Childhood Rhabdomyosarcoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Childhood Rhabdomyosarcoma

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1] For rhabdomyosarcoma, the 5-year survival rate increased over the same time, from 53% to 67% for children younger than 15 years and from 30% to 51% for adolescents aged 15 to 19 years.[1] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Incidence

Childhood rhabdomyosarcoma is a soft tissue malignant tumor of mesenchymal origin. It accounts for approximately 3.5% of the cases of cancer among children aged 0 to 14 years and 2% of the cases among adolescents and young adults aged 15 to 19 years.[2,3] The incidence is 4.5 cases per 1 million children, and 50% of cases are seen in the first decade of life.[4]

Incidence may depend on the histologic subtype of rhabdomyosarcoma, as follows:

• Embryonal: Patients with embryonal rhabdomyosarcoma are predominantly male (male to female ratio, 1.5). The peak incidence is in the 0- to 4-year age group at approximately 4 cases per 1 million children, with a lower rate in adolescents, approximately 1.5 cases per 1 million adolescents. This subtype constitutes 57% of patients in the Surveillance, Epidemiology, and End Results (SEER) database.[4]
• Alveolar: The incidence of alveolar rhabdomyosarcoma does not vary by gender and is constant from ages 0 to 19 years at approximately 1 case per 1 million children and adolescents. This subtype constitutes 23% of patients in the SEER database.[4]
• Other: Pleomorphic/anaplastic, mixed type, and spindle cell subtypes each constitute less than 2% of children with rhabdomyosarcoma.[4]

The following are the most common primary sites for rhabdomyosarcoma:[5,6]

• Head and neck region (approximately 25%).
• Genitourinary tract (approximately 22%).
• Extremities (approximately 18%). Within extremity tumors, tumors of the hand and foot occur more often in older patients and have an alveolar histology.[7]

Other less common primary sites include the trunk, chest wall, perineal/anal region, and abdomen, including the retroperitoneum and biliary tract.[6]

Risk Factors

Most cases of rhabdomyosarcoma occur sporadically, with no recognized predisposing risk factor, with the exception of the following:[8]

• Genetic conditions associated with rhabdomyosarcoma:
  • Li-Fraumeni cancer susceptibility syndrome (with germline TP53 mutations).[9,10,11]
  • Pleuropulmonary blastoma (with DICER1 mutations).[12,13]
  • Neurofibromatosis type I.[14,15]
  • Costello syndrome (with germline HRAS mutations).[16,17,18,19]
  • Beckwith-Wiedemann syndrome (with which Wilms tumor and hepatoblastoma are more commonly associated).[20,21]
  • Noonan syndrome.[19,22,23]
• High birth weight and large size for gestational age are associated with an increased incidence of embryonal rhabdomyosarcoma.[24]

Prognostic Factors

Rhabdomyosarcoma is usually curable in most children with localized disease who receive combined-modality therapy, with more than 70% surviving 5 years after diagnosis.[5,6,25] Relapses are uncommon after 5 years of disease-free survival, with a 9% late-event rate at 10 years. Relapses, however, are more common in patients who have gross residual disease in unfavorable sites after initial surgery and in those who have metastatic disease at diagnosis.[26]

The prognosis for a child or adolescent with rhabdomyosarcoma is related to the following clinical and biological factors with proven or possible prognostic significance:

• Age: Children aged 1 to 9 years have the best prognosis, while those younger and older fare less well. In recent Intergroup Rhabdomyosarcoma Study Group (IRSG) trials, 5-year failure-free survival (FFS) was 57% for patients younger than 1 year, 81% for patients aged 1 to 9 years, and 68% for patients older than 10 years. Five-year survival for these groups was 76%, 87%, and 76%, respectively.[27] Historical data show that adults fare less well than children (5-year overall survival [OS] rates, 27% ± 1.4% and 61% ± 1.4%, respectively; P < .0001).[28,29,30,31]
  • Infants: Infants may do poorly because their bone marrow is less tolerant of chemotherapy doses that older children can receive; thus, infants are relatively underdosed compared with older patients. In addition, infants younger than 1 year are less likely to receive radiation therapy for local control, because of bias and/or concern about the high incidence of late effects in this age group.[25,32,33] The 5-year FFS for infants was found to be 67%, compared with 81% in a matched group of older patients treated by the Children's Oncology Group (COG).[27] This inferior FFS was largely because of a relatively high rate of local failure.
  • Older children: In older children, vincristine and dactinomycin have upper dosage limits based on body surface area (BSA), and these patients may also require reduced vincristine doses because of neurotoxicity.[33,34]
  • Adolescents: A report from the AIEOP (Italian) Soft Tissue Sarcoma Committee suggests that adolescents may have more frequent unfavorable tumor characteristics, including alveolar histology, regional lymph node involvement, and metastatic disease at diagnosis, accounting for their poor prognosis. This study also found that 5-year OS and progression-free survival (PFS) rates were somewhat lower in adolescents than in children, but the differences among age groups younger than 1 year and aged 10 to 19 years at diagnosis were significantly worse than those in the group aged 1 to 9 years.[35]
• Site of origin: Prognosis for childhood rhabdomyosarcoma varies according to the primary tumor site.

  Table 1. 5-Year Survival by Primary Site of Disease

  Primary Site	Number of Patients	Survival at 5 Years (%)
  a Patients treated on Intergroup Rhabdomyosarcoma Study III.[5]
  b Patients treated on Intergroup Rhabdomyosarcoma Studies I-IV.[36]
  Orbita	107	95
  Superficial head and neck (nonparameningeal)a	106	78
  Cranial parameningeala	134	74
  Genitourinary (excluding bladder/prostate)a	158	89
  Bladder/prostatea	104	81
  Extremitya	156	74
  Trunk, abdomen, perineum, etc.a	147	67
  Biliaryb	25	78

• Tumor size: Children with smaller tumors (≤5 cm) have improved survival compared with children with larger tumors (>5 cm).[5] Both tumor volume and maximum tumor diameter are associated with outcome.[37][Level of evidence: 3iiA]

  A retrospective review of soft tissue sarcomas in children and adolescents suggests that the 5 cm cutoff used for adults with soft tissue sarcoma may not be ideal for smaller children, especially infants. The review identified an interaction between tumor diameter and BSA.[38] This was not confirmed by a COG study of patients with intermediate-risk rhabdomyosarcoma.[39] This relationship requires prospective study to determine the therapeutic implications of the observation.

• Resectability: The extent of disease after the primary surgical procedure (i.e., the Surgical-pathologic Group, also called the Clinical Group) is also correlated with outcome.[5] In the IRS-III study, patients with localized, gross residual disease after initial surgery (Surgical-pathologic Group III) had a 5-year survival rate of approximately 70%, compared with a more than 90% 5-year survival rate for patients without residual tumor after surgery (Group I) and an approximately 80% 5-year survival rate for patients with microscopic residual tumor after surgery (Group II).[5,40]

  Resectability without functional impairment is related to initial size and site of the tumor, making the Grouping system less useful than a TNM system. Regardless, outcome is optimized with the use of multimodality therapy. All patients require chemotherapy and at least 85% also benefit from radiation therapy, with favorable outcome even for those patients with nonresectable disease. In IRS-IV, the Group III patients with localized unresectable disease who were treated with chemotherapy and radiation therapy had a 5-year FFS of about 75% and a local control rate of 87%.[41]

• Histopathologic subtype: The alveolar subtype is more prevalent among patients with less favorable clinical features (e.g., younger than 1 year or older than 10 years, extremity primary tumors, and metastatic disease at diagnosis), and is generally associated with a worse outcome than in similar patients with embryonal rhabdomyosarcoma.
  • In the IRS-I and IRS-II studies, the alveolar subtype was associated with a less favorable outcome even in patients whose primary tumor was completely resected (Group I).[42]
  • A statistically significant difference in 5-year survival by histopathologic subtype (82% for embryonal rhabdomyosarcoma vs. 65% for alveolar rhabdomyosarcoma), was not noted when 1,258 IRS-III and IRS-IV patients with rhabdomyosarcoma were analyzed.[43]
  • In the IRS-III study, outcome for patients with Group I alveolar subtype tumors was similar to that for other patients with Group I tumors, but the alveolar patients received more intensive therapy.[5]
  • Patients with alveolar rhabdomyosarcoma who have regional lymph node involvement have significantly worse outcomes (5-year FFS, 43%) than patients who do not have regional lymph node involvement (5-year FFS, 73%).[44]

  Anaplasia has been observed in 13% of embryonal rhabdomyosarcoma cases and its presence may adversely influence clinical outcome in patients with intermediate-risk embryonal rhabdomyosarcoma. However, anaplasia was not shown to be an independent prognostic variable in a multivariate analysis (P = .081).[45]

• PAX3/PAX7-FOXO1: Occasionally, patients with histology consistent with alveolar rhabdomyosarcoma do not have one of the two gene fusions that are characteristic of the disease. Patients with translocation-negative alveolar rhabdomyosarcoma have outcomes similar to those for patients with embryonal rhabdomyosarcoma and do better than patients with fusion-positive alveolar rhabdomyosarcoma.[46,47,48] For example, in a study from the Soft Tissue Sarcoma Committee of the COG of 434 cases of intermediate-risk rhabdomyosarcoma, fusion-positive patients had a lower event-free survival (EFS) (PAX3, 54% and PAX7, 65%) than did those with embryonal rhabdomyosarcoma (EFS, 77%). Patients with fusion-negative alveolar rhabdomyosarcoma had outcomes similar to those for patients with embryonal rhabdomyosarcoma.[48] These studies also demonstrated that fusion status was a better predictor of outcome than was histology and will replace histology in COG studies going forward. Similar conclusions were reached in a retrospective study of three consecutive trials in the United Kingdom. The authors underscored the probable value of treating fusion-negative patients whose tumors have alveolar histology with therapy that is stage appropriate for embryonal histology tumors.[49][Level of evidence: 3iiA]
• Metastases at diagnosis: Children with metastatic disease at diagnosis have the worst prognosis.

  The prognostic significance of metastatic disease is modified by the following:

  • Tumor histology (embryonal rhabdomyosarcoma is more favorable than alveolar). Only patients with alveolar histology and regional node disease have a worse prognosis provided that regional disease is treated with radiation therapy.[44]
  • Age at diagnosis (<10 years for children with embryonal rhabdomyosarcoma).
  • The site of metastatic disease. Patients with metastatic genitourinary (nonbladder, nonprostate) primary tumors have a more favorable outcome than do patients with metastatic disease from other primary sites.[50]
  • The number of metastatic sites.[51,52,53,54]
• Lymph node involvement at diagnosis: Lymph node involvement at diagnosis is associated with an inferior prognosis, and clinical and/or imaging evaluation is performed before treatment and preoperatively. Sentinel lymph node identification by appropriate methodology can aid in this evaluation. Suspicious nodes are sampled surgically with open biopsy preferred to needle aspiration, although this may occasionally be appropriate. Pathologic evaluation of clinically uninvolved nodes is site specific; in the United States, it is performed for extremity sites or for boys older than 10 years with paratesticular primaries.

  Data on the frequency of lymph node involvement in various sites is informative in clinical decision making. For example, up to 40% of patients with rhabdomyosarcoma in genitourinary sites have lymph node involvement, while patients with head and neck sites have a much lower likelihood (<10%). Patients with nongenitourinary pelvic sites (e.g. anus/perineum) have an intermediate frequency of lymph node involvement.[55]

  In the extremities and trunk, sentinel lymph node evaluation is a more accurate form of diagnosis than is random regional lymph node sampling. In clinically negative lymph nodes of the extremity or trunk, sentinel lymph node biopsy is the preferred form of node sampling by the COG. Technical considerations are obtained from surgical experts. Needle or open biopsy of clinically enlarged nodes is appropriate.[56,57,58,59]

  Adjuvant radiation therapy is administered to patients with lymph node involvement to enhance regional control.

• Biological characteristics: Refer to the Molecular Characteristics of Rhabdomyosarcoma section of this summary for more information.

