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Childhood Rhabdomyosarcoma Treatment (PDQ®)

Health Professional Version

.

Published online: January 14, 2020.

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

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

General Information About Childhood Rhabdomyosarcoma

Continual 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 side effects of cancer and its therapy 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, which translates into about 350 cases per year. Fifty percent of these cases are seen in the first decade of life.[4] Males have a higher incidence of embryonal tumors, and blacks have a slightly higher incidence of alveolar tumors.[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, with 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 sex and is constant from ages 0 to 19 years, with 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 (parameningeal) (approximately 25%).
  • Genitourinary tract (approximately 31%).
  • Extremities (approximately 13%). 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 factors:
    -

    Li-Fraumeni cancer susceptibility syndrome (with germline TP53 mutations).[9-11]

    -

    DICER1 syndrome.[12,13]

    -

    Neurofibromatosis type I.[14,15]

    -

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

    -

    Beckwith-Wiedemann syndrome (more commonly associated with Wilms tumor and hepatoblastoma).[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 children with localized disease who receive combined-modality therapy, with more than 70% of patients surviving 5 years after diagnosis.[5,6,25] Relapses are uncommon in patients who were alive and event free at 5 years, with a 10-year late-event rate of 9%. Relapses are more common, however, in patients who have unresectable disease in an unfavorable site at diagnosis and in patients 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:

Because treatment and prognosis partly depend 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.

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, the 5-year failure-free survival (FFS) rate 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 rates were 76% for patients younger than one year, 87% for patients aged 1 to 9 years, and 76% for patients older than 10 years.[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]

  • Young age: Infants may do poorly because chemotherapy doses are reduced by 50% on the basis of reports that they have higher death rates related to chemotherapy toxicity when compared with older patients; therefore, young patients may be underdosed.[32] In addition, infants younger than 1 year are less likely to receive radiation therapy for local control, because of concern about the high incidence of late effects in this age group.[25,33,34]
    The 5-year FFS rate 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).[27,35] This inferior FFS rate was largely because of a relatively high rate of local failure.
    In another retrospective study of 126 patients (aged ≤24 months) who were enrolled on the ARST0331 (NCT00075582) and ARST0531 (NCT00354835) trials, the 5-year local failure rate was 24%, the 5-year event-free survival (EFS) rate was 68.3%, and the OS rate was 81.9%. Forty-three percent of the patients had an individualized local therapy plan that more frequently omitted radiation therapy. These patients had inferior local control and EFS rates.[35]
    Members of the Cooperative Weichteilsarkom Studiengruppe (CWS) reviewed 155 patients with rhabdomyosarcoma presenting from birth to age 12 months; 144 patients had localized disease; 11 patients had metastases; 32 patients presented with alveolar rhabdomyosarcoma pathology. The following results were reported:[36][Level of evidence: 3iiA]
    • Of the 144 patients with localized disease, 129 patients had a complete response.
    • Fifty-one infants had a recurrence of their disease; 63% of patients with alveolar rhabdomyosarcoma relapsed, and 28% of patients with embryonal rhabdomyosarcoma relapsed.
    • Five-year OS rates were 69% for patients with localized disease, 14% for patients with metastatic disease, and 41% for patients with relapsed disease.
  • Older children: In older children, the upper dosage limits of vincristine and dactinomycin are based on body surface area (BSA), and these patients may require reduced vincristine doses because of neurotoxicity.[34,37]
  • Adolescents: A report from the Associazione Italiana Ematologia Oncologia Paediatrica (AIEOP) 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.[38]
  • Adults: 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]

Site of origin

Prognosis for childhood rhabdomyosarcoma varies according to the primary tumor site (refer to Table 1).

