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) data base.[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 data base.[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 p53 mutations).[9-11]

  -

  Pleuropulmonary blastoma (with DICER1 mutations).[12,13]

  -

  Neurofibromatosis type I.[14,15]

  -

  Costello syndrome (with germline HRAS mutations).[16-19]

  -

  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).[28-31]

  -

  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

  View in own window

  Primary Site	Number of Patients	Survival at 5 Years (%)
  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

  ^aPatients treated on Intergroup Rhabdomyosarcoma Study III.[5]

  ^bPatients treated on Intergroup Rhabdomyosarcoma Studies I–IV.[36]

• 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 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: Cohort studies have provided somewhat conflicting data regarding the outcome for patients with translocation-negative tumors.[46,47] One study showed that this group had an outcome indistinguishable from embryonal rhabdomyosarcoma;[47] however, a German study of 121 patients with alveolar rhabdomyosarcoma found no significant difference in EFS at 5 years among patients who were PAX-FOXO1–positive compared with those who were translocation-negative.[48] These studies also demonstrated that fusion status was a better predictor of outcome than histology and will replace histology in COG studies going forward.[49]
  PAX-FOX01 fusion status has been found to drive unfavorable outcome for children with rhabdomyosarcoma. Fusion-positive patients had a lower EFS (PAX3 54% and PAX7 65%) than did those with embryonal rhabdomyosarcoma (77%). Patients with fusion-negative alveolar rhabdomyosarcoma had outcomes similar to those with embryonal rhabdomyosarcoma.[50]
• 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.[51]
  • The number of metastatic sites.[52-55]
• 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.[56]
  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.[57]; [58][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.[59-64]

Response as judged by sequential functional imaging studies with (18F) fluorodeoxyglucose positron emission tomography (PET) may be an early indicator of outcome [65] 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.[65] 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.

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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.

Molecular Characteristics of Rhabdomyosarcoma

1. Embryonal histology: Embryonal tumors often show loss of heterozygosity at 11p15 and gains on chromosome 8.[14-16] 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.[17,18] 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.[17,18]
   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.[7,8] Rhabdomyosarcoma with nonalveolar, anaplastic morphology may be a presenting feature for children with Li-Fraumeni syndrome and germline TP53 mutations.[19] 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)).[9,14,20] Other rare fusions include PAX3-NCOA1 and PAX3-INO80D.[17] 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.[21] 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.[22]
   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.[23-28] 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.[13,21] 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.[17,18] 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.[29] 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.[30] 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.[30] 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.[30-33] Activating PIK3CA mutations were common in MYOD1-mutated cases (4 of 10); when they were present, they were associated with sclerosing histology.[30] The presence of the MYOD1 mutation is associated with an increased risk of treatment failure.[30-32] 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.[30]

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.[13,34-37] 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