It is unlikely that response to induction chemotherapy, as judged by anatomic imaging, correlates with the likelihood of survival in patients with rhabdomyosarcoma, based on the IRSG and COG studies that found no association.[60]; [61][Level of evidence: 3iiDi] However, an Italian study did find that patient response correlated with likelihood of survival.[37][Level of evidence: 3iiA] Other studies have investigated response to induction therapy, showing benefit to response. These data are somewhat flawed because therapy is usually tailored based on response and thus, the situation is not as clear as the COG data suggests.[62,63,64,65,66,67]

Response as judged by sequential functional imaging studies with (18F) fluorodeoxyglucose positron emission tomography (PET) may be an early indicator of outcome [68] and is under investigation by several pediatric cooperative groups. A retrospective analysis of 107 patients from a single institution examined PET scans performed at baseline, after induction chemotherapy, and after local therapy.[68] Standardized uptake value measured at baseline predicted PFS and OS, but not local control. A negative scan after induction chemotherapy correlated with statistically significantly better PFS. A positive scan after local therapy predicted worse PFS, OS, and local control.

Adult patients with rhabdomyosarcoma have a higher incidence of pleomorphic histology (19%) than do children (<2%). Adults also have a higher incidence of tumors in unfavorable sites than do children.[28]

Because treatment and prognosis depend, in part, on the histology and molecular genetics of the tumor, it is necessary that the tumor tissue be reviewed by pathologists and cytogeneticists/molecular geneticists with experience in the evaluation and diagnosis of tumors in children. Additionally, the diversity of primary sites, the distinctive surgical and radiation therapy treatments for each primary site, and the subsequent site-specific rehabilitation underscore the importance of treating children with rhabdomyosarcoma in medical centers with appropriate experience in all therapeutic modalities.

References:

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Cellular Classification for Childhood Rhabdomyosarcoma

Histologic Subtypes

Rhabdomyosarcoma can be divided into several histologic subsets, as follows:[1,2]

• Embryonal rhabdomyosarcoma, which has embryonal, botryoid, and spindle/sclerosing cell subtypes.
• Alveolar rhabdomyosarcoma.
• Pleomorphic (anaplastic) rhabdomyosarcoma.

Embryonal rhabdomyosarcoma

Embryonal rhabdomyosarcoma has the following three subtypes:

• Embryonal.
• Botryoid.
• Spindle cell/sclerosing.

Embryonal-subtype rhabdomyosarcoma. The embryonal subtype is the most frequently observed subtype in children, accounting for approximately 60% to 70% of childhood rhabdomyosarcomas.[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.

Anaplasia has been observed in 13% of embryonal rhabdomyosarcoma cases, and its presence may adversely influence clinical outcome in patients with intermediate-risk embryonal rhabdomyosarcoma. However, anaplasia was not shown to be an independent prognostic variable in a multivariate analysis (P = .081).[3]

Botryoid-subtype rhabdomyosarcoma. 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 World Health Organization (WHO) Classification of Tumours of Soft Tissue and Bone (4th edition) eliminated botryoid rhabdomyosarcoma, with these cases classified as typical embryonal rhabdomyosarcoma.[4]

A study of 2,192 children with rhabdomyosarcoma enrolled on clinical trials and diagnosed with embryonal histology (including botryoid and spindle cell variants) showed improved event-free survival (EFS) for patients with botryoid tumors (80%; 95% confidence interval [CI], 74%-84%) compared with typical embryonal rhabdomyosarcoma (73%; 95% CI, 71%-75%).[5] However, after adjusting for primary site, resection, and metastatic status, there was no difference in EFS by histologic subtype. This observation supports the elimination of the botryoid variant as a specific histologic subtype of rhabdomyosarcoma.

Spindle cell/sclerosing-subtype rhabdomyosarcoma. The 4th edition of the WHO Classification of Tumours of Soft Tissue and Bone added spindle cell/sclerosing rhabdomyosarcoma as a separate subtype of rhabdomyosarcoma.[4] The spindle cell variant of embryonal rhabdomyosarcoma is most frequently observed at the paratesticular site.[5,6]

A study of 2,192 children with rhabdomyosarcoma enrolled on clinical trials and diagnosed with embryonal histology (including botryoid and spindle cell variants) showed improved EFS for patients with spindle cell rhabdomyosarcoma (83%; 95% CI, 77%-87%) compared with typical embryonal rhabdomyosarcoma (73%; 95% CI, 71%-75%).[5] Patients with spindle cell rhabdomyosarcoma with parameningeal primary tumors (n = 18) were the exception to the overall favorable prognosis for this subtype; they had a 5-year EFS of 28% (compared with >70% EFS for parameningeal non-spindle cell embryonal rhabdomyosarcoma). As discussed in the Molecular Characteristics of Rhabdomyosarcoma section of this summary, the variable outcome by primary site for spindle cell rhabdomyosarcoma may reflect distinctive molecular subtypes with divergent prognostic significance within this histology.

In the WHO classification, sclerosing rhabdomyosarcoma is considered a variant pattern of spindle cell rhabdomyosarcoma, as descriptions note increasing degrees of hyalinization and matrix formation in spindle cell tumors. Sclerosing rhabdomyosarcoma is more common in adults, arises in the extremities and head and neck region, and has a more aggressive course. Recurrent MyoD1 mutations in sclerosing rhabdomyosarcoma were also identified.[7] Data on the outcome of sclerosing rhabdomyosarcoma in the pediatric population are limited, however. The largest previous study of sclerosing rhabdomyosarcoma in children had a follow-up of 0.01 to 3.58 years; of 13 patients, three relapsed and one died from the disease.[5]

Alveolar rhabdomyosarcoma

Approximately 30% of children with rhabdomyosarcoma have the alveolar subtype when histology alone is used to determine subtype.[8] 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] Eighty percent of patients with alveolar histology will have one of two gene fusions, PAX3 on chromosome 2 or PAX7 on chromosome 1, with FOXO1 gene on chromosome 13.[9,10,11] Patients without a fusion have outcomes that are similar to those for patients with embryonal rhabdomyosarcoma.[12,13,14]

The current trial for intermediate-risk patients from the Soft Tissue Sarcoma Committee of the Children's Oncology Group (ARST1431 [NCT02567435]) and all future trials will use fusion status rather than histology to determine eligibility; fusion-negative patients with alveolar histology will undergo the same treatments as patients with embryonal histology.

Pleomorphic (anaplastic) rhabdomyosarcoma

Pleomorphic rhabdomyosarcoma occurs predominantly in adults aged 30 to 50 years and is rarely seen in children.[15] In adults, pleomorphic rhabdomyosarcoma is associated with a worse prognosis. In children, the term anaplastic is preferred.[16]

Molecular Characteristics of Rhabdomyosarcoma

The embryonal and alveolar histologies have distinctive molecular characteristics that have been used for diagnostic confirmation, and may be useful for assigning risk group, determining therapy, and monitoring residual disease during treatment.[9,17,18,19,20]

1. Embryonal histology: Embryonal tumors often show loss of heterozygosity at 11p15 and gains on chromosome 8.[10,21,22] Embryonal tumors have a higher background mutation rate and higher single-nucleotide variant rate than do alveolar tumors, and the number of somatic mutations increases with older age at diagnosis.[23,24] Genes with recurring mutations include those in the RAS pathway (e.g., NRAS, KRAS, HRAS, and NF1), which together are observed in approximately one-third of cases. Other genes with recurring mutations include FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR, all of which are present in fewer than 10% of cases.[23,24]

   Embryonal histology with anaplasia: Anaplasia has been reported in a minority of children with rhabdomyosarcoma, primarily arising in children with the embryonal subtype who are younger than 10 years.[3,16] Rhabdomyosarcoma with nonalveolar, anaplastic morphology may be a presenting feature for children with Li-Fraumeni syndrome and germline TP53 mutations.[25] Among eight consecutively presenting children with rhabdomyosarcoma and TP53 germline mutations, all showed anaplastic morphology. Among an additional seven children with anaplastic rhabdomyosarcoma and unknown TP53 germline mutation status, three of the seven children had functionally relevant TP53 germline mutations. The median age at diagnosis of the 11 children with TP53 germline mutation status was 40 months (range, 19-67 months).

2. Alveolar histology: About 70% to 80% of alveolar tumors are characterized by translocations between the FOXO1 gene on chromosome 13 and either the PAX3 gene on chromosome 2 (t(2;13)(q35;q14)) or the PAX7 gene on chromosome 1 (t(1;13)(p36;q14)).[9,10,11] Other rare fusions include PAX3-NCOA1 and PAX3-INO80D.[23] 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.[9] Patients with solid-variant alveolar histology have a lower incidence of PAX-FOXO1 gene fusions than do patients showing classical alveolar histology.[26] For the diagnosis of alveolar rhabdomyosarcoma, FOXO1 gene rearrangement may be detected with good sensitivity and specificity using either fluorescence in situ hybridization or reverse transcription-polymerase chain reaction.[27]

   The alveolar histology that is associated with the PAX7 gene in patients with or without metastatic disease appears to occur at a younger age and may be associated with longer event-free survival rates than those associated with PAX3 gene rearrangements.[28,29,30,31,32,33] Patients with alveolar histology and 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.[20,26] In addition to FOXO1 rearrangements, alveolar tumors are characterized by a lower mutational burden than are fusion-negative tumors, with fewer genes having recurring mutations.[23,24]BCOR and PIK3CA mutations and amplification of MYCN, MIR17HG, and CDK4 have also been described.

3. Spindle cell/sclerosing histology: Spindle cell/sclerosing rhabdomyosarcoma has been proposed as a separate entity in the World Health Organization Classification of Tumours of Soft Tissue and Bone.[34] For congenital/infantile spindle cell rhabdomyosarcoma, a study reported that 10 of 11 patients showed recurrent fusion genes. Most of these cases had truncal primary tumors, and no paratesticular tumors were found. Novel VGLL2 rearrangements were observed in seven patients (63%), including VGLL2-CITED2 fusion in four patients and VGLL2-NCOA2 in two patients.[35] Three patients (27%) harbored different NCOA2 gene fusions, including TEAD1-NCOA2 in two patients and SRF-NCOA2 in one patient. All fusion-positive congenital/infantile spindle cell rhabdomyosarcoma patients with available long-term follow-up were alive and well, and no patients developed distant metastases.[35] Further study is needed to better define the prevalence and prognostic significance of these gene rearrangements in young children with spindle cell rhabdomyosarcoma.

   In older children and adults with spindle cell/sclerosing rhabdomyosarcoma, a specific MYOD1 mutation (p.L122R) has been observed in a large proportion of patients.[7,35,36,37] Activating PIK3CA mutations were common in MYOD1-mutated cases (4 of 10); when they were present, they were associated with sclerosing histology.[35] The presence of the MYOD1 mutation is associated with an increased risk of treatment failure.[7,35,36] In one study that included nine children aged 1 year or older with spindle cell/sclerosing histology and MYOD1 mutations, seven had a fatal outcome despite aggressive multimodality treatment.[35]

These findings highlight the important differences between embryonal and alveolar tumors. Data demonstrate that PAX-FOX01 fusion-positive alveolar tumors are biologically and clinically different from fusion-negative alveolar tumors and embryonal tumors.[13,14,20,38,39] In a study of Intergroup Rhabdomyosarcoma Study Group cases, which captured an entire cohort from a single prospective clinical trial, the outcome for patients with translocation-negative alveolar rhabdomyosarcoma was better than that observed for translocation-positive cases. The outcome was similar to that seen in patients with embryonal rhabdomyosarcoma and demonstrated that fusion status is a critical factor for risk stratification in pediatric rhabdomyosarcoma.