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

Primary SiteNumber of PatientsSurvival at 5 Years (%)
Orbita 107 95
Superficial head and neck (nonparameningeal)a10678
Cranial parameningeala 13474
Genitourinary (excluding bladder/prostate)a 158 89
Bladder/prostatea104 81
Extremitya156 74
Trunk, abdomen, perineum, etc.a147 67
Biliaryb25 78

aPatients treated on Intergroup Rhabdomyosarcoma Study III.[5]

bPatients treated on Intergroup Rhabdomyosarcoma Studies I–IV.[39]

Tumor size

Children with tumors 5 cm or less have improved survival compared with children with tumors larger than 5 cm.[5] Both tumor volume and maximum tumor diameter are associated with outcome.[40][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.[41] This was not confirmed by a COG study of patients with intermediate-risk rhabdomyosarcoma.[42] 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 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 rate of more than 90% for patients without residual tumor after surgery (Group I) and a rate of approximately 80% for patients with microscopic residual tumor after surgery (Group II).[5,43] Group I and Group II represent a minority of patients; approximately 50% of patients have unresectable Group III disease at time of diagnosis.[5]

Resectability without functional impairment is related to initial size and site of the tumor and does not account for the biology of the disease. Outcome is optimized with the use of multimodality therapy. All patients require chemotherapy, and at least 85% of patients also benefit from radiation therapy, with favorable outcomes even for patients with nonresectable disease. In the IRS-IV study, the Group III patients with localized unresectable disease who were treated with chemotherapy and radiation therapy had a 5-year FFS rate of about 75% and a local control rate of 87%.[44]

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 and truncal 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).[45]
  • 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.[46]
  • 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%).[47]

Anaplasia has been observed in 13% of embryonal rhabdomyosarcoma cases and its presence may adversely influence clinical outcome in patients with intermediate-risk disease. However, anaplasia was not shown to be an independent prognostic variable in a multivariate analysis (P = .081).[48]

PAX3/PAX7-FOXO1 gene fusion status

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 fare better than patients with fusion-positive alveolar rhabdomyosarcoma.[49-51] 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 EFS rate (PAX3, 54% and PAX7, 65%) than did those with embryonal rhabdomyosarcoma (EFS rate, 77%).

In a COG study, patients with Stage 2 or 3, Group III PAX3-positive tumors had worse OS rates than did those with PAX7 tumors.[51] Comparable results were observed in another study; patients with PAX7-positive tumors and patients with fusion-negative tumors had similar outcomes.[52]

These studies also demonstrated that fusion status was a better predictor of outcome than was histology and this variable has now been incorporated into the risk stratification of patients in the current COG ARST1431 (NCT02567435) study for patients with intermediate-risk rhabdomyosarcoma. 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.[53][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 the regional disease is treated with radiation therapy.[47]
  • 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.[54]
  • The number of metastatic sites.[55-58]

The COG performed a retrospective review of patients enrolled on high-risk protocols for rhabdomyosarcoma. PAX fusion status correlated with clinical characteristics at diagnosis, including age, stage, histology, and extent of metastatic disease (Oberlin status). Among patients with metastatic disease, PAX-FOXO1 fusion status was not an independent predictor of outcome.[59][Level of evidence: 1iiDi]

Lymph node involvement at diagnosis

Lymph node involvement at diagnosis is associated with an inferior prognosis,[46] 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 are useful for making clinical decisions. For example, up to 40% of patients with rhabdomyosarcoma in genitourinary sites have lymph node involvement, while patients with certain 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.[60]

In the extremities and select truncal sites, 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.[61-64]

Radiation therapy is administered to patients with lymph node involvement in order to enhance regional control.

Biological characteristics

Refer to the Molecular Characteristics of Rhabdomyosarcoma section of this summary for more information.

Response to therapy

It is unlikely that response to induction chemotherapy, as judged by anatomic imaging, correlates with the likelihood of survival in patients with rhabdomyosarcoma, on the basis of the IRSG, COG, and International Society of Pediatric Oncology (SIOP) studies that found no association.[65]; [66][Level of evidence: 3iiDi]; [67][Level of evidence: 3iiiA] However, an Italian study did find that patient response correlated with likelihood of survival.[40][Level of evidence: 3iiA] In patients with embryonal rhabdomyosarcoma who had metastases only in the lungs, the CWS assessed the relationship between complete response of the lung metastases at weeks 7 to 10 after chemotherapy and outcome in 53 patients.[68][Level of evidence: 3iiA] Five-year survival was 68% for 26 complete responders at weeks 7 to 10 versus 36% for 27 patients who achieved complete responses at later time points (P = .004).