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2. Newton WA Jr, Gehan EA, Webber BL, et al.: Classification of rhabdomyosarcomas and related sarcomas. Pathologic aspects and proposal for a new classification--an Intergroup Rhabdomyosarcoma Study. Cancer 76 (6): 1073-85, 1995. [PubMed: 8625211]
3. 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.
4. 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. [PMC free article: PMC4651658] [PubMed: 25989287]
5. Leuschner I: Spindle cell rhabdomyosarcoma: histologic variant of embryonal rhabdomyosarcoma with association to favorable prognosis. Curr Top Pathol 89: 261-72, 1995. [PubMed: 7882713]
6. Sultan I, Qaddoumi I, Yaser S, et al.: Comparing adult and pediatric rhabdomyosarcoma in the surveillance, epidemiology and end results program, 1973 to 2005: an analysis of 2,600 patients. J Clin Oncol 27 (20): 3391-7, 2009. [PubMed: 19398574]
7. Kodet R, Newton WA Jr, Hamoudi AB, et al.: Childhood rhabdomyosarcoma with anaplastic (pleomorphic) features. A report of the Intergroup Rhabdomyosarcoma Study. Am J Surg Pathol 17 (5): 443-53, 1993. [PubMed: 8470759]
8. 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. [PMC free article: PMC2727712] [PubMed: 18985676]
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. [PMC free article: PMC1867584] [PubMed: 16645206]
10. Kelly KM, Womer RB, Barr FG: Minimal disease detection in patients with alveolar rhabdomyosarcoma using a reverse transcriptase-polymerase chain reaction method. Cancer 78 (6): 1320-7, 1996. [PubMed: 8826957]
11. Edwards RH, Chatten J, Xiong QB, et al.: Detection of gene fusions in rhabdomyosarcoma by reverse transcriptase-polymerase chain reaction assay of archival samples. Diagn Mol Pathol 6 (2): 91-7, 1997. [PubMed: 9098647]
12. Sartori F, Alaggio R, Zanazzo G, et al.: Results of a prospective minimal disseminated disease study in human rhabdomyosarcoma using three different molecular markers. Cancer 106 (8): 1766-75, 2006. [PubMed: 16544315]
13. 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. [PMC free article: PMC2630563] [PubMed: 19147825]
14. Merlino G, Helman LJ: Rhabdomyosarcoma--working out the pathways. Oncogene 18 (38): 5340-8, 1999. [PubMed: 10498887]
15. Koufos A, Hansen MF, Copeland NG, et al.: Loss of heterozygosity in three embryonal tumours suggests a common pathogenetic mechanism. Nature 316 (6026): 330-4, 1985 Jul 25-31. [PubMed: 2991766]
16. Scrable H, Witte D, Shimada H, et al.: Molecular differential pathology of rhabdomyosarcoma. Genes Chromosomes Cancer 1 (1): 23-35, 1989. [PubMed: 2487144]
17. 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. [PMC free article: PMC4462130] [PubMed: 24436047]
18. Chen X, Stewart E, Shelat AA, et al.: Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell 24 (6): 710-24, 2013. [PMC free article: PMC3904731] [PubMed: 24332040]
19. Hettmer S, Archer NM, Somers GR, et al.: Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer 120 (7): 1068-75, 2014. [PMC free article: PMC4173134] [PubMed: 24382691]
20. 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. [PMC free article: PMC3932368] [PubMed: 22089931]
21. Parham DM, Qualman SJ, Teot L, et al.: Correlation between histology and PAX/FKHR fusion status in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group. Am J Surg Pathol 31 (6): 895-901, 2007. [PubMed: 17527077]
22. 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. [PubMed: 25912319]
23. Sorensen PH, Lynch JC, Qualman SJ, et al.: PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 20 (11): 2672-9, 2002. [PubMed: 12039929]
24. Krsková L, Mrhalová M, Sumerauer D, et al.: Rhabdomyosarcoma: molecular diagnostics of patients classified by morphology and immunohistochemistry with emphasis on bone marrow and purged peripheral blood progenitor cells involvement. Virchows Arch 448 (4): 449-58, 2006. [PubMed: 16365729]
25. Kelly KM, Womer RB, Sorensen PH, et al.: Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J Clin Oncol 15 (5): 1831-6, 1997. [PubMed: 9164192]
26. Barr FG, Qualman SJ, Macris MH, et al.: Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Cancer Res 62 (16): 4704-10, 2002. [PubMed: 12183429]
27. 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. [PubMed: 22454413]
28. 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. [PMC free article: PMC3348443] [PubMed: 22447499]
29. 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.
30. 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. [PMC free article: PMC4712098] [PubMed: 26501226]
31. 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. [PMC free article: PMC4231202] [PubMed: 24793135]
32. 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. [PMC free article: PMC4108340] [PubMed: 24824843]
33. 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. [PubMed: 24272621]
34. 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. [PMC free article: PMC3040045] [PubMed: 20124188]
35. Williamson D, Missiaglia E, de Reyniès A, et al.: Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol 28 (13): 2151-8, 2010. [PubMed: 20351326]
36. Davicioni E, Finckenstein FG, Shahbazian V, et al.: Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas. Cancer Res 66 (14): 6936-46, 2006. [PubMed: 16849537]
37. 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. [PMC free article: PMC4646073] [PubMed: 23526739]

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).
• Bilateral bone marrow aspirates and biopsies.
• Bone scan.
• 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. One study has demonstrated that sentinel lymph node biopsies can be safely performed in children with rhabdomyosarcoma, and tumor-positive biopsies alter the treatment plan.[1] Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose (FDG) scans can identify areas of possible metastatic disease not seen by other imaging modalities.[2-4] 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.

A retrospective study of 1,687 children with rhabdomyosarcoma enrolled in Intergroup studies from 1991 to 2004 suggests that about one-third of patients (those with localized noninvasive embryonal tumors) can have limited staging procedures that eliminate bone marrow and bone scan examinations at diagnosis.[5]

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.