References:

1. Parham DM, Ellison DA: Rhabdomyosarcomas in adults and children: an update. Arch Pathol Lab Med 130 (10): 1454-65, 2006.
2. Newton WA Jr, Gehan EA, Webber BL, et al.: Classification of rhabdomyosarcomas and related sarcomas. Pathologic aspects and proposal for a new classification--an Intergroup Rhabdomyosarcoma Study. Cancer 76 (6): 1073-85, 1995.
3. 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.
4. Fletcher CDM, Bridge JA, Hogendoorn P, et al., eds.: WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC Press, 2013.
5. Rudzinski ER, Anderson JR, Hawkins DS, et al.: The World Health Organization Classification of Skeletal Muscle Tumors in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group. Arch Pathol Lab Med 139 (10): 1281-7, 2015.
6. Leuschner I: Spindle cell rhabdomyosarcoma: histologic variant of embryonal rhabdomyosarcoma with association to favorable prognosis. Curr Top Pathol 89: 261-72, 1995.
7. Agaram NP, Chen CL, Zhang L, et al.: Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a common pathogenesis. Genes Chromosomes Cancer 53 (9): 779-87, 2014.
8. Meza JL, Anderson J, Pappo AS, et al.: Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: the Children's Oncology Group. J Clin Oncol 24 (24): 3844-51, 2006.
9. 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.
10. Merlino G, Helman LJ: Rhabdomyosarcoma--working out the pathways. Oncogene 18 (38): 5340-8, 1999.
11. Dumont SN, Lazar AJ, Bridge JA, et al.: PAX3/7-FOXO1 fusion status in older rhabdomyosarcoma patient population by fluorescent in situ hybridization. J Cancer Res Clin Oncol 138 (2): 213-20, 2012.
12. Arnold MA, Anderson JR, Gastier-Foster JM, et al.: Histology, Fusion Status, and Outcome in Alveolar Rhabdomyosarcoma With Low-Risk Clinical Features: A Report From the Children's Oncology Group. Pediatr Blood Cancer 63 (4): 634-9, 2016.
13. 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.
14. Skapek SX, Anderson J, Barr FG, et al.: PAX-FOXO1 fusion status drives unfavorable outcome for children with rhabdomyosarcoma: a children's oncology group report. Pediatr Blood Cancer 60 (9): 1411-7, 2013.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. Scrable H, Witte D, Shimada H, et al.: Molecular differential pathology of rhabdomyosarcoma. Genes Chromosomes Cancer 1 (1): 23-35, 1989.
23. Shern JF, Chen L, Chmielecki J, et al.: Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov 4 (2): 216-31, 2014.
24. Chen X, Stewart E, Shelat AA, et al.: Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell 24 (6): 710-24, 2013.
25. Hettmer S, Archer NM, Somers GR, et al.: Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer 120 (7): 1068-75, 2014.
26. 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.
27. Thway K, Wang J, Wren D, et al.: The comparative utility of fluorescence in situ hybridization and reverse transcription-polymerase chain reaction in the diagnosis of alveolar rhabdomyosarcoma. Virchows Arch 467 (2): 217-24, 2015.
28. 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.
29. 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.
30. 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.
31. 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.
32. Missiaglia E, Williamson D, Chisholm J, et al.: PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. J Clin Oncol 30 (14): 1670-7, 2012.
33. Duan F, Smith LM, Gustafson DM, et al.: Genomic and clinical analysis of fusion gene amplification in rhabdomyosarcoma: a report from the Children's Oncology Group. Genes Chromosomes Cancer 51 (7): 662-74, 2012.
34. Nascimento AF, Barr FG, Fletcher CD, et al., eds.: Spindle cell/sclerosing rhabdomyosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn P, et al., eds.: WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC Press, 2013, pp 134-5.
35. Alaggio R, Zhang L, Sung YS, et al.: A Molecular Study of Pediatric Spindle and Sclerosing Rhabdomyosarcoma: Identification of Novel and Recurrent VGLL2-related Fusions in Infantile Cases. Am J Surg Pathol 40 (2): 224-35, 2016.
36. Kohsaka S, Shukla N, Ameur N, et al.: A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations. Nat Genet 46 (6): 595-600, 2014.
37. Szuhai K, de Jong D, Leung WY, et al.: Transactivating mutation of the MYOD1 gene is a frequent event in adult spindle cell rhabdomyosarcoma. J Pathol 232 (3): 300-7, 2014.
38. 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.
39. 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.

Stage Information for Childhood Rhabdomyosarcoma

Staging Evaluation

Before a biopsy of a suspected tumor mass is performed, imaging studies of the mass and baseline laboratory studies should be obtained. After the patient is diagnosed with rhabdomyosarcoma, an extensive evaluation to determine the extent of the disease should be performed before instituting therapy. This evaluation typically includes the following:

• Chest x-ray.
• Computed tomography (CT) scan of the chest.
• CT scan of the abdomen and pelvis (for lower extremity or genitourinary primary tumors).
• Magnetic resonance imaging (MRI) of the base of the skull and brain (for parameningeal primary tumors).
• Regional lymph node evaluation.

  Cross-sectional imaging (CT or MRI scan) of regional lymph nodes should be obtained. Abnormal-appearing lymph nodes should be biopsied when possible. Many studies have demonstrated that sentinel lymph node biopsies can be safely performed in children with rhabdomyosarcoma, and tumor-positive biopsies alter the treatment plan.[1,2,3,4,5] Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose (FDG) scans can identify areas of possible metastatic disease not seen by other imaging modalities.[6,7,8] The efficacy of these imaging studies for identifying involved lymph nodes or other sites of disease is important for staging, and PET imaging is recommended on current Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG-STS) treatment protocols.

  Pathologic evaluation of regional nodes is currently required for all COG-STS study participants with extremity primary rhabdomyosarcoma and boys aged 10 years and older with paratesticular rhabdomyosarcoma, because microscopic tumor is often documented even when the nodes are not enlarged. (Refer to the Regional and in-transit lymph nodes section of this summary for more information.)

• Bilateral bone marrow aspirates and biopsies for selected patients.
• Bone scan for selected patients.

A retrospective study of 1,687 children with rhabdomyosarcoma enrolled in Intergroup studies from 1991 to 2004 suggests that about one-third of patients (those with localized negative regional lymph nodes, noninvasive embryonal tumors, and Group I alveolar tumors) can have limited staging procedures that eliminate bone marrow and bone scan examinations at diagnosis.[9]

Staging Process

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

1. Assigning a Stage: Determined by primary site, tumor size (widest dimension), and presence or absence of regional lymph node and/or distant metastases.
2. Assigning a Group: Determined by status of the initial surgical resection/biopsy, with pathologic assessment of the tumor margin and of lymph node involvement, before the initiation of therapy.
3. Assigning a Risk Group: Determined by Stage, Group, and histology.

Prognosis for children with rhabdomyosarcoma depends predominantly 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 patient assignment 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 COG. New protocols for children with soft tissue sarcoma are developed by the COG-STS.

Assignment of Stage

Current COG-STS protocols for rhabdomyosarcoma use the TNM-based pretreatment staging system that incorporates the primary tumor site, presence or absence of tumor invasion of surrounding tissues, tumor size, regional lymph node status, and the presence or absence of metastases. This staging system is described in Table 3 below.[10,11]

Terms defining the TNM criteria are below in Table 2.

Assignment of Group

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 completeness or extent of initial surgical resection after pathologic review of the tumor specimen(s). The definitions for these Groups are shown in Table 4 below.[12,13]

Assignment of Risk Group

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.[14,15] Treatment assignment is based on Risk Group, as shown in Table 5.

References:

1. Kayton ML, Delgado R, Busam K, et al.: Experience with 31 sentinel lymph node biopsies for sarcomas and carcinomas in pediatric patients. Cancer 112 (9): 2052-9, 2008.
2. Dall'Igna P, De Corti F, Alaggio R, et al.: Sentinel node biopsy in pediatric patients: the experience in a single institution. Eur J Pediatr Surg 24 (6): 482-7, 2014.
3. Alcorn KM, Deans KJ, Congeni A, et al.: Sentinel lymph node biopsy in pediatric soft tissue sarcoma patients: utility and concordance with imaging. J Pediatr Surg 48 (9): 1903-6, 2013.
4. Wright S, Armeson K, Hill EG, et al.: The role of sentinel lymph node biopsy in select sarcoma patients: a meta-analysis. Am J Surg 204 (4): 428-33, 2012.
5. Parida L, Morrisson GT, Shammas A, et al.: Role of lymphoscintigraphy and sentinel lymph node biopsy in the management of pediatric melanoma and sarcoma. Pediatr Surg Int 28 (6): 571-8, 2012.
6. 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.
7. 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.
8. Federico SM, Spunt SL, Krasin MJ, et al.: Comparison of PET-CT and conventional imaging in staging pediatric rhabdomyosarcoma. Pediatr Blood Cancer 60 (7): 1128-34, 2013.
9. Weiss AR, Lyden ER, Anderson JR, et al.: Histologic and clinical characteristics can guide staging evaluations for children and adolescents with rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee. J Clin Oncol 31 (26): 3226-32, 2013.
10. 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.
11. 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.
12. 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.
13. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995.
14. 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.
15. Breneman JC, Lyden E, Pappo AS, et al.: Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma--a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21 (1): 78-84, 2003.

Treatment Option Overview for Childhood Rhabdomyosarcoma

Multimodality Therapy

All children with rhabdomyosarcoma require multimodality therapy with systemic chemotherapy, in conjunction with either surgery, radiation therapy (RT), or both modalities to maximize local tumor control.[1,2,3] Surgical resection is performed before chemotherapy if it will not result in disfigurement, functional compromise, or organ dysfunction. If this is not possible, only an initial biopsy is performed.

Most patients (about 50%) have Group III (gross residual) disease; the remaining patients have Group I (about 15%), Group II (about 20%), and Group IV (about 15%) disease.[4] After initial chemotherapy, Group III patients receive definitive RT for control of the primary tumor. Some patients with initially unresected tumors may undergo delayed primary excision to remove residual tumor before the initiation of RT. This is appropriate only if the delayed excision is deemed feasible with acceptable functional/cosmetic outcome and if a grossly complete resection is anticipated. If a delayed primary excision results in complete resection or microscopic residual disease, a modest reduction in RT could be utilized. RT is given to clinically suspicious lymph nodes (detected by palpation or imaging) unless the suspicious lymph nodes are biopsied and shown to be free of rhabdomyosarcoma.

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

• Surgery (local control management).
• RT (local control management).
• Chemotherapy.

Rhabdomyosarcoma treatment options used by the Children's Oncology Group (COG) and by groups in Europe (as exemplified by trials from the Soft Tissue Sarcoma Committee of the COG [COG-STS], the Intergroup Rhabdomyosarcoma Study Group [IRSG], and the International Society of Pediatric Oncology Malignant Mesenchymal Tumor [MMT] Group) differ in management and overall treatment philosophy, as noted below:[2]

• The primary COG-STS objective has been to employ local therapy soon after the initial operation or biopsy (except in patients with metastatic disease), using RT for patients with residual disease. Event-free survival (EFS) is the target endpoint, attempting to avoid relapse and subsequent salvage therapy.[3]
• In the MMT trials, the main objective has been to reduce the use of local therapies using initial front-line chemotherapy followed by second-line therapy in the presence of poor response. Subsequent surgical resection is preferred over RT, which is used only after incomplete resection, documented regional lymph node involvement, or a poor clinical response to initial chemotherapy. This approach is designed to avoid major surgical procedures and long-term damaging effects from RT.

The MMT Group approach led to an overall survival (OS) rate of 71% in the European MMT89 study, compared with an OS rate of 84% in the IRS-IV study. Similarly, EFS rates at 5 years were 57% in the MMT89 study versus 78% in the IRS-IV study. Differences in outcome were most striking for patients with extremity and head and neck nonparameningeal tumors. Failure-free survival was lower for patients with bladder/prostate primary tumors who did not receive RT as part of their initial treatment, but there was no difference in OS between the two strategies for these patients.[5] The overall impression is that survival for most patient subsets is superior with the use of early local therapy, including RT. In the MMT trials, some patients have been spared aggressive local therapy, which may reduce the potential for morbidities associated with such therapy.[1,2,3]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[6] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following individuals to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

• Primary care physician.
• Pediatric surgeon.
• Radiation oncologist.
• Pediatric oncologist and hematologist.
• Pediatric radiologist.
• Rehabilitation specialist.
• Pediatric nurse specialist.
• Social workers.
• Psychologist.