Other studies have investigated response to induction therapy, showing benefit to response. These data are somewhat flawed because therapy is usually tailored on the basis of response and thus, the situation is not as clear as the COG data suggests.[69-74]

Response as judged by sequential functional imaging studies with fluorine F 18-fludeoxyglucose positron emission tomography (PET) may be an early indicator of outcome [75] 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.[75] 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. PET scans have been shown to be useful in understanding patterns of spread, particularly in patients with extremity disease.[76][Level of evidence: 3iiiDiii]

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  52. 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]
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  56. Bisogno G, Ferrari A, Prete A, et al.: Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma. Eur J Cancer 45 (17): 3035-41, 2009. [PubMed: 19783136]
  57. Dantonello TM, Winkler P, Boelling T, et al.: Embryonal rhabdomyosarcoma with metastases confined to the lungs: report from the CWS Study Group. Pediatr Blood Cancer 56 (5): 725-32, 2011. [PubMed: 21370403]
  58. 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]
  59. Rudzinski ER, Anderson JR, Chi YY, et al.: Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: A report from the Children's Oncology Group. Pediatr Blood Cancer 64 (12): , 2017. [PMC free article: PMC5647228] [PubMed: 28521080]
  60. Lawrence W, Hays DM, Heyn R, et al.: Lymphatic metastases with childhood rhabdomyosarcoma. A report from the Intergroup Rhabdomyosarcoma Study. Cancer 60 (4): 910-5, 1987. [PubMed: 3297302]
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  62. 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. [PubMed: 24074665]
  63. 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. [PubMed: 22578407]
  64. 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. [PMC free article: PMC3608674] [PubMed: 22526545]
  65. Burke M, Anderson JR, Kao SC, et al.: Assessment of response to induction therapy and its influence on 5-year failure-free survival in group III rhabdomyosarcoma: the Intergroup Rhabdomyosarcoma Study-IV experience--a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. J Clin Oncol 25 (31): 4909-13, 2007. [PubMed: 17971587]
  66. Rosenberg AR, Anderson JR, Lyden E, et al.: Early response as assessed by anatomic imaging does not predict failure-free survival among patients with Group III rhabdomyosarcoma: a report from the Children's Oncology Group. Eur J Cancer 50 (4): 816-23, 2014. [PMC free article: PMC3944684] [PubMed: 24361229]
  67. Vaarwerk B, van der Lee JH, Breunis WB, et al.: Prognostic relevance of early radiologic response to induction chemotherapy in pediatric rhabdomyosarcoma: A report from the International Society of Pediatric Oncology Malignant Mesenchymal Tumor 95 study. Cancer 124 (5): 1016-1024, 2018. [PubMed: 29211298]
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Cellular Classification for Childhood Rhabdomyosarcoma

Histologic Subtypes

The 4th edition of the World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone recognizes the following four categories of rhabdomyosarcoma:[1,2]

Embryonal rhabdomyosarcoma

The embryonal subtype, which includes the botryoid pattern, 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 disease. However, anaplasia was not shown to be an independent prognostic variable in a multivariate analysis (P = .081).[3]

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 WHO Classification of Tumors of Soft Tissue and Bone (4th edition) and the Children's Oncology Group (COG) eliminated botryoid rhabdomyosarcoma, with these cases classified as typical embryonal rhabdomyosarcoma.[4]

A COG study of 2,192 children with rhabdomyosarcoma diagnosed with embryonal histology (including botryoid and spindle cell variants) and enrolled on clinical trials 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. In this COG report, botryoid tumors accounted for 14% of intermediate-risk patients and 15% of low-risk patients; this histology retained prognostic significance in only a small proportion of patients with low-risk head and neck tumors, which are known to have excellent outcomes. For these reasons, the COG concluded that the addition of this histologic classification of rhabdomyosarcoma has limited clinical utility and endorsed the recommendations of the WHO to remove this subtype from the current COG pathology classification.

Alveolar rhabdomyosarcoma

Approximately 30% of children with rhabdomyosarcoma have the alveolar subtype, when histology alone is used to determine subtype.[6] 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 the FOXO1 gene on chromosome 13.[7-9] Patients without a fusion have outcomes that are similar to those for patients with embryonal rhabdomyosarcoma.[10-12]

The current trial for intermediate-risk patients from the Soft Tissue Sarcoma Committee of the COG (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.