References

1. Kayton ML, Delgado R, Busam K, et al.: Experience with 31 sentinel lymph node biopsies for sarcomas and carcinomas in pediatric patients. Cancer 112 (9): 2052-9, 2008. [PubMed: 18338809]
2. Völker T, Denecke T, Steffen I, et al.: Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 25 (34): 5435-41, 2007. [PubMed: 18048826]
3. Tateishi U, Hosono A, Makimoto A, et al.: Comparative study of FDG PET/CT and conventional imaging in the staging of rhabdomyosarcoma. Ann Nucl Med 23 (2): 155-61, 2009. [PubMed: 19225939]
4. Federico SM, Spunt SL, Krasin MJ, et al.: Comparison of PET-CT and conventional imaging in staging pediatric rhabdomyosarcoma. Pediatr Blood Cancer 60 (7): 1128-34, 2013. [PMC free article: PMC4266929] [PubMed: 23255260]
5. Weiss AR, Lyden ER, Anderson JR, et al.: Histologic and clinical characteristics can guide staging evaluations for children and adolescents with rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee. J Clin Oncol 31 (26): 3226-32, 2013. [PMC free article: PMC3757291] [PubMed: 23940218]
6. Lawrence W Jr, Gehan EA, Hays DM, et al.: Prognostic significance of staging factors of the UICC staging system in childhood rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study (IRS-II). J Clin Oncol 5 (1): 46-54, 1987. [PubMed: 3543238]
7. Lawrence W Jr, Anderson JR, Gehan EA, et al.: Pretreatment TNM staging of childhood rhabdomyosarcoma: a report of the Intergroup Rhabdomyosarcoma Study Group. Children's Cancer Study Group. Pediatric Oncology Group. Cancer 80 (6): 1165-70, 1997. [PubMed: 9305719]
8. Crist WM, Garnsey L, Beltangady MS, et al.: Prognosis in children with rhabdomyosarcoma: a report of the intergroup rhabdomyosarcoma studies I and II. Intergroup Rhabdomyosarcoma Committee. J Clin Oncol 8 (3): 443-52, 1990. [PubMed: 2407808]
9. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995. [PubMed: 7884423]
10. Raney RB, Anderson JR, Barr FG, et al.: Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol 23 (4): 215-20, 2001. [PubMed: 11846299]
11. Breneman JC, Lyden E, Pappo AS, et al.: Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma--a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21 (1): 78-84, 2003. [PubMed: 12506174]

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.[1-3] 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.[1-3]

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. [PubMed: 11597814]
2. Stevens MC, Rey A, Bouvet N, et al.: Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology--SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol 23 (12): 2618-28, 2005. [PubMed: 15728225]
3. Donaldson SS, Anderson JR: Rhabdomyosarcoma: many similarities, a few philosophical differences. J Clin Oncol 23 (12): 2586-7, 2005. [PubMed: 15728222]
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. [PubMed: 20473932]
6. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PMC free article: PMC4136455] [PubMed: 24853691]
7. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PubMed: 15173520]

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]

Clinical and/or imaging evaluation of regional lymph nodes is an important part of pretreatment staging. Pathologic evaluation of regional nodes is currently required for all Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG-STS) patients with extremity primary rhabdomyosarcoma and boys aged 10 years and older with paratesticular rhabdomyosarcoma, because microscopic tumor is often documented even when the nodes are not enlarged. (Refer to the Regional and in-transit lymph nodes section of this summary for more information.)

There is little evidence that debulking surgery (i.e., surgery that is expected to leave macroscopic residual tumor) improves outcome, compared with biopsy alone.[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]

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]

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

Chemotherapy Treatment Options

All children with rhabdomyosarcoma should receive chemotherapy. The intensity and duration of the chemotherapy are dependent on the Risk Group assignment.[123] (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.[124]