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[7] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

References:

1. Donaldson SS, Meza J, Breneman JC, et al.: Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma--a report from the IRSG. Int J Radiat Oncol Biol Phys 51 (3): 718-28, 2001.
2. Stevens MC, Rey A, Bouvet N, et al.: Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology--SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol 23 (12): 2618-28, 2005.
3. Donaldson SS, Anderson JR: Rhabdomyosarcoma: many similarities, a few philosophical differences. J Clin Oncol 23 (12): 2586-7, 2005.
4. Wexler LH, Skapek SX, Helman LJ: Rhabdomyosarcoma. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2015, pp 798-826.
5. Rodeberg DA, Anderson JR, Arndt CA, et al.: Comparison of outcomes based on treatment algorithms for rhabdomyosarcoma of the bladder/prostate: combined results from the Children's Oncology Group, German Cooperative Soft Tissue Sarcoma Study, Italian Cooperative Group, and International Society of Pediatric Oncology Malignant Mesenchymal Tumors Committee. Int J Cancer 128 (5): 1232-9, 2011.
6. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
7. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004.

Treatment of Previously Untreated Childhood Rhabdomyosarcoma

Because rhabdomyosarcoma can arise from multiple sites, surgical care decisions and radiotherapeutic options must be tailored to the specific aspects of each site, and should be discussed with a multidisciplinary team, including representatives of those specialties and pediatric oncologists. 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.

Surgery (Local Control Management)

In recent years, the predominant site of treatment failure in patients with initially localized rhabdomyosarcoma has been local recurrence. Both surgery and radiation therapy (RT) are primarily measures taken to produce local control, but each has risks and benefits. Surgical removal of the entire tumor should be considered initially, but only if functional and cosmetic impairment will not result.[1] With that stipulation, complete resection of the primary tumor, with a surrounding margin of normal tissue and sampling of 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 an alternative approach if easily accomplished without loss of form (cosmesis) and function.

Patients with microscopic residual tumor after 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 the tumor without loss of form and function.[4]

There is little evidence that debulking surgery (i.e., surgery that is expected to leave macroscopic residual tumor) improves outcome, compared with biopsy alone; therefore, debulking surgery is not recommended for patients with rhabdomyosarcoma.[5][Level of evidence: 2A] In a retrospective study of 73 selected patients, second-look procedures (also called delayed primary excision) identified viable tumor that remained after initial chemotherapy; 65 of these patients had also received RT. 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] Thus, delaying surgery until after chemotherapy is preferred.

For children with low-risk rhabdomyosarcoma, local control was not diminished with reduced doses of RT after surgical resection.[7] Subsequently, delayed primary excision was evaluated by the COG-STS in 73 intermediate-risk rhabdomyosarcoma patients enrolled on D9803 (1999-2005).[8] Delayed primary excision was completed in 45% of Group III rhabdomyosarcoma patients with tumors of the bladder dome, extremity, and trunk; 84% of those who had a delayed primary excision with no gross residual disease remaining were eligible for modest radiation dose reduction (patients with no or only microresidual tumor after delayed primary excision). Local control outcomes were similar to IRS-IV results with RT alone.[6]

Radiation Therapy (RT) (Local Control Management)

Local control remains a significant problem in children with rhabdomyosarcoma. In IRS II, of patients who achieved a complete remission with chemotherapy and surgery, almost 20% of patients with Groups I to III disease relapsed locally or regionally, and 30% of patients with Group IV disease relapsed locally or regionally. Local or regional relapses accounted for 70% to 80% of all relapses in children with Groups I to III disease and 46% of all relapses in patients with Group IV disease.[9] RT is an effective method for achieving local control of the tumor for patients with microscopic or gross residual disease after biopsy, initial surgical resection, or chemotherapy.

• Patients with completely resected embryonal rhabdomyosarcoma (Group I) do well without RT. However, because approximately 75% of embryonal rhabdomyosarcoma patients are Groups II to IV, RT is used in most patients with rhabdomyosarcoma.[10]
• An earlier study of Group I patients with alveolar rhabdomyosarcoma and undifferentiated soft tissue sarcoma found that omission of RT was followed by decreased local control.[11] A subsequent review of patients with only alveolar rhabdomyosarcoma found that the improvement in outcome with RT did not reach statistical significance for patients with Stage 1 and Stage 2 tumors. There were very few patients (n = 4) with large tumors (Stage 3, >5 cm) who did not receive RT, but their outcome was poor.[12][Level of evidence: 3iiiDii]

In more than 50% of Group II rhabdomyosarcoma patients, local recurrence was the result of noncompliance with guidelines or omission of RT.[9] A review of European trials was conducted by the German Cooperative Weichteilsarkom Studiengruppe (CWS) between 1981 and 1998, in which RT was omitted for some Group II patients. This review 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.[13]

The predominant type of relapse for patients with Group III disease is local failure. Approximately 35% of patients with Group III disease either fail to achieve a complete remission or relapse locally. Patients with tumor-involved regional lymph nodes at diagnosis also have a higher risk of local and distant failure than do patients whose lymph nodes are uninvolved.[14]

External-beam RT

As with the surgical management of patients with rhabdomyosarcoma, recommendations for RT depend on the following:

• Site of primary tumor.
• Postsurgical amount of residual disease (none vs. microscopic vs. macroscopic), if surgery was performed.
• Presence of involved lymph nodes.

For optimal care of pediatric patients undergoing radiation treatments, it is imperative that radiation oncologists, radiation technicians, and nurses who are experienced in treating children are available. An anesthesiologist may be necessary to sedate young patients. Computerized treatment planning with a 3-dimensional planning system should be available. Techniques to deliver radiation specifically to the tumor while sparing normal tissue (e.g., conformal radiation therapy, intensity-modulated radiation therapy [IMRT], volumetrical modulated arc therapy [VMAT], proton-beam therapy [charged-particle radiation therapy], or brachytherapy) are appropriate.[15,16,17,18,19,20]

Evidence (radiation delivery techniques):

1. Dosimetric comparison of proton-beam RT and IMRT treatment plans has shown that proton-beam treatment plans can spare more normal tissue adjacent to the targeted volume than IMRT plans.[21,22] A prospective, phase II trial compared proton and IMRT in pediatric rhabdomyosarcoma.[23]
   • Target coverage was comparable between proton and IMRT plans. However, the mean integral dose for IMRT was 1.8 to 3.5 times higher than with proton therapy, depending on the site. Proton radiation lowers the radiation dose in the uninvolved tissues surrounding the tumor and, thus, improves normal tissue sparing when compared with IMRT.
   • Follow-up of treated patients remains short, and there are no data available to determine if the reduction in dose to adjacent tissue will result in improved functional outcome or reduce the risk of secondary malignancy.
2. A retrospective review of patients with intermediate-risk rhabdomyosarcoma compared 3-dimensional conformal RT with IMRT.[24][Level of evidence: 2B]
   • IMRT improved the target coverage but did not show a difference in local failure rate or EFS.

The radiation dose according to Group, histology, and disease site for children with rhabdomyosarcoma is described in Table 6:

The RT dose depends predominantly on the histology and amount of residual disease, if any, after the primary surgical resection.

• Group II. In general, patients with microscopic residual disease (Group II) receive 36 Gy of RT if they do not have involved lymph nodes and 41 Gy in the presence of involved nodes.[11,25] Low-risk patients (embryonal histology and favorable sites with microscopic residual disease) treated on a COG study had excellent local control with 36 Gy, which was comparable to historic controls who received 41.4 Gy.[7] For Group II patients, 36 Gy to 41.4 Gy is recommended depending on nodal status.
• Group III. 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%, but higher doses of radiation (>60 Gy) were associated with unacceptable long-term toxic effects.[26,27] Group III patients on the IRS-IV standard treatment arm received 50.4 Gy to 59.4 Gy, with 5-year progression-free survival of 55% to 75% and a local control rate of 85% to 88%.[28] Select COG subgroups with Group III disease received somewhat reduced radiation doses of 36 Gy after delayed gross total resection with negative margins, and 41.4 Gy if the margins were microscopically involved or the nodes were positive. In the recent COG-D9602 study, a limited number of low-risk patients had a greater than 85% likelihood of local control with 36 Gy.[7] This approach is only appropriate for select site-specific subgroups.

In the D9803 study of patients with intermediate-risk rhabdomyosarcoma, local control was 90% in 41 patients with Groups I and II alveolar rhabdomyosarcoma, but was lower in 280 patients with Group III embryonal (80%) and alveolar (83%) rhabdomyosarcoma. Histology, regional lymph node status, and primary site were not related to the likelihood of local failure; however, the local failure rate for 47 patients with retroperitoneal tumors was 33% (probably caused by tumors ≥5 cm in diameter) compared with 14% to 19% for patients with bladder/prostate, extremity, and parameningeal tumors. Tumor size was the strongest predictor of local failure (10% for patients with primary tumors <5 cm vs. 25% for larger tumors; P = .0004).[29][Level of evidence: 3iiiDi]

The treated radiation volume should be determined by the extent of tumor at diagnosis before surgical resection and before chemotherapy. A margin of 2 cm is generally used, including clinically involved regional lymph nodes. However, with conformal plans and image-guided RT, a margin of 1 cm to 1.3 cm to a clinical target volume or planning target volume may be used.[11] While the volume irradiated may be modified because of considerations for normal tissue tolerance, gross residual disease at the time of radiation should receive full-dose radiation. A reduction in volume after 36 Gy is appropriate in chemoresponsive disease for patients with noninvasive displacement (T1) that have regressed in size, but not for invasive tumors (T2).

The timing of RT generally allows for chemotherapy to be given for 1 to 3 months before RT is initiated. RT is usually given over 5 to 6 weeks (e.g., 1.8 Gy once per day, 5 days per week), 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 that the administration of RT twice a day, 6 to 8 hours apart, at 1.1 Gy per dose (hyperfractionated schedule), 5 days per week, was feasible but difficult to accomplish in small children who required sedation twice daily. Patients with localized, gross residual tumors (Group III) were randomly assigned to receive conventional, once-daily RT (total dose of 50.4 Gy) or the twice-daily hyperfractionated schedule (total dose of 59.4 Gy). There was no demonstrated advantage in terms of local control, but increased acute toxicity was observed with the increased dose.[30]

Thus, conventional RT remains the standard for treating patients who have rhabdomyosarcoma with gross residual disease.[31]

Brachytherapy

Brachytherapy, using either intracavitary or interstitial implants, is another method of local control and has been used in selected situations for children with rhabdomyosarcoma, especially for patients with primary tumors at a vaginal site [32,33,34,35,36] and selected bladder/prostate sites.[37][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.[33,38]; [39][Level of evidence: 3iiDii] Other sites, especially head and neck, have also been treated with brachytherapy.[40] Patients with initial Group III disease, who subsequently have microscopic residual disease after chemotherapy with or without delayed surgery, are likely to achieve local control with RT at doses of 40 Gy or more.[41]

Treatment of children aged 3 years and younger

Very young children (aged ≤36 months) diagnosed with rhabdomyosarcoma pose a therapeutic challenge because of their increased risk of treatment-related morbidity.[7] As suggested above, reduced radiation doses may be appropriate if delayed surgery can provide negative margins. However, for patients who are unable to undergo surgical resection, higher doses of RT remain appropriate.[42] Radiation techniques are designed to maximize normal tissue sparing and should include conformal approaches, often with intensity-modulated techniques.

Delayed primary excision and radiation dose reduction are appropriate for all ages. However, the youngest patients frequently do not get appropriate RT because of concerns about normal tissue toxicity, and these are ideal patients for whom surgical resection by delayed primary excision is a particularly important consideration. Local control can be achieved by both RT and surgery; it may be optimal if both treatments are used, but at least one approach is necessary in addition to chemotherapy.

One of the few studies of infants younger than 1 year included 77 patients with nonmetastatic rhabdomyosarcoma (median age, 7.4 months); 57% of patients had embryonal rhabdomyosarcoma. In this study, the 5-year failure-free survival (FFS) was 57%, and OS was 76%. Most failures were local, often because RT was withheld in violation of protocol guidelines. In contrast, for infants treated according to guidelines, both FFS and OS were clearly superior.[43]

Local Control Management With Surgery and RT by Primary Site of Disease

Head and neck

Primary sites for childhood rhabdomyosarcoma within the head and neck include the orbit; nonorbital head and neck and cranial parameningeal; and nonparameningeal, nonorbital head and neck. Specific considerations for the surgical and radiotherapeutic management of tumors arising at each of these sites are discussed below.

