBMED Abstract]
    
    
90. 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]
    
    
91. 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]
    
    
92. Cribbs RK, Shehata BM, Ricketts RR: Primary ovarian rhabdomyosarcoma in children. Pediatr Surg Int 24 (5): 593-5, 2008.  [PUBMED Abstract]
    
    
93. Dantonello TM, Winkler P, Boelling T, et al.: Embryonal rhabdomyosarcoma with metastases confined to the lungs: report from the CWS Study Group. Pediatr Blood Cancer 56 (5): 725-32, 2011.  [PUBMED Abstract]
    
    
94. 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]
    
    
95. Mandell LR: Ongoing progress in the treatment of childhood rhabdomyosarcoma. Oncology (Huntingt) 7 (1): 71-83; discussion 84-6, 89-90, 1993.  [PUBMED Abstract]
    
    
96. Beverly Raney R, Walterhouse DO, Meza JL, et al.: Results of the Intergroup Rhabdomyosarcoma Study Group D9602 protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. J Clin Oncol 29 (10): 1312-8, 2011.  [PUBMED Abstract]
    
    
97. 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]
    
    
98. 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]
    
    
99. 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]
    
    
100. 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]
     
     
101. 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]
     
     
102. 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]
     
     
103. 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]
     
     
104. Arndt CA, Stoner JA, Hawkins DS, et al.: Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: children's oncology group study D9803. J Clin Oncol 27 (31): 5182-8, 2009.  [PUBMED Abstract]
     
     
105. Rodeberg DA, Stoner JA, Hayes-Jordan A, et al.: Prognostic significance of tumor response at the end of therapy in group III rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 27 (22): 3705-11, 2009.  [PUBMED Abstract]
     
     
106. Minn AY, Lyden ER, Anderson JR, et al.: Early treatment failure in intermediate-risk rhabdomyosarcoma: results from IRS-IV and D9803--a report from the Children's Oncology Group. J Clin Oncol 28 (27): 4228-32, 2010.  [PUBMED Abstract]
     
     
107. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995.  [PUBMED Abstract]
     
     
108. 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]
     
     
109. 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]
     
     
110. 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]
     
     
111. 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]
     
     
112. 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]
     
     
113. 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]
     
     
114. McDowell HP, Foot AB, Ellershaw C, et al.: Outcomes in paediatric metastatic rhabdomyosarcoma: results of The International Society of Paediatric Oncology (SIOP) study MMT-98. Eur J Cancer 46 (9): 1588-95, 2010.  [PUBMED Abstract]
     
     
115. Admiraal R, van der Paardt M, Kobes J, et al.: High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma. Cochrane Database Syst Rev (12): CD006669, 2010.  [PUBMED Abstract]
     
     
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117. 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]
     
     
118. Mackall CL, Rhee EH, Read EJ, et al.: A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas. Clin Cancer Res 14 (15): 4850-8, 2008.  [PUBMED Abstract]
     
     

Recurrent Childhood Rhabdomyosarcoma

Although patients with recurrent or progressive rhabdomyosarcoma sometimes achieve complete remission with secondary therapy, the long-term prognosis is usually poor.[1,2] The prognosis is most favorable (50% to 70% 5-year survival rates) for children who initially present with Stage 1 or Group I disease and embryonal histology and who have smaller tumors or present with a local or regional recurrence.[1-3] The small number of children with botryoid histology who relapse have a similarly favorable prognosis.[1] Most other children who relapse have an extremely poor prognosis.[1] A retrospective review of rhabdomyosarcoma patients from German soft tissue sarcoma trials identified time to recurrence as an important independent prognostic factor. Shorter time to recurrence was associated with higher risk of mortality from recurrent rhabdomyosarcoma.[4][Level of evidence: 3iiB] European investigators performed a retrospective review of patients with rhabdomyosarcoma enrolled on cooperative group trials who experienced recurrence. They identified metastatic (as opposed to local) recurrence, prior radiation therapy, initial tumor size (>5 cm), and time to relapse (<18 months) as unfavorable prognostic features for survival postrecurrence.[5]

The selection of further treatment depends on many factors, including the site(s) of recurrence, previous treatment, and individual patient considerations. Treatment for local or regional recurrence may include wide local excision or aggressive surgical removal of tumor, particularly in the absence of widespread bony metastases.[6,7] Some survivors have also been reported after surgical removal of only one or a few metastases in the lung.[6] Radiation therapy should be considered for patients who have not already received radiation therapy in the area of recurrence, or rarely for those who have received radiation therapy but for whom surgical excision is not possible. Previously unused, active, single agents or combinations of drugs may also enhance the likelihood of disease control.