Spindle cell/sclerosing rhabdomyosarcoma

The 4th edition of the WHO Classification of Tumors 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.[5,13]

A COG study of 2,192 children with rhabdomyosarcoma diagnosed with embryonal histology (including botryoid and spindle cell variants) and enrolled on clinical trials 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, with a 5-year EFS of 28% (compared with >70% EFS for parameningeal nonspindle cell embryonal rhabdomyosarcoma).

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.[14] Data on the outcome of sclerosing rhabdomyosarcoma in the pediatric population are limited. 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 of their disease.[5] 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.

Pleomorphic rhabdomyosarcoma

Pleomorphic rhabdomyosarcoma occurs predominantly in adults in their sixth and seventh decades, most commonly involves the extremities, and is associated with a poor prognosis. This histologic variant is extremely rare and not well characterized in the pediatric population.[15,16]

Molecular Characteristics of Rhabdomyosarcoma

Genomics 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.[7,17-20]

  1. Embryonal histology: Embryonal tumors often show loss of heterozygosity at 11p15 and gains on chromosome 8.[8,21,22] Embryonal tumors have a higher background mutation rate and a 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.[3,25] Rhabdomyosarcoma with nonalveolar anaplastic morphology may be a presenting feature for children with Li-Fraumeni syndrome and germline TP53 mutations.[26] 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)).[7-9] 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.[7] Patients with solid-variant alveolar histology have a lower incidence of PAX-FOXO1 gene fusions than do patients showing classical alveolar histology.[27]
    For the diagnosis of alveolar rhabdomyosarcoma, a FOXO1 gene rearrangement may be detected with good sensitivity and specificity using either fluorescence in situ hybridization or reverse transcription–polymerase chain reaction.[28]
    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.[29-34] 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.[20,27]
    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 Tumors of Soft Tissue and Bone.[35]
    For congenital/infantile spindle cell rhabdomyosarcoma, a study reported that 10 of 11 patients showed recurrent fusion genes. Most of these patients had truncal primary tumors, and no paratesticular tumors were found. Novel VGLL2 rearrangements were observed in seven patients (63%), including the VGLL2-CITED2 fusion in four patients and the VGLL2-NCOA2 fusion in two patients.[36] 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.[36] 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.[14,36-38] Activating PIK3CA mutations are seen in about one-half of the cases, and 60% of these cases have pure sclerosing morphology.[39] The presence of the MYOD1 mutation is associated with an increased risk of local and distant failure.[14,36,37] In one study that included 15 children with MYOD1-mutant tumors, the most common primary site was the head and neck region.[13] These patients had sclerosing spindle or mixed histology, and 10 of 15 patients died of disease despite aggressive multimodal therapy.

These findings highlight the important differences between embryonal and alveolar tumors. Data demonstrate that PAX-FOXO1 fusion–positive alveolar tumors are biologically and clinically different from fusion-negative alveolar tumors and embryonal tumors.[11,12,20,40,41] In a study of Intergroup Rhabdomyosarcoma Study Group patients, 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 patients. 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.

Genome-wide methylation assays can accurately identify PAX3 and PAX7 fusion–positive rhabdomyosarcomas, as well as wild-type and RAS mutant fusion–negative tumors.[42]

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Stage Information for Childhood Rhabdomyosarcoma

Staging Evaluation

Before a suspected tumor mass is biopsied, 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:

  1. Chest x-ray.
  2. Computed tomography (CT) scan of the chest.
    The European Pediatric Soft Tissue Sarcoma Study Group reviewed 367 patients enrolled in the CCLG-EPSSG-RMS-2005 (NCT00379457) study.[1][Level of evidence: 2A] By prospective study design, patients with indeterminate pulmonary nodules identified on baseline CT scan of the chest (defined as ≤4 pulmonary nodules measuring <5 mm; or 1 nodule measuring ≥5 mm and <10 mm) received the same treatment as did patients with no pulmonary nodules identified on baseline CT of the chest. Rates of event-free survival and overall survival for both groups were the same. The authors concluded that indeterminate pulmonary nodules at diagnosis, as defined in this summary, do not affect outcome in patients with localized rhabdomyosarcoma.
  3. CT scan of the abdomen and pelvis (for lower extremity or genitourinary primary tumors).
  4. Magnetic resonance imaging (MRI) of the base of the skull and brain (for parameningeal primary tumors) and of the primary site of other nonparameningeal primary tumors, as appropriate.
  5. Regional lymph node evaluation.
    • CT or MRI: Cross-sectional imaging (CT or MRI scan) of regional lymph nodes should be obtained.
    • Lymph node evaluation: Clearly enlarged lymph nodes should be biopsied when possible. Sentinel lymph node biopsy is more accurate than random lymph node sampling and is preferred in patients with extremity and trunk rhabdomyosarcoma, in which enlarged lymph nodes are not revealed on imaging or by physical examination.[2] 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.[2-7]
      Pathologic evaluation of normal-appearing regional nodes is currently required for all Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG-STS) study participants with extremity and trunk primary rhabdomyosarcoma. In boys aged 10 years and older with paratesticular rhabdomyosarcoma, retroperitoneal node dissection (ipsilateral nerve sparing) is currently required for normal-appearing lymph nodes, because microscopic tumor is often documented even when the nodes are not enlarged.[8] (Refer to the Regional and in-transit lymph nodes for extremity tumors section of this summary for more information.)
    • Positron emission tomography (PET): PET with fluorine F 18-fludeoxyglucose scans can identify areas of possible metastatic disease not seen by other imaging modalities.[9-11]
    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 COG-STS treatment protocols.
  6. Bilateral bone marrow aspirates and biopsies for selected patients.
  7. Bone scan for selected patients.

A retrospective study of 1,687 children with rhabdomyosarcoma enrolled in Intergroup Rhabdomyosarcoma Study Group (IRSG) and COG studies from 1991 to 2004 suggests those with localized negative regional lymph nodes, noninvasive embryonal tumors, and Group I alveolar tumors (about one-third of patients) can have limited staging procedures that eliminate bone marrow and bone scan examinations at diagnosis.[12]

Staging Process

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

  1. Assignment of Stage: Determined by primary site, tumor size (widest dimension), and presence or absence of regional lymph node and/or distant metastases (tumor-node-metastasis [TNM] criteria).
  2. Assignment of Group: Determined by status of the initial surgical procedure (resection/biopsy) with pathologic assessment of the tumor margin and of lymph node involvement, before the initiation of therapy.
  3. Assignment of 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 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.[13,14]

Terms defining the TNM criteria are described in Table 2.

Table 2. Definition of Terms

TermDefinition
Favorable siteOrbit; nonparameningeal head and neck; genitourinary tract other than kidney, bladder, and prostate; biliary tract.
Unfavorable siteAny site other than a favorable site.
T1Tumor confined to organ or tissue of origin (noninvasive).
T2Tumor extension beyond the organ or tissue of origin (invasive).
aTumor ≤5 cm in maximum dimension.
bTumor >5 cm in maximum dimension.
N0No clinical regional lymph node involvement.
N1Clinical regional lymph node involvement.
NXRegional lymph nodes not examined; no information.
M0No metastatic disease.
M1Metastatic disease.

T = primary tumor; N = regional lymph node; M = distant metastasis.

Table 3. Soft Tissue Sarcoma Committee of the Children's Oncology Group: Pretreatment Staging System

Stage Sites of Primary TumorT StageaTumor SizeRegional Lymph NodesaDistant Metastasisa
1Favorable sitesT1 or T2Any sizeN0 or N1 or NXM0
2Unfavorable sitesT1 or T2a, ≤5 cmN0 or NXM0
3Unfavorable sitesT1 or T2a, ≤5 cmN1M0
b, >5 cmN0 or N1 or NX
4Any siteT1 or T2Any sizeN0 or N1 or NXM1

aRefer to Table 2 for the definitions of the TNM criteria.

Assignment of Group

The IRS-I, IRS-II, IRS-III, and IRS-IV studies prescribed treatment plans on the basis of 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.[15-17]

Table 4. Soft Tissue Sarcoma Committee of the Children's Oncology Group: Surgical-pathologic Group System

GroupIncidenceDefinition
IApproximately 13%Localized tumor, completely removed with microscopically clear margins and no regional lymph node involvement.
IIApproximately 20%Localized tumor, completely removed with: (a) microscopic residual disease; (b) regional disease with involved, grossly removed regional lymph nodes; or (c) regional disease with involved nodes, grossly removed but with microscopic residual and/or histologic involvement of the most distal node from the primary tumor.
IIIApproximately 48%Localized tumor, incompletely removed with gross, residual disease after: (a) biopsy only or (b) subtotal resection.
IVApproximately 18%Distant metastases present at diagnosis. This category includes: (a) radiographically identified evidence of tumor spread or (b) positive tumor cells in cerebral spinal fluid, pleural or peritoneal fluids, or implants in these regions.