1. Orbit.

   Rhabdomyosarcomas of the orbit should not undergo exenteration, but biopsy is needed for diagnosis.[44,45] Biopsy is followed by chemotherapy and RT, with orbital exenteration reserved for the small number of patients with locally persistent or recurrent disease.[46,47] RT and chemotherapy are the standard of care, with survival in excess of 90% to 95%. For patients with orbital tumors, precaution should be taken to limit the RT dose to the lens, conjunctiva, and cornea.

2. Nonorbital and cranial parameningeal.

   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.[48,49,50] If skull erosion and/or transdural extension is equivocal, a computed tomography (CT) scan with contrast of the same regions is indicated. Also, if there is any suspicion of extension down the spinal cord, an MRI scan with contrast of the entire cord should be obtained. The cerebrospinal fluid (CSF) should be examined for malignant cells in all patients with parameningeal tumors. Because complete removal of these tumors is difficult, owing to their location, the initial surgical procedure for these patients is usually only a biopsy for diagnosis.

   Nonorbital head and neck rhabdomyosarcomas, including cranial parameningeal tumors, are optimally managed by conformal RT and chemotherapy. Patients with parameningeal disease with intracranial extension in contiguity with the primary tumor and/or signs of meningeal impingement (i.e., cranial base bone erosion and/or cranial nerve palsy) do not require whole-brain irradiation or intrathecal therapy, unless tumor cells are present in the CSF at diagnosis.[48] 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.[49]

   The following studies have addressed the timing of RT. Both studies administered early irradiation to all patients with intracranial extension of the primary tumor.

   1. In a retrospective trial, starting RT within 2 weeks of diagnosis for patients with signs of meningeal impingement was associated with lower rates of local failure but was of borderline significance. When no signs of meningeal impingement were present, delay of RT for more than 10 weeks did not impact local failure rates.[49]
   2. A subsequent comparison of local control, FFS, and OS rates showed no statistical difference between early irradiation (day 0) for Group III patients in IRS-IV with cranial nerve palsy and/or cranial base erosion versus later initiation of RT (week 12) for Group III patients in D9803 who had similar evidence of meningeal involvement, suggesting that early RT for this group of patients is not necessary.[51][Level of evidence: 2A]
   3. A retrospective analysis of 47 patients with parameningeal primary sites suggested that the subgroup of adolescent patients with alveolar rhabdomyosarcoma (n = 13) might benefit from the addition of prophylactic irradiation (36 Gy) to bilateral cervical nodes.[52][Level of evidence: 3iiDii]

   An analysis of 1,105 patients with localized parameningeal rhabdomyosarcoma treated on protocols from 1984 to 2004 in North America and Europe found that several prognostic factors could be used to define subgroups of patients with significantly different survival rates. The OS rate at 10 years for the entire cohort was 66%. Patients with zero or one adverse factor (age <3 or >10 years at diagnosis, presence of meningeal involvement, tumor diameter >5 cm, unfavorable primary parameningeal site) had a 10-year OS rate of 80.7%; those with two factors had a 10-year OS rate of 68.4%; and those with three or four factors had a 10-year OS rate of 52.2%. Patients who did not receive RT as a component of their initial therapy had a poor prognosis, and their tumors were not salvaged with introduction of RT after relapse, establishing RT as a necessary component of initial treatment.[53][Level of evidence: 3iiiA]

   Children who present with tumor cells in the CSF (Stage 4) may or may not have other evidence of diffuse meningeal disease and/or distant metastases. In a review of experience from IRSG protocols II though IV, eight patients had tumor cells in the CSF at diagnosis; three of four without other distant metastases were alive at 6 to 16 years after diagnosis, as was one of four who had concomitant metastases elsewhere.[54] 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 and RT for the primary tumor. Craniospinal axis RT may also be indicated.[55,56]

3. Nonparameningeal, nonorbital head and neck tumors.

   For nonparameningeal, nonorbital head and neck tumors, wide excision of the primary tumor (when feasible without functional impairment) and ipsilateral neck lymph node sampling of clinically involved nodes may be appropriate but requires postoperative RT if margins or nodes are positive.[57] Narrow resection margins (<1 mm) are acceptable because of anatomic restrictions. Cosmetic and functional factors should always be considered, but with modern techniques, complete resection in patients with superficial tumors need not be inconsistent with good cosmetic and functional results. Specialized, multidisciplinary surgical teams also have performed resections of anterior skull-based tumors in areas previously considered inaccessible to definitive surgical management, including the nasal areas, paranasal sinuses, and temporal fossa. These procedures should only be considered, however, in children with recurrent locoregional disease or residual disease after chemotherapy and RT.

For patients with head and neck primary tumors that are considered unresectable, chemotherapy and RT with organ preservation are the mainstay of primary management.[46,50,58,59,60,61] Several studies have reported excellent local control in patients with rhabdomyosarcoma of the head and neck treated with IMRT, fractionated stereotactic radiation therapy, or proton RT, and chemotherapy. Further study is needed, but the use of IMRT and chemotherapy in patients with head and neck rhabdomyosarcoma may result in less severe late effects.[62,63,64]; [65][Level of evidence: 3iiiA]

Extremity sites

Delayed primary excision has been studied in the D9803 intermediate-risk rhabdomyosarcoma trial. (Refer to the Surgery (Local Control Management) section of this summary for more information.) Delayed primary excision may be most appropriate for infants because the late effects of RT are more severe than they are in older patients; thus, even a moderate reduction in radiation dose is desirable.

A pooled analysis of 642 patients from four international cooperative groups in Europe and North America was performed to identify prognostic factors in patients with localized extremity rhabdomyosarcoma. Regional lymph node involvement was approximately 2.5 times higher with alveolar rhabdomyosarcoma than with embryonal rhabdomyosarcoma. The overall 5-year survival rate was 67%. Multivariate analysis showed that decreased OS was correlated with age older than 3 years, T2 and N1 status, incomplete initial surgery, treatment before 1995, and treatment by European groups. This analysis also suggested that duration of chemotherapy might have an impact on outcome in these patients.[66]

IMRT can be used to spare the bone, yet provide optimal soft tissue coverage, and it 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.[67][Level of evidence: 3iiA] For children presenting with a primary tumor of the hands or feet, COG studies have shown 100% 10-year local control using RT along with chemotherapy, avoiding amputation in these children.[68][Level of evidence: 3iiiA] Definitive RT and chemotherapy for Group III tumors resulted in 90% to 95% local control in the IRS-IV trial.[30]

Primary re-excision before beginning chemotherapy (i.e., not delayed) may be appropriate in patients whose initial surgical procedure leaves microscopic residual disease that is deemed resectable by a second procedure.[4] Chemotherapy and RT or delayed primary excision with or without RT results in comparable outcomes.[8]

Regional and in-transit lymph nodes

For patients enrolled in clinical trials, the COG-STS recommends biopsy of all enlarged or clinically suspicious lymph nodes. In the trunk and extremity, if no enlarged lymph nodes are identified in the draining nodal basin, a sentinel lymph node biopsy is recommended; this is a more accurate way of assessing regional lymph nodes, instead of random lymph node sampling. Techniques for sentinel lymph node biopsy are standardized and should be completed by an experienced surgeon.[69,70,71,72,73,74,75,76]

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 also in-transit) nodes is warranted.[69,77,78,79,80]; [81][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 are defined as axillary/infraclavicular nodes for upper-extremity tumors and inguinal/femoral nodes for lower-extremity tumors.

• 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.[81]

Positron emission tomography (PET) scanning is recommended for evaluation and staging of extremity primary tumors before initiation of therapy.[81]

Truncal sites

Primary sites for childhood rhabdomyosarcoma within the trunk include the chest wall or abdominal wall, intrathoracic or intra-abdominal area, biliary tree, and perineum or anus. Specific considerations for the surgical and radiotherapeutic management of tumors arising at each of these sites are discussed below.

1. Chest wall or abdominal wall.

   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 if cosmetic and functional outcomes are acceptable). These resections may require use of prosthetic materials. Initial surgery is performed if there is a realistic expectation of achieving negative margins. However, most patients who present with large tumors in these sites have localized disease that becomes amenable to complete resection with negative margins after preoperative chemoradiation therapy; those patients may have excellent long-term survival.[82,83,84,85]

   Chest wall rhabdomyosarcoma, which is usually Group III, does not require R0 resection (no microresidual disease) at delayed primary resection. The COG data show equivalent survival for R0 and R1 (microresidual disease at the margin) resections in chest wall rhabdomyosarcoma, likely because of the addition of postoperative radiation therapy.[85] Aggressive resections at diagnosis before chemotherapy are not necessary because rhabdomyosarcoma is very chemosensitive and radiosensitive.

   Nodal involvement is difficult to predict, but pretreatment PET scanning may prove useful in staging.

2. Intrathoracic or intra-abdominal sarcomas.

   Intrathoracic or intra-abdominal sarcomas may not be resectable at diagnosis because of the massive size of the tumor and extension into vital organs or vessels.[86]

   For patients with initially unresectable retroperitoneal/pelvic tumors, complete surgical removal after chemotherapy, with or without RT, offers a significant survival advantage (73% vs. 34%-44% without removal).[86]

   • The International Society of Pediatric Oncology Malignant Mesenchymal Tumor (SIOP-MMT) Group found that RT improved local control in patients with localized pelvic rhabdomyosarcoma whose initial surgical procedure was biopsy only, leaving macroscopic residual tumor. Age older than 10 years and lymph node involvement were unfavorable prognostic factors.[87][Level of evidence: 2A]
   • A German study found 100 patients with intra-abdominal nonmetastatic embryonal rhabdomyosarcoma larger than 5 cm in dimension; 61% had tumors larger than 10 cm and 88% were T2. Eighty-one patients were treated with chemotherapy and delayed primary excision, while 19 patients with emergency presentations (tumor rupture, ileus, hydronephrosis, oliguria, and venous congestion) underwent initial debulking surgery. EFS was 52% ± 10%, and OS was 65% ± 9%. Unfavorable factors were initial diagnosis at age older than 10 years, lack of achieving complete remission, and inadequate local control (incomplete secondary resection or no RT).[88][Level of evidence: 3iiA]
   • A small series of seven rhabdomyosarcoma patients with peritoneal dissemination and/or malignant ascites had good outcomes with whole-abdomen irradiation using IMRT with dose painting.[89][Level of evidence: 3iiA] This technique involves simultaneously irradiating the whole abdomen with a lower dose than that used for the primary tumor (or resection-bed); the larger volume receives a lower (fractional) daily dose than the high-dose target receives.
3. Biliary tree.

   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.[90]

4. Perineum or anus.

   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.[91] Because of the inferior prognosis of patients with nodal involvement, the current recommendation is to sample the regional lymph nodes. When feasible and without unacceptable morbidity, removing all gross tumor before chemotherapy improves the likelihood of cure.

   • In IRSG protocols I through IV, the OS rate after aggressive therapy for 71 patients with tumors in this location was 49%, best for patients with Stage 2 disease (small tumors, negative regional nodes), intermediate for those with Stage 3 disease, and worst for those with Stage 4 disease at diagnosis.[92]
   • In a subsequent report from the German CWS trials, 32 patients had an EFS and OS of 47% at 5 years; in addition, patients with embryonal histology fared significantly better than did patients with alveolar histology.[93][Level of evidence: 3iiiA]

     With the goal of organ preservation, patients with tumors of the perineum/anus are preferentially managed with chemotherapy and RT without aggressive surgery, which may result in loss of sphincter control.

Genitourinary system

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 below.[94]

1. Testis or spermatic cord.

   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 spermatic cord, utilizing an inguinal incision with proximal vascular control (i.e., radical orchiectomy).[95] Resection of hemiscrotal skin is required when there is tumor fixation or invasion.

   Hemiscrotectomy has been recommended by the COG, German groups, and Italian groups when a previous transscrotal biopsy had been performed. By contrast, a retrospective German CWS study of 28 patients with embryonal rhabdomyosarcoma found a 5-year EFS rate of 91.7% in 12 patients with an initial transscrotal excision followed by hemiscrotectomy, while the 5-year EFS in 16 patients without subsequent hemiscrotectomy was 93.8%. All of these patients also received chemotherapy with vincristine, dactinomycin, an alkylator, and other agents.[96][Level of evidence: 3iiiDi] This area is controversial, and more data are needed.