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

• Carboplatin/etoposide.[8]

• Ifosfamide, carboplatin, and etoposide.[9,10]

• Cyclophosphamide/topotecan.[11]

• Irinotecan with or without vincristine.[12-15] A Children's Oncology Group (COG) prospective, randomized, up-front window trial showed no difference between vincristine plus irinotecan (20 mg/m²/d) daily × 5 days for 4 weeks per 6-week treatment cycle and irinotecan (50 mg/m²/d) daily × 5 days for 2 weeks per 6-week treatment cycle in poor-risk patients with relapsed or progressive rhabdomyosarcoma and recommended the shorter regimen for further investigation.[16][Level of evidence: 1iiA]

• Vinorelbine. In a phase II trial, four patients (N = 11) with recurrent rhabdomyosarcoma responded to single-agent vinorelbine.[17]

• Vinorelbine and cyclophosphamide. In a pilot study, three patients (N = 9) with rhabdomyosarcoma had an objective response.[18]

• Gemcitabine and docetaxel. In a single institution trial, two patients (N = 5) with recurrent rhabdomyosarcoma achieved an objective response.[19]

Treatment options under clinical evaluation for recurrent rhabdomyosarcoma:

• COG-ARST0921 (Vinorelbine Ditartrate and Cyclophosphamide in Combination With Bevacizumab or Temsirolimus in Treating Patients With Recurrent or Refractory Rhabdomyosarcoma): A randomized phase II trial of bevacizumab and temsirolimus in combination with intravenous (IV) vinorelbine and cyclophosphamide in patients with recurrent/refractory rhabdomyosarcoma. This is a randomized study for patients experiencing their first relapse or progression of rhabdomyosarcoma. The goals of this study are to determine the feasibility of administering bevacizumab or temsirolimus with a chemotherapy regimen of IV vinorelbine and cyclophosphamide and to compare the event-free survival between patients treated with vinorelbine/cyclophosphamide and temsirolimus and those treated with vinorelbine/cyclophosphamide and bevacizumab.

• COG-ADVL1121 (Sorafenib Tosylate in Treating Younger Patients With Relapsed or Refractory Rhabdomyosarcoma, Wilms Tumor, Liver Cancer, or Thyroid Cancer): A phase II study of sorafenib, a Raf kinase and receptor tyrosine kinase inhibitor, in children and young adults with relapsed/refractory rhabdomyosarcoma, Wilms tumor, hepatocellular carcinoma, and papillary thyroid carcinoma. The goal of this study is to determine the objective response rate of sorafenib in children with refractory or relapsed rhabdomyosarcoma. Patients must be aged 2 to 30 years.

• Intensive chemotherapy followed by autologous bone marrow transplantation. Very intensive chemotherapy followed by autologous bone marrow reinfusion is also under investigation for patients with recurrent rhabdomyosarcoma. However, a review of the published data did not determine a significant benefit for patients who underwent this salvage treatment approach.[20-22]

• Single-agent vinorelbine.[23]

• Combination vinorelbine and low-dose cyclophosphamide.[18]

• Rapamycin.[24]

• Topotecan, vincristine, and doxorubicin.[25][Level of evidence: 3iiiDiv]

• 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 list of cancer clinical trials that are now accepting patients with recurrent childhood rhabdomyosarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

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

References

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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. 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]
   
   
4. Mattke AC, Bailey EJ, Schuck A, et al.: Does the time-point of relapse influence outcome in pediatric rhabdomyosarcomas? Pediatr Blood Cancer 52 (7): 772-6, 2009.  [PUBMED Abstract]
   
   
5. Chisholm JC, Marandet J, Rey A, et al.: Prognostic factors after relapse in nonmetastatic rhabdomyosarcoma: a nomogram to better define patients who can be salvaged with further therapy. J Clin Oncol 29 (10): 1319-25, 2011.  [PUBMED Abstract]
   