Assignment of Risk Group

After patients are categorized by Stage and Surgical-pathologic Group, a Risk Group is assigned in which the Stage, Group, and histology are taken into account. Patients are classified for protocol purposes as having a low risk, intermediate risk, or high risk of disease recurrence.[18,19] Treatment assignment is based on Risk Group, as shown in Table 5.

Table 5. Soft Tissue Sarcoma Committee of the Children's Oncology Group: Rhabdomyosarcoma Risk Group Classification Based on the Ongoing ARST1431 Trial

Risk Group HistologyStageGroup
Low risk Embryonal1I, II, III (orbit only)
Embryonal2I, II
Intermediate riskEmbryonal1III (nonorbit)
2, 3III
3I, II
4IV (age <10 years)
Alveolar1, 2, 3I, II, III
High risk Alveolar4IV
Embryonal4IV (age ≥10 years)

The most recent COG protocol uses fusion status, as opposed to histology, to define Risk Groups.

References

  1. Vaarwerk B, Bisogno G, McHugh K, et al.: Indeterminate Pulmonary Nodules at Diagnosis in Rhabdomyosarcoma: Are They Clinically Significant? A Report From the European Paediatric Soft Tissue Sarcoma Study Group. J Clin Oncol 37 (9): 723-730, 2019. [PubMed: 30702969]
  2. Wagner LM, Kremer N, Gelfand MJ, et al.: Detection of lymph node metastases in pediatric and adolescent/young adult sarcoma: Sentinel lymph node biopsy versus fludeoxyglucose positron emission tomography imaging-A prospective trial. Cancer 123 (1): 155-160, 2017. [PubMed: 27563842]
  3. 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]
  4. 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. [PubMed: 25478665]
  5. 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. [PubMed: 24074665]
  6. 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. [PubMed: 22578407]
  7. 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. [PMC free article: PMC3608674] [PubMed: 22526545]
  8. Hamilton EC, Miller CC, Joseph M, et al.: Retroperitoneal lymph node staging in paratesticular rhabdomyosarcoma-are we meeting expectations? J Surg Res 224: 44-49, 2018. [PubMed: 29506850]
  9. 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]
  10. 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]
  11. 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]
  12. 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]
  13. Lawrence W, 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]
  14. Lawrence W, 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]
  15. 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]
  16. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995. [PubMed: 7884423]
  17. Crist WM, Anderson JR, Meza JL, et al.: Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol 19 (12): 3091-102, 2001. [PubMed: 11408506]
  18. 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]
  19. 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]

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.[1-3] 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.[5]

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. RT is also administered to lymph node basins where a sentinel lymph node biopsy has identified microscopic disease.[5]

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

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 objective of the COG-STS 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 utilizing 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. Some patients have been spared aggressive local therapy, which may reduce the potential for morbidities associated with such therapy.[1-3]

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.[6] The overall impression is that survival for most patient subsets is superior with the use of early local therapy, including RT.[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.[7] 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.[8] 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. Wolden SL, Lyden ER, Arndt CA, et al.: Local Control for Intermediate-Risk Rhabdomyosarcoma: Results From D9803 According to Histology, Group, Site, and Size: A Report From the Children's Oncology Group. Int J Radiat Oncol Biol Phys 93 (5): 1071-6, 2015. [PMC free article: PMC5147527] [PubMed: 26581144]
  6. 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]
  7. 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]
  8. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PubMed: 15173520]

Treatment of 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. These multidisciplinary discussions occur after the diagnostic biopsy and before initiation of therapy.

Surgical and radiotherapeutic management of the more common primary sites is provided in the Surgery and RT by Primary Site of Disease (Local Control Management) section of this summary.

Treatment options for childhood rhabdomyosarcoma include the following:

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 RT are primarily measures taken to produce local control, but each treatment 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 by the authors. 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 also received RT. Patients with viable tumor had shorter event-free survival (EFS) rates than did patients without viable tumor, but there was no effect on overall survival (OS).[6] Thus, it is preferable to delay surgery until after chemotherapy. There is also no evidence that performing surgical resection on residual masses detected by imaging at completion of all planned therapy improves outcome.[7] Thus, residual masses can be monitored without therapeutic intervention.