   For patients with incompletely removed paratesticular tumors that require RT, temporarily repositioning the contralateral testicle into the adjacent thigh before scrotal radiation may preserve hormone production, but again, more data are needed.[97][Level of evidence: 3iiiC]

   Paratesticular tumors have a relatively high incidence of lymphatic spread (26% in IRS-I and IRS-II),[77] and all patients with paratesticular primary tumors should have thin-cut abdominal and pelvic CT scans with IV contrast to evaluate nodal involvement. For patients who have Group I disease, are younger than 10 years, and in whom CT scans show no evidence of lymph node enlargement, retroperitoneal node biopsy/sampling is unnecessary, but a repeat CT scan every 3 months is recommended.[98,99] 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.[3,31,100]

   Staging ipsilateral retroperitoneal lymph node sampling is currently required for all children aged 10 years and older with paratesticular rhabdomyosarcoma on COG-STS studies. However, node dissection was not routine in Europe for adolescents with resected paratesticular rhabdomyosarcoma. Many European investigators relied on radiographic, rather than surgical-pathologic assessment, for retroperitoneal lymph node involvement.[95,98] In the International Society of Paediatric Oncology (SIOP) Malignant Mesenchymal Tumour (MMT) 89 and 95 studies, patients with paratesticular rhabdomyosarcoma were evaluated with imaging but did not undergo routine ipsilateral lymph node sampling.[101][Level of evidence: 2Di] Thirty-one percent of Stage N0 patients aged 10 years and older developed node relapse, compared with 8% of Stage N0 patients younger than 10 years (P = .0005). The SIOP MMT group subsequently recommended ipsilateral lymph node sampling for all patients aged 10 years and older.

2. Bladder and/or prostate.

   Bladder preservation is a major goal of therapy for patients with tumors arising in the bladder and/or prostate. Two reviews provide information about the historical, current, and future treatment approaches for patients with bladder and prostate rhabdomyosarcomas.[102,103]

   In rare cases, the tumor is confined to the dome of the bladder and can be completely resected. Otherwise, to preserve a functional bladder in patients with gross residual disease, chemotherapy and RT have been used in North America and some parts of Europe to reduce tumor bulk,[104,105] followed, when necessary, by a more limited surgical procedure such as partial cystectomy.[106] Early experience with this approach was disappointing, with only 20% to 40% of patients with bladder/prostate tumors alive and with functional bladders 3 years after diagnosis (3-year OS was 70% in IRS-II).[106,107] 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%.[105,108,109] Patients with a primary tumor of the bladder/prostate who present with a large pelvic mass resulting from a distended bladder caused by outlet obstruction at diagnosis receive RT to a volume defined by imaging studies after initial chemotherapy to relieve outlet obstruction. This approach to therapy remains generally accepted, with the belief that more effective chemotherapy and RT will continue to increase the frequency of bladder salvage.

   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.[37][Level of evidence: 3iiiB] For patients with biopsy-proven, residual malignant tumor after 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.[110]

   An alternative strategy, used in European SIOP protocols, has been to avoid major radical surgery when possible and omit external-beam RT if complete disappearance of tumor can be achieved by chemotherapy and conservative surgical procedures. The goal is to preserve a functional bladder and prostate without incurring the late effects of RT or having to perform a total cystectomy/prostatectomy. From 1984 to 2003, 172 patients with nonmetastatic bladder and/or bladder/prostate rhabdomyosarcoma were accrued in a SIOP-MMT study. Of the 119 survivors, 50% had no significant local therapy, and only 26% received RT. The 5-year OS rate was 77%.[111][Level of evidence: 3iiA]

   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.[108,112,113] 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.[108] Surgery should be considered only if malignant tumor cells do not disappear over time after 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.

3. Kidney.

   The kidney is rarely the primary site for sarcoma. Ten patients were identified from among 5,746 eligible patients enrolled on IRSG protocols, including six with embryonal rhabdomyosarcoma and four with undifferentiated sarcoma. The tumors were large (mean widest diameter, 12.7 cm), and anaplasia was present in four (67%) patients. Of the patients with embryonal rhabdomyosarcoma, three Group I and Group II patients survived, one Group III patient died of infection, and two Group IV patients died of recurrent disease; these children were 5.8 and 6.1 years old at diagnosis. This very limited experience concluded that the kidney is an unfavorable site for primary sarcoma.[114]

4. Vulva/Vagina/Uterus.

   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 II or III), results in excellent 5-year survival rates.[115,116,117][Level of evidence: 3iA]

   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.[116][Level of evidence: 3iiiDiii] In 21 girls with genitourinary tract disease who were not treated with radiation therapy (mostly Group III vaginal primary tumors), the 3-year failure-free survival (FFS) rate was 57%, compared with an FFS rate of 77% in the other 45 patients with non-female genitourinary primary tumors (P = .02).[118][Level of evidence: 2Dii] Therefore, the COG-STS recommended that RT be administered to patients with residual viable vaginal tumor, beginning at week 12.[119][Level of evidence: 3iA]

   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.[115,120] Twelve of 14 girls with primary cervical embryonal (mainly botryoid) rhabdomyosarcoma were disease-free after vincristine, dactinomycin, and cyclophosphamide (VAC) chemotherapy and conservative surgery. Of note, two girls also had a pleuropulmonary blastoma and another had Sertoli-Leydig cell tumor.[121] 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.

   For girls with genitourinary primary tumors who will receive pelvic irradiation, ovarian transposition (oophoropexy) before radiation therapy should be considered unless dose estimations suggest that ovarian function is likely to be preserved. Alternatively, ovarian tissue preservation is under investigation and can be considered.

Unusual primary sites

Rhabdomyosarcoma occasionally arises in sites other than those previously discussed.

1. Brain.

   Patients with localized primary rhabdomyosarcoma of the brain can occasionally be cured using a combination of tumor excision, RT, and chemotherapy.[122][Level of evidence: 3iiiDiii]

2. Larynx.

   Patients with laryngeal rhabdomyosarcoma will usually be treated with chemotherapy and RT after biopsy in an attempt to preserve the larynx.[123]

3. Diaphragm.

   Patients with diaphragmatic 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; removal of residual tumor at a later date if clinically indicated should be considered.[124]

4. Ovary.

   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.[125][Level of evidence: 3iiiDiii] Treatment with combination chemotherapy followed by removal of the residual mass or masses can sometimes be successful.[125]

Metastatic sites

Primary resection of metastatic disease at diagnosis (Stage 4, M1, Group IV) is rarely indicated.

Evidence (treatment of lung-only metastatic disease):

1. The CWS reviewed four consecutive trials and identified 29 patients with M1 embryonal rhabdomyosarcoma and metastasis limited to the lung at diagnosis.[126][Level of evidence: 3iiiA]
   • They reported a 5-year EFS of approximately 38% 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).
2. The IRSG reviewed 46 IRS-IV (1991-1997) patients with metastatic disease at diagnosis confined to the lungs. Only 11 patients (24%) had a biopsy of the lung, including six at the time of primary diagnosis. They were compared with 234 patients with single non-lung metastatic sites or multiple other sites of metastases. The lung-only patients were more likely to have embryonal rhabdomyosarcoma and parameningeal primary tumors than the larger group of 234 patients, and were less likely to have regional lymph node disease at diagnosis.[127][Level of evidence: 3iiiB]
   • At 4 years, the FFS rate was 35% and the OS rate was 42%, better than for those with two or more sites of metastases (P = .005 and .002, respectively).
   • Age 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).

Chemotherapy Treatment Options

All children with rhabdomyosarcoma should receive chemotherapy. The intensity and duration of the chemotherapy are dependent on the Risk Group assignment.[128] (Refer to Table 5 in the Stage Information for Childhood Rhabdomyosarcoma section of this summary for more information about Risk Groups.)

Adolescents treated with therapy for rhabdomyosarcoma experience less hematologic toxicity and more peripheral nerve toxicity than do younger patients.[129]

Low-risk Group

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). (Refer to Table 4 in the Stage Information for Childhood Rhabdomyosarcoma section of this summary for more information.) Only approximately 25% of newly diagnosed patients are, by definition, low risk.

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. Refer to Table 7 below.

Evidence (chemotherapy for low-risk Group patients):

1. Two-drug regimen.
   1. The COG-D9602 study stratified 388 patients with low-risk embryonal rhabdomyosarcoma into two groups.[130] 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 for 48 weeks with or without RT. Patients with subgroup B disease (n = 78; Stage 1 Group IIB/C, Stage I Group III nonorbit, Stage 2 Group II, and Stage 3 Group I/II disease) received VAC (total cumulative cyclophosphamide 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 89%, and the OS rate was 97%.
      • For subgroup B patients, the 5-year FFS rate was 85%, and the OS rate was 93%.
   2. The Children's Oncology Group clinical trial ARST0331 for subset 2 low-risk patients was designed to test the safety of reducing total cumulative cyclophosphamide dose to decrease the risk of permanent infertility.[118][Level of evidence: 2Dii]
      • Using reduced total cyclophosphamide, researchers observed suboptimal FFS rates among patients with subset 2 low-risk rhabdomyosarcoma. Eliminating RT for girls with Group III vaginal tumors in combination with reduced total cyclophosphamide appeared to contribute to the suboptimal outcome. However, the OS rate appeared to be similar to the OS rate in previous studies with higher-dose cyclophosphamide.
2. Three-drug regimen.

   Other subgroups of low-risk patients have achieved survival rates of at least 90% with three-drug chemotherapy with VAC (total cyclophosphamide dose of 28.6 g/m²) plus RT for residual tumor. Refer to Table 8 below.

   Table 8. Characteristics of Low-Risk Patients With High Survival Rates Using Three-Drug Therapy With Vincristine, Dactinomycin, and Cyclophosphamide With or Without Radiation Therapy (Subset B)

   Site	Size	Group	Nodes
   N0 = absence of nodal spread; N1 = presence of regional nodal spread beyond the primary site.
   Favorable (orbital or nonorbital)	Any	IIB, IIC, III	N0, N1
   Unfavorable	≤5 cm	II	N0
   Unfavorable	>5 cm	I, II	N0, N1

3. Treatment duration.

   The subsequent COG-ARST0331 trial evaluated a refinement of therapy for two subsets of low-risk patients. The study enrolled 271 newly diagnosed patients with Subset 1 low-risk rhabdomyosarcoma, defined as patients with Stage 1 or Stage 2 tumors; Group I or Group II embryonal tumors; or Stage 1, Group III orbital embryonal tumors, with a shorter duration chemotherapy regimen that included four cycles of VAC chemotherapy followed by 10 weeks of therapy with vincristine and dactinomycin.[119] Study results are pending for Subset 2.

   • The 3-year FFS rate was 89%, and the OS rate was 98%. Thus, shorter duration of therapy did not appear to compromise outcome in these patients.

Intermediate-risk Group

Approximately 50% of newly diagnosed patients are in the intermediate-risk category. VAC is the standard multiagent chemotherapy regimen used for intermediate-risk patients.

Evidence (chemotherapy for intermediate-risk Group patients):

1. 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. 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).[31]
   • Intermediate-risk patients had survival rates at 3 years from 84% to 88%.[31]
   • There was no difference in outcome between these three treatments, and the VAC regimen was easier to administer, confirming VAC as the standard chemotherapy combination for children with intermediate-risk rhabdomyosarcoma.[31]
   • Survival in patients with tumors of embryonal histology treated on IRS-IV (who received higher doses of alkylating agents) was compared with similar patients treated on IRS-III (who received lower doses of alkylating agents); a benefit was suggested 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.[131] For other groups of intermediate-risk patients, an intensification of cyclophosphamide was feasible but did not improve outcome.[132]
2. 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.[133,134] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity both in patients with recurrent disease and in newly diagnosed patients with metastatic disease.[135,136] 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.
   • 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 plus vincristine, topotecan, and cyclophosphamide (VTC).[135][Level of evidence: 1iiA]
3. 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 requires further investigation.[137][Level of evidence: 3iiiA]
4. In a European trial (SIOP-MMT-95), 457 patients with incompletely resected embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, undifferentiated sarcoma, or soft tissue primitive neuroectodermal tumor, carboplatin, epirubicin, and etoposide was added to standard ifosfamide, vincristine, and dactinomycin (IVA) therapy.[138]
   • The addition of carboplatin, epirubicin, and etoposide did not improve outcome (3-year OS for IVA was 82%; 3-year OS for IVA plus carboplatin, epirubicin, and etoposide was 80%).
   • Toxicity was significantly worse in the six-drug arm.