   
6. Hayes-Jordan A, Doherty DK, West SD, et al.: Outcome after surgical resection of recurrent rhabdomyosarcoma. J Pediatr Surg 41 (4): 633-8; discussion 633-8, 2006.  [PUBMED Abstract]
   
   
7. De Corti F, Bisogno G, Dall'Igna P, et al.: Does surgery have a role in the treatment of local relapses of non-metastatic rhabdomyosarcoma? Pediatr Blood Cancer 57 (7): 1261-5, 2011.  [PUBMED Abstract]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. Vassal G, Couanet D, Stockdale E, et al.: Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group. J Clin Oncol 25 (4): 356-61, 2007.  [PUBMED Abstract]
    
    
15. Furman WL, Stewart CF, Poquette CA, et al.: Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17 (6): 1815-24, 1999.  [PUBMED Abstract]
    
    
16. Mascarenhas L, Lyden ER, Breitfeld PP, et al.: Randomized phase II window trial of two schedules of irinotecan with vincristine in patients with first relapse or progression of rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 28 (30): 4658-63, 2010.  [PUBMED Abstract]
    
    
17. Kuttesch JF Jr, Krailo MD, Madden T, et al.: Phase II evaluation of intravenous vinorelbine (Navelbine) in recurrent or refractory pediatric malignancies: a Children's Oncology Group study. Pediatr Blood Cancer 53 (4): 590-3, 2009.  [PUBMED Abstract]
    
    
18. 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]
    
    
19. Rapkin L, Qayed M, Brill P, et al.: Gemcitabine and docetaxel (GEMDOX) for the treatment of relapsed and refractory pediatric sarcomas. Pediatr Blood Cancer : , 2012.  [PUBMED Abstract]
    
    
20. Weigel BJ, Breitfeld PP, Hawkins D, et al.: Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. J Pediatr Hematol Oncol 23 (5): 272-6, 2001 Jun-Jul.  [PUBMED Abstract]
    
    
21. Admiraal R, van der Paardt M, Kobes J, et al.: High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma. Cochrane Database Syst Rev (12): CD006669, 2010.  [PUBMED Abstract]
    
    
22. Peinemann F, Kröger N, Bartel C, et al.: High-dose chemotherapy followed by autologous stem cell transplantation for metastatic rhabdomyosarcoma--a systematic review. PLoS One 6 (2): e17127, 2011.  [PUBMED Abstract]
    
    
23. Casanova M, Ferrari A, Spreafico F, et al.: Vinorelbine in previously treated advanced childhood sarcomas: evidence of activity in rhabdomyosarcoma. Cancer 94 (12): 3263-8, 2002.  [PUBMED Abstract]
    
    
24. Houghton PJ, Morton CL, Kolb EA, et al.: Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer 50 (4): 799-805, 2008.  [PUBMED Abstract]
    
    
25. Meazza C, Casanova M, Zaffignani E, et al.: Efficacy of topotecan plus vincristine and doxorubicin in children with recurrent/refractory rhabdomyosarcoma. Med Oncol 26 (1): 67-72, 2009.  [PUBMED Abstract]
    
    

Changes to This Summary (05/18/2012)

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

Stage Information

Added Baum et al. as reference 4.

Previously Untreated Childhood Rhabdomyosarcoma

Added text to state that in a review of experience from IRSG Protocols II though IV, eight patients had tumor cells in the CSF at diagnosis; three of four without other distant metastases were alive at 6 to 16 years after diagnosis, as was one of four who had concomitant metastases elsewhere (cited Raney et al. as reference 40).

Added text to state that in selected cases in one series, bladder-conserving surgery plus brachytherapy for boys with prostate or bladder-neck rhabdomyosarcoma led to excellent survival, bladder preservation, and short-term functional results (cited Martelli et al. as reference 28 and level of evidence 3iiiB).

Recurrent Childhood Rhabdomyosarcoma

Added De Corti et al. as reference 7.

Added text about how vinorelbine, vinorelbine and cyclophosphamide, and gemcitabine and docetaxel are standard chemotherapy regimens that have been used to treat recurrent rhabdomyosarcoma (cited Kuttesch et al. and Rapkin et al. as references 17 and 19, respectively).

About This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood rhabdomyosarcoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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

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

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Rhabdomyosarcoma Treatment are:

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

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

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

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

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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.

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