Other Therapeutic Approaches

• High-dose chemotherapy with autologous and allogeneic stem cell rescue has been evaluated in a limited number of patients with rhabdomyosarcoma.[146-148] The use of this modality has failed to improve the outcomes of patients with newly diagnosed or recurrent rhabdomyosarcoma.[148]
• 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.[149][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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108. Godbole P, Outram A, Wilcox DT, et al.: Myogenin and desmin immunohistochemistry in the assessment of post-chemotherapy genitourinary embryonal rhabdomyosarcoma: prognostic and management implications. J Urol 176 (4 Pt 2): 1751-4, 2006. [PubMed: 16945640]
109. Arndt CA, Hammond S, Rodeberg D, et al.: Significance of persistent mature rhabdomyoblasts in bladder/prostate rhabdomyosarcoma: Results from IRS IV. J Pediatr Hematol Oncol 28 (9): 563-7, 2006. [PubMed: 17006261]
110. 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. [PMC free article: PMC2803057] [PubMed: 18523987]
111. Arndt CA, Donaldson SS, Anderson JR, et al.: What constitutes optimal therapy for patients with rhabdomyosarcoma of the female genital tract? Cancer 91 (12): 2454-68, 2001. [PubMed: 11413538]
112. 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. [PMC free article: PMC3459820] [PubMed: 21298768]
113. Kirsch CH, Goodman M, Esiashvili N: Outcome of female pediatric patients diagnosed with genital tract rhabdomyosarcoma based on analysis of cases registered in SEER database between 1973 and 2006. Am J Clin Oncol 37 (1): 47-50, 2014. [PubMed: 23111355]
114. Walterhouse DO, Pappo AS, Meza JL, et al.: Shorter-duration therapy using vincristine, dactinomycin, and lower-dose cyclophosphamide with or without radiotherapy for patients with newly diagnosed low-risk rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. J Clin Oncol 32 (31): 3547-52, 2014. [PMC free article: PMC4209105] [PubMed: 25267746]
115. Corpron CA, Andrassy RJ, Hays DM, et al.: Conservative management of uterine pediatric rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study III and IV pilot. J Pediatr Surg 30 (7): 942-4, 1995. [PubMed: 7472949]
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117. Guilcher GM, Hendson G, Goddard K, et al.: Successful treatment of a child with a primary intracranial rhabdomyosarcoma with chemotherapy and radiation therapy. J Neurooncol 86 (1): 79-82, 2008. [PubMed: 17579809]
118. Kato MA, Flamant F, Terrier-Lacombe MJ, et al.: Rhabdomyosarcoma of the larynx in children: a series of five patients treated in the Institut Gustave Roussy (Villejuif, France). Med Pediatr Oncol 19 (2): 110-4, 1991. [PubMed: 2011095]
119. Raney RB, Anderson JR, Andrassy RJ, et al.: Soft-tissue sarcomas of the diaphragm: a report from the Intergroup Rhabdomyosarcoma Study Group from 1972 to 1997. J Pediatr Hematol Oncol 22 (6): 510-4, 2000 Nov-Dec. [PubMed: 11132218]
120. Cribbs RK, Shehata BM, Ricketts RR: Primary ovarian rhabdomyosarcoma in children. Pediatr Surg Int 24 (5): 593-5, 2008. [PubMed: 18004572]
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122. Rodeberg D, Arndt C, Breneman J, et al.: Characteristics and outcomes of rhabdomyosarcoma patients with isolated lung metastases from IRS-IV. J Pediatr Surg 40 (1): 256-62, 2005. [PubMed: 15868594]
123. Mandell LR: Ongoing progress in the treatment of childhood rhabdomyosarcoma. Oncology (Huntingt) 7 (1): 71-83; discussion 84-6, 89-90, 1993. [PubMed: 8420543]
124. Gupta AA, Anderson JR, Pappo AS, et al.: Patterns of chemotherapy-induced toxicities in younger children and adolescents with rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee. Cancer 118 (4): 1130-7, 2012. [PMC free article: PMC4008942] [PubMed: 21761400]
125. Beverly Raney R, Walterhouse DO, Meza JL, et al.: Results of the Intergroup Rhabdomyosarcoma Study Group D9602 protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. J Clin Oncol 29 (10): 1312-8, 2011. [PMC free article: PMC3083999] [PubMed: 21357783]
126. Baker KS, Anderson JR, Link MP, et al.: Benefit of intensified therapy for patients with local or regional embryonal rhabdomyosarcoma: results from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 18 (12): 2427-34, 2000. [PubMed: 10856103]
127. Spunt SL, Smith LM, Ruymann FB, et al.: Cyclophosphamide dose intensification during induction therapy for intermediate-risk pediatric rhabdomyosarcoma is feasible but does not improve outcome: a report from the soft tissue sarcoma committee of the children's oncology group. Clin Cancer Res 10 (18 Pt 1): 6072-9, 2004. [PubMed: 15447992]
128. Houghton PJ, Cheshire PJ, Myers L, et al.: Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemother Pharmacol 31 (3): 229-39, 1992. [PubMed: 1464161]
129. Pappo AS, Lyden E, Breneman J, et al.: Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study. J Clin Oncol 19 (1): 213-9, 2001. [PubMed: 11134215]
130. Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001. [PubMed: 11481351]