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.[139,140] Aggressive alternative therapy is not warranted for rhabdomyosarcoma patients with a residual mass at the end of planned therapy unless it has biopsy-proven residual malignant disease. For Group III patients, best response (complete remission versus partial or no response) to initial chemotherapy had no impact on overall outcome.[140] 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.[141]

High-risk Group

High-risk patients have metastatic disease in one or more sites at diagnosis (Stage IV, Group IV). These patients continue to have a relatively poor prognosis with current therapy (5-year survival rate of ≤50%), and new approaches to treatment are needed to improve survival in this group.[127,142,143] Two retrospective studies have examined patients who present with metastases limited to the lungs;[126,127] results are summarized in the Metastatic sites section of this summary.

The standard systemic therapy for children with metastatic rhabdomyosarcoma is the three-drug combination of VAC.

Evidence (chemotherapy for high-risk Group patients):

1. A multinational pooled analysis included 788 high-risk rhabdomyosarcoma patients treated with multiagent chemotherapy (all regimens used cyclophosphamide or ifosfamide plus dactinomycin and vincristine with or without other agents), followed by local therapy (surgery with or without RT) within 3 to 5 months after starting chemotherapy.[144][Level of evidence: 3iiiA]

   Analysis identified several adverse prognostic factors (Oberlin risk factors):

   • Age at diagnosis younger than 1 year or 10 years and older.
   • Unfavorable primary site (all sites that are not orbit, nonparameningeal head and neck, genitourinary tract other than bladder/prostate, and biliary tract).
   • Bone and/or bone marrow involvement.
   • Three or more different metastatic sites or tissues.

   The EFS rate at 3 years depended upon the number of adverse prognostic factors:[144][Level of evidence: 3iiiA]

   • The EFS rate 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 with three adverse prognostic factors, and 5% for patients with four adverse prognostic factors (P < .0001).

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:

1. In the IRS-IV study, three combinations of drug pairs were studied in an up-front window-ifosfamide/etoposide (IE), vincristine/melphalan (VM),[145] and ifosfamide/doxorubicin (ID).[146] 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%).[146]

     Results with VAC chemotherapy for Stage IV rhabdomyosarcoma in the North American experience are similar.

2. 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.[135,136]
   • Survival was not different from that seen with previous regimens.
   • An up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma showed similar results.[134]
3. Irinotecan and irinotecan with vincristine have also been evaluated as up-front window trials by the COG-STS.[147]
   • The response rates were better when irinotecan was administered with vincristine than without it, but survival in a preliminary analysis was not improved over previous experience.
4. In a French study, 20 patients with metastatic disease at diagnosis received window therapy with doxorubicin for two courses.[148]
   • Thirteen of 20 patients responded to therapy, and four patients had progressive disease.
5. A study from the 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 VDC maintenance versus an arm that evaluated a window of single-agent doxorubicin or carboplatin followed by sequential high-dose monotherapy courses including cyclophosphamide, etoposide, and carboplatin followed by maintenance VAC.[149]
   • No benefit was seen for the high-dose therapy arm.
6. A study of patients with previously untreated metastatic rhabdomyosarcoma from the COG-STS examined outcome of 109 patients with the disease.[144] Several treatment strategies, all given over 54 planned weeks, were used:
   1. A period of compressed (every 2 weeks) schedule of chemotherapy using vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide plus etoposide.
   2. The addition of vincristine and irinotecan including during RT.
   3. A period of vincristine, actinomycin, and cyclophosphamide therapy.

   The following results were observed:

   • Using Oberlin risk factors (age <1 or >10 years, unfavorable primary site, number of metastatic sites and presence or absence of bone/bone marrow involvement), the strategy improved outcome compared with historic controls for patients with lower-risk disease. Three-year EFS rates were 69% for those with Oberlin risk factor score of 0 or 1 and 60% for patients younger than 10 years of age with embryonal rhabdomyosarcoma.[150][Level of evidence: 3iiDi]
   • However, patients with more than 2 Oberlin risk factors had a 20% 3-year EFS, comparable to historic outcomes. This intensive protocol did not appear to improve outcome for the highest-risk patients.

Other Therapeutic Approaches

• High-dose chemotherapy with autologous and allogeneic stem cell rescue has been evaluated in a limited number of patients with rhabdomyosarcoma.[151,152,153] The use of this modality has failed to improve the outcomes of patients with newly diagnosed or recurrent rhabdomyosarcoma.[153]
• The National Cancer Institute's intramural Pediatric Oncology Branch conducted a pilot study of cytoreductive treatment followed by consolidative immunotherapy incorporating T-cell reconstitution, plus a dendritic-cell and tumor-peptide vaccine that was given with minimal toxicity to patients with translocation-positive metastatic or recurrent Ewing sarcoma (n = 37) and alveolar rhabdomyosarcoma (n = 15). Ten patients with alveolar rhabdomyosarcoma had improved survival compared with five patients who did not receive immunotherapy.[154][Level of evidence: 3iiiA]

Current Clinical Trials

Check the list of NCI-supported 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 website.

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105. 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.
106. Pappo AS, Shapiro DN, Crist WM, et al.: Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 13 (8): 2123-39, 1995.
107. 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.
108. Heyn R, Newton WA, Raney RB, et al.: Preservation of the bladder in patients with rhabdomyosarcoma. J Clin Oncol 15 (1): 69-75, 1997.
109. 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.
110. 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.
111. Jenney M, Oberlin O, Audry G, et al.: Conservative approach in localised rhabdomyosarcoma of the bladder and prostate: results from International Society of Paediatric Oncology (SIOP) studies: malignant mesenchymal tumour (MMT) 84, 89 and 95. Pediatr Blood Cancer 61 (2): 217-22, 2014.
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114. 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.
115. 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.
116. 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.
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118. Walterhouse DO, Pappo AS, Meza JL, et al.: Reduction of cyclophosphamide dose for patients with subset 2 low-risk rhabdomyosarcoma is associated with an increased risk of recurrence: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Cancer : , 2017.
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123. 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.
124. 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.
125. Cribbs RK, Shehata BM, Ricketts RR: Primary ovarian rhabdomyosarcoma in children. Pediatr Surg Int 24 (5): 593-5, 2008.
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131. 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.
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135. 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.
136. 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.
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Treatment of Recurrent Childhood Rhabdomyosarcoma

Prognosis and Prognostic Factors

Although patients with recurrent or progressive rhabdomyosarcoma sometimes achieve complete remission with secondary therapy, the long-term prognosis is usually poor.[1,2]

The following studies reported on the prognostic factors associated with recurrent or progressive disease:

• In a 1999 study of 605 children, the prognosis was most favorable (5-year survival rates, 50%-70%) for children who initially presented with Stage 1 or Group I disease and embryonal/botryoid histology with small tumors and for those with local or regional nodal recurrence. Patients with Group I alveolar rhabdomyosarcoma or undifferentiated sarcoma had a 5-year overall survival (OS) of 40% to 50%. Only 20% of the relapsed patients were in these groups.[1][Level of evidence: 3iiiA]
• In a 2014 study of 24 children, 22 (82%) children with initially localized orbital sarcoma survived at least 5 years after relapse following re-treatment with curative intent.[3][Level of evidence: 3iiA]
• A 2005 study of 125 patients with nonmetastatic rhabdomyosarcoma who recurred after previous complete remission observed that favorable factors at initial diagnosis included: nonalveolar histology, primary site in the orbit, genitourinary/nonbladder-prostate or head/neck nonparameningeal regions, tumor size of 5 cm or smaller, local relapse, relapse after 18 months from the primary diagnosis, and lack of initial radiation therapy.[2]
• A report of 337 patients with nonmetastatic rhabdomyosarcoma in 2008 observed that favorable factors at initial diagnosis were age 10 years or younger, embryonal histology, tumor size of 5 cm or smaller, favorable site, and lack of initial radiation therapy.[4]
• In a 2009 study of 234 patients who relapsed after achieving complete remission and completing primary treatment, the favorable prognostic factors for 3-year OS were reported; the factors were favorable primary site, local relapse, time to relapse more than 12 months, tumor size of 5 cm or smaller, and no previous radiation therapy.[5][Level of evidence: 3iiB]
• A study of 474 patients in 2011 with nonmetastatic rhabdomyosarcoma who had complete local control at the primary site noted the unfavorable factors for survival 3 years after first relapse. These unfavorable factors included relapse with metastatic disease, previous (initial) radiation therapy, tumor size more than 5 cm, time to relapse less than 18 months, regional lymph node involvement, alveolar histology, and unfavorable disease at primary diagnosis.[6]
• In 2013, 90 patients with nonmetastatic alveolar rhabdomyosarcoma were re-treated with additional chemotherapy with or without local re-excision of the primary site (if indicated) with or without radiation therapy. The four most important factors for survival after relapse were no lymph node involvement, no metastases, adequate local therapy, and achieving a second complete remission. OS at 5 years was 21%.[7][Level of evidence: 3iiA]

Treatment Options for Recurrent Childhood Rhabdomyosarcoma

The selection of further treatment depends on many factors, including the site(s) of recurrence, previous treatment, and individual patient considerations.

Treatment options for recurrent childhood rhabdomyosarcoma include the following:

1. Surgery. 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.[8,9] Some survivors have also been reported after surgical removal of only one or a few metastases in the lung.[8]
2. Radiation therapy. Radiation therapy should be considered for patients with embryonal rhabdomyosarcoma 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.
3. Chemotherapy. A German study found that treatment with multiagent chemotherapy incorporating carboplatin and etoposide, plus RT, was efficacious for patients with embryonal rhabdomyosarcoma (5-year event-free survival [EFS], 41%), but it was less effective for patients with alveolar rhabdomyosarcoma (5-year EFS, 25%).[10] Previously unused, active, single agents or combinations of drugs may also enhance the likelihood of disease control.

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

1. Carboplatin/etoposide.[10]
2. Ifosfamide, carboplatin, and etoposide.[11,12]
3. Cyclophosphamide/topotecan.[13]
4. Irinotecan with or without vincristine.[14,15,16,17]
   • A Children's Oncology Group (COG) prospective, randomized, up-front window trial, COG-ARST0121, showed no difference between vincristine plus irinotecan (20 mg/m² /d) daily × 5 days for 4 weeks per 6-week treatment cycle (Regimen 1A) and irinotecan (50 mg/m² /d) daily × 5 days for 2 weeks per 6-week treatment cycle (Regimen 1B) in poor-risk patients with relapsed or progressive rhabdomyosarcoma. At 1 year after initiation of treatment for recurrence, the failure-free survival (FFS) rate was 37% and the OS rate was 55% for Regimen 1A; the FFS rate was 38% and OS rate was 60% for Regimen 1B. The Soft Tissue Sarcoma Committee of the COG recommended the more convenient Regimen 1B for further investigation.[18][Level of evidence: 1iiA]
5. Single-agent vinorelbine.
   • In one phase II trial, four of eleven patients with recurrent rhabdomyosarcoma responded to single-agent vinorelbine.[19]
   • In another trial, 6 of 12 young patients (aged 9-29 years) had a partial response.[20]
6. Vinorelbine and cyclophosphamide.
   • In a pilot study, three of nine patients with rhabdomyosarcoma had an objective response.[21]
   • In a phase II study in France (N = 50), children with recurrent or refractory rhabdomyosarcoma were treated with vinorelbine and low-dose oral cyclophosphamide. Four complete responses and 14 partial responses were observed, for an objective response rate of 36%.[22][Level of evidence: 3iiiDiv]
7. Gemcitabine and docetaxel.
   • In a single institution trial, two patients (N = 5) with recurrent rhabdomyosarcoma achieved an objective response.[23]
8. Sirolimus.[24]
9. Topotecan, vincristine, and doxorubicin.[25][Level of evidence: 3iiiDiv]
10. Vincristine, irinotecan, and temozolomide.
    • One of four patients with recurrent alveolar rhabdomyosarcoma had a complete radiographic response sustained for 27 weeks with no grade 3 or 4 toxicities.[26]; [27][Level of evidence: 3iiiDiii]
11. Temsirolimus, irinotecan, and temozolomide.
    • In a phase I trial of these agents, four patients had rhabdomyosarcoma. The regimen was well tolerated, and one patient had a partial response and another had stable disease.[28]
12. Temsirolimus, cyclophosphamide, and vinorelbine.
    • In a COG randomized, phase II, selection-design study in patients with relapsed rhabdomyosarcoma that compared bevacizumab with temsirolimus, both administered with cyclophosphamide and vinorelbine, the temsirolimus arm had a superior 6-month EFS (65%; 95% CI, 44%-79%) compared with the bevacizumab arm (50%; 95% CI, 32%-66%; P = .0031). The complete response rate (complete remission plus partial remission) was higher on the temsirolimus arm (47%) than on the bevacizumab arm (28%).[29]

Treatment options under clinical evaluation for 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 website.

• 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.[30,31,32]
• ADVL1522 (NCT02452554) (Lorvotuzumab Mertansine in Treating Younger Patients with Relapsed or Refractory Wilms Tumor, Rhabdomyosarcoma, Neuroblastoma, Pleuropulmonary Blastoma, Malignant Peripheral Nerve Sheath Tumor, or Synovial Sarcoma): This is a phase II study of IMGN901 (lorvotuzumab mertansine) in children with relapsed or refractory Wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, malignant peripheral nerve sheath tumor, and synovial sarcoma. This trial is studying the effects of IMGN901, an antibody-drug conjugate that links a potent antimitotic to antibodies that target CD56.
• ADVL1412 (NCT02304458) (Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas): This phase I/II trial is studying the side effects and best dose of nivolumab when given with or without ipilimumab to see how well they work in treating younger patients with solid tumors or sarcomas that have come back (recurrent) or do not respond to treatment (refractory). Monoclonal antibodies such as nivolumab and ipilimumab may block tumor growth in different ways by targeting certain cells. It is not yet known whether nivolumab works better alone or with ipilimumab in treating patients with recurrent or refractory solid tumors or sarcomas.
• ADVL1621 (NCT02332668) (A Study of Pembrolizumab [MK-3475] in Pediatric Participants With Advanced Melanoma or Advanced, Relapsed, or Refractory PD-L1-Positive Solid Tumors or Lymphoma [MK-3475-051/KEYNOTE-051]): This is a two-part study of pembrolizumab (MK-3475) in pediatric participants who have either advanced melanoma or a programmed cell death ligand 1 (PD-L1)-positive advanced, relapsed, or refractory solid tumor or lymphoma. Part 1 will find the maximum tolerated dose/maximum administered dose, confirm the dose, and find the recommended phase II dose for pembrolizumab therapy. Part 2 will further evaluate the safety and efficacy at the pediatric recommended phase II dose.
• ADVL1312 (NCT02095132) (WEE1 Inhibitor MK-1775 and Irinotecan Hydrochloride in Treating Younger Patients With Relapsed or Refractory Solid Tumors): This phase I/II trial is studying the side effects and best dose of WEE1 inhibitor MK-1775 and irinotecan hydrochloride in treating younger patients with solid tumors that have come back or that have not responded to standard therapy. WEE1 inhibitor MK-1775 and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
• New agents under clinical evaluation in phase I and phase II trials should be considered for relapsed patients.

Current Clinical Trials

Check the list of NCI-supported 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 website.

References:

1. Pappo AS, Anderson JR, Crist WM, et al.: Survival after relapse in children and adolescents with rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group. J Clin Oncol 17 (11): 3487-93, 1999.
2. Mazzoleni S, Bisogno G, Garaventa A, et al.: Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma. Cancer 104 (1): 183-90, 2005.
3. Raney B, Huh W, Hawkins D, et al.: Outcome of patients with localized orbital sarcoma who relapsed following treatment on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols-III and -IV, 1984-1997: a report from the Children's Oncology Group. Pediatr Blood Cancer 60 (3): 371-6, 2013.
4. 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.
5. Mattke AC, Bailey EJ, Schuck A, et al.: Does the time-point of relapse influence outcome in pediatric rhabdomyosarcomas? Pediatr Blood Cancer 52 (7): 772-6, 2009.
6. Chisholm JC, Marandet J, Rey A, et al.: Prognostic factors after relapse in nonmetastatic rhabdomyosarcoma: a nomogram to better define patients who can be salvaged with further therapy. J Clin Oncol 29 (10): 1319-25, 2011.
7. Dantonello TM, Int-Veen C, Schuck A, et al.: Survival following disease recurrence of primary localized alveolar rhabdomyosarcoma. Pediatr Blood Cancer 60 (8): 1267-73, 2013.
8. Hayes-Jordan A, Doherty DK, West SD, et al.: Outcome after surgical resection of recurrent rhabdomyosarcoma. J Pediatr Surg 41 (4): 633-8; discussion 633-8, 2006.
9. De Corti F, Bisogno G, Dall'Igna P, et al.: Does surgery have a role in the treatment of local relapses of non-metastatic rhabdomyosarcoma? Pediatr Blood Cancer 57 (7): 1261-5, 2011.
10. Klingebiel T, Pertl U, Hess CF, et al.: Treatment of children with relapsed soft tissue sarcoma: report of the German CESS/CWS REZ 91 trial. Med Pediatr Oncol 30 (5): 269-75, 1998.
11. Kung FH, Desai SJ, Dickerman JD, et al.: Ifosfamide/carboplatin/etoposide (ICE) for recurrent malignant solid tumors of childhood: a Pediatric Oncology Group Phase I/II study. J Pediatr Hematol Oncol 17 (3): 265-9, 1995.
12. Van Winkle P, Angiolillo A, Krailo M, et al.: Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer 44 (4): 338-47, 2005.
13. Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001.
14. Cosetti M, Wexler LH, Calleja E, et al.: Irinotecan for pediatric solid tumors: the Memorial Sloan-Kettering experience. J Pediatr Hematol Oncol 24 (2): 101-5, 2002.
15. Pappo AS, Lyden E, Breitfeld P, et al.: Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the Children's Oncology Group. J Clin Oncol 25 (4): 362-9, 2007.
16. Vassal G, Couanet D, Stockdale E, et al.: Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group. J Clin Oncol 25 (4): 356-61, 2007.
17. Furman WL, Stewart CF, Poquette CA, et al.: Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17 (6): 1815-24, 1999.
18. Mascarenhas L, Lyden ER, Breitfeld PP, et al.: Randomized phase II window trial of two schedules of irinotecan with vincristine in patients with first relapse or progression of rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 28 (30): 4658-63, 2010.
19. Kuttesch JF Jr, Krailo MD, Madden T, et al.: Phase II evaluation of intravenous vinorelbine (Navelbine) in recurrent or refractory pediatric malignancies: a Children's Oncology Group study. Pediatr Blood Cancer 53 (4): 590-3, 2009.
20. Casanova M, Ferrari A, Spreafico F, et al.: Vinorelbine in previously treated advanced childhood sarcomas: evidence of activity in rhabdomyosarcoma. Cancer 94 (12): 3263-8, 2002.
21. Casanova M, Ferrari A, Bisogno G, et al.: Vinorelbine and low-dose cyclophosphamide in the treatment of pediatric sarcomas: pilot study for the upcoming European Rhabdomyosarcoma Protocol. Cancer 101 (7): 1664-71, 2004.
22. Minard-Colin V, Ichante JL, Nguyen L, et al.: Phase II study of vinorelbine and continuous low doses cyclophosphamide in children and young adults with a relapsed or refractory malignant solid tumour: good tolerance profile and efficacy in rhabdomyosarcoma--a report from the Société Française des Cancers et leucémies de l'Enfant et de l'adolescent (SFCE). Eur J Cancer 48 (15): 2409-16, 2012.
23. Rapkin L, Qayed M, Brill P, et al.: Gemcitabine and docetaxel (GEMDOX) for the treatment of relapsed and refractory pediatric sarcomas. Pediatr Blood Cancer 59 (5): 854-8, 2012.
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.
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.
26. McNall-Knapp RY, Williams CN, Reeves EN, et al.: Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory solid tumors. Pediatr Blood Cancer 54 (7): 909-15, 2010.
27. Mixon BA, Eckrich MJ, Lowas S, et al.: Vincristine, irinotecan, and temozolomide for treatment of relapsed alveolar rhabdomyosarcoma. J Pediatr Hematol Oncol 35 (4): e163-6, 2013.
28. Bagatell R, Norris R, Ingle AM, et al.: Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: a Children's Oncology Group Study. Pediatr Blood Cancer 61 (5): 833-9, 2014.
29. Mascarenhas L, Meyer WH, Lyden E, et al.: Randomized phase II trial of bevacizumab and temsirolimus in combination with vinorelbine (V) and cyclophosphamide (C) for first relapse/disease progression of rhabdomyosarcoma (RMS): a report from the Children's Oncology Group (COG). [Abstract] J Clin Oncol 32 (Suppl 5): A-10003, 2014. Also available online. Last accessed April 06, 2017.
30. 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.
31. 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.
32. 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.

Changes to This Summary (04 / 06 / 2017)

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.

General Information About Childhood Rhabdomyosarcoma

Added text to state that similar conclusions were reached in a retrospective study of three consecutive trials in the United Kingdom. The authors underscored the probable value of treating fusion-negative patients whose tumors have alveolar histology with therapy that is stage appropriate for embryonal histology tumors (cited Selfe et al. as reference 49 and level of evidence 3iiA).

Stage Information for Childhood Rhabdomyosarcoma

Revised text to state that many studies have demonstrated that sentinel lymph node biopsies can be safely performed in children with rhabdomyosarcoma, and tumor-positive biopsies alter the treatment plan (cited Dall'Igna et al., Alcorn et al., Wright et al., and Parida et al. as references 2, 3, 4, and 5, respectively).

Added text to state that pathologic evaluation of regional nodes is currently required for all Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG-STS) study participants with extremity primary rhabdomyosarcoma and boys aged 10 years and older with paratesticular rhabdomyosarcoma, because microscopic tumor is often documented even when the nodes are not enlarged.

Treatment of Previously Untreated Childhood Rhabdomyosarcoma

Revised text to state that there is little evidence that debulking surgery improves outcome, compared with biopsy alone; therefore, debulking surgery is not recommended for patients with rhabdomyosarcoma. Also added text to state that delaying surgery until after chemotherapy is preferred.

Added Leiser et al. as reference 22.

Added text about the COG-STS recommendations on biopsies for regional and in-transit lymph nodes (cited Dall'Igna et al., Alcorn et al., Wright et al., and Parida et al. as references 73, 74, 75, and 76, respectively).

Added text about the treatment of chest wall rhabdomyosarcoma.

Added text about the results of the International Society of Paediatric Oncology Malignant Mesenchymal Tumour 89 and 95 studies and the recommendation for ipsilateral lymph node sampling for all patients aged 10 years and older (cited Rogers et al. as reference 101 and level of evidence 2Di).

Added text to state that in 21 girls with genitourinary tract disease who were not treated with radiation therapy, the 3-year failure-free survival (FFS) rate was 57%, compared with an FFS rate of 77% in the other 45 patients with non-female genitourinary primary tumors (cited Walterhouse et al. as reference 118 and level of evidence 2Dii).

Added text about the results of the Children's Oncology Group clinical trial ARST0331 for subset 2 low-risk patients that was designed to test the safety of reducing total cumulative cyclophosphamide dose.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

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

Reviewers and Updates

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

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

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

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

The lead reviewers for Childhood Rhabdomyosarcoma Treatment are:

• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Holcombe Edwin Grier, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
• Andrea A. Hayes-Jordan, MD, FACS, FAAP (M.D. Anderson 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 NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

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

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Rhabdomyosarcoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/soft-tissue-sarcoma/hp/rhabdomyosarcoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389243]

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Last Revised: 2017-04-06