131. Walterhouse DO, Lyden ER, Breitfeld PP, et al.: Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: a Children's Oncology Group study. J Clin Oncol 22 (8): 1398-403, 2004. [PubMed: 15007087]
132. Arndt CA, Hawkins DS, Meyer WH, et al.: Comparison of results of a pilot study of alternating vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide with IRS-IV in intermediate risk rhabdomyosarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 50 (1): 33-6, 2008. [PubMed: 17091486]
133. Oberlin O, Rey A, Sanchez de Toledo J, et al.: Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study. J Clin Oncol 30 (20): 2457-65, 2012. [PubMed: 22665534]
134. Arndt CA, Stoner JA, Hawkins DS, et al.: Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: children's oncology group study D9803. J Clin Oncol 27 (31): 5182-8, 2009. [PMC free article: PMC2773476] [PubMed: 19770373]
135. Rodeberg DA, Stoner JA, Hayes-Jordan A, et al.: Prognostic significance of tumor response at the end of therapy in group III rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 27 (22): 3705-11, 2009. [PMC free article: PMC3020959] [PubMed: 19470937]
136. Minn AY, Lyden ER, Anderson JR, et al.: Early treatment failure in intermediate-risk rhabdomyosarcoma: results from IRS-IV and D9803--a report from the Children's Oncology Group. J Clin Oncol 28 (27): 4228-32, 2010. [PMC free article: PMC2953975] [PubMed: 20713850]
137. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995. [PubMed: 7884423]
138. Breneman JC, Lyden E, Pappo AS, et al.: Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma--a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21 (1): 78-84, 2003. [PubMed: 12506174]
139. Oberlin O, Rey A, Lyden E, et al.: Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups. J Clin Oncol 26 (14): 2384-9, 2008. [PMC free article: PMC4558625] [PubMed: 18467730]
140. Breitfeld PP, Lyden E, Raney RB, et al.: Ifosfamide and etoposide are superior to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when administered with irradiation and combination chemotherapy: a report from the Intergroup Rhabdomyosarcoma Study Group. J Pediatr Hematol Oncol 23 (4): 225-33, 2001. [PubMed: 11846301]
141. Sandler E, Lyden E, Ruymann F, et al.: Efficacy of ifosfamide and doxorubicin given as a phase II "window" in children with newly diagnosed metastatic rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group. Med Pediatr Oncol 37 (5): 442-8, 2001. [PubMed: 11745872]
142. Pappo AS, Lyden E, Breitfeld P, et al.: Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the Children's Oncology Group. J Clin Oncol 25 (4): 362-9, 2007. [PubMed: 17264331]
143. Bergeron C, Thiesse P, Rey A, et al.: Revisiting the role of doxorubicin in the treatment of rhabdomyosarcoma: an up-front window study in newly diagnosed children with high-risk metastatic disease. Eur J Cancer 44 (3): 427-31, 2008. [PubMed: 18215514]
144. McDowell HP, Foot AB, Ellershaw C, et al.: Outcomes in paediatric metastatic rhabdomyosarcoma: results of The International Society of Paediatric Oncology (SIOP) study MMT-98. Eur J Cancer 46 (9): 1588-95, 2010. [PubMed: 20338746]
145. Weigel BJ, Lyden E, Anderson JR, et al.: Intensive Multiagent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide and Vincristine/Doxorubicin/Cyclophosphamide, Irinotecan, and Radiation, in Patients With High-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol 34 (2): 117-22, 2016. [PMC free article: PMC5070550] [PubMed: 26503200]
146. Admiraal R, van der Paardt M, Kobes J, et al.: High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma. Cochrane Database Syst Rev (12): CD006669, 2010. [PubMed: 21154373]
147. 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. [PMC free article: PMC3044147] [PubMed: 21373200]
148. Thiel U, Koscielniak E, Blaeschke F, et al.: Allogeneic stem cell transplantation for patients with advanced rhabdomyosarcoma: a retrospective assessment. Br J Cancer 109 (10): 2523-32, 2013. [PMC free article: PMC3833217] [PubMed: 24149176]
149. Mackall CL, Rhee EH, Read EJ, et al.: A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas. Clin Cancer Res 14 (15): 4850-8, 2008. [PMC free article: PMC2497450] [PubMed: 18676758]

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.[14-17]

   • 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. Rapamycin.[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.[30-32]
• 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.
• 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

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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. [PMC free article: PMC3044147] [PubMed: 21373200]

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.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

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: http://www.cancer.gov/types/soft-tissue-sarcoma/hp/rhabdomyosarcoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389243]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

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

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.