For children with low-risk rhabdomyosarcoma, local control was not diminished with reduced doses of RT after surgical resection.[8] Subsequently, delayed primary excision was evaluated by the Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG-STS) in 73 patients with intermediate-risk rhabdomyosarcoma enrolled on the D9803 study (1999–2005).[7] Delayed primary excision was completed in 45% of select patients with Group III rhabdomyosarcoma tumors of the bladder dome, extremity, and trunk (or 16% of the total patient population); 84% of those who had a delayed primary excision with no remaining gross residual disease were eligible for modest radiation dose reduction (patients with no or only microresidual tumor after delayed primary excision). Local control outcomes were similar to the results reported in the Intergroup Rhabdomyosarcoma Study Group (IRSG) IRS-IV study that used RT alone.[6]

Radiation Therapy (RT) (Local Control Management)

Local control remains a significant problem in children with rhabdomyosarcoma. In the IRS-II study, 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.

  • Group I: 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.[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]
  • Group II: 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]
  • Group III: 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.
  • Histologic subtype/fusion status.
  • 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 is essential. 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.[15-20]

Dosimetric comparison of proton-beam RT and photon 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]

Evidence (radiation delivery techniques):

  1. A prospective, phase II trial compared proton-beam therapy with IMRT in pediatric rhabdomyosarcoma.[23]
    • Target coverage was comparable between proton-beam therapy 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 may lower the radiation dose in the uninvolved tissue 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 whether the reduction in dose to adjacent tissue will result in improved functional outcomes or reduce the risk of secondary malignancy or other toxicities.
  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.
  3. In a study on the patterns of failure in 11 of 66 children with nonmetastatic rhabdomyosarcoma who were treated with proton RT, the following was observed:[25]
    • A 2-year local control rate of 88%.
    • All 11 children with local recurrences were Group III (gross residual disease) and relapsed in the radiation field, suggesting that the conformality of the proton field did not lead to out-of-field failures. The radiation dose was 41.4 Gy (relative biological effectiveness [RBE]) to the prechemotherapy tumor volume and 50.4 Gy (RBE) to the visible disease at the time of RT.
    • Eight patients with local recurrences had tumors larger than 5 cm at diagnosis, and the COG ARST1431 (NCT02567435) protocol is testing escalated doses to 59.4 Gy for these patients.
    • This study does not delineate whether the recurrence was in the 41.4 Gy or 50.4 Gy irradiated volumes.

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

Table 6. Radiation Therapy (RT) Dose According to Rhabdomyosarcoma Group, Histology, and Site of Disease (Children's Oncology Group [COG])

GroupTreatment
Group I
Embryonal, fusion negativeNo RT required.
FOXO1 positive36 Gy to involved (prechemotherapy) site.
Group II
N0 (microscopic residual disease after surgery) 36 Gy to involved (prechemotherapy) site.
N1 (resected regional lymph node involvement)41.4 Gy to involved (prechemotherapy) site and nodes.
Group III
Orbital and nonorbital tumors 45 Gy for orbital tumors in complete remission. For other sites and orbital tumors in partial remission, 50.4 Gy with volume reduction after 36 Gy if excellent response to chemotherapy (or complete remission after delayed re-excision) and noninvasive pushing tumors; no volume reduction for invasive tumors. 59.4 Gy boost to residual disease at 9 weeks for tumors >5 cm (if enrolled on the COG ARST1431 [NCT02567435]) protocol.
Group IV
As for other Groups and including all metastatic sites, if safe and possible. Exception: lung (pulmonary metastases) treated with 12 Gy to 15 Gy depending on age.

N = regional lymph node.

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.[11,26] 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.[8] 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.[27,28] 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%.[29]
    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 COG-D9602 study, a limited number of low-risk patients had a greater than 85% likelihood of local control with 36 Gy.[8] 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).[30][Level of evidence: 3iiiDi]

The treated radiation volume should be determined by the extent of tumor at diagnosis before surgical resection and before chemotherapy, including clinically involved regional lymph nodes. 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 has 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 administered 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 was a randomized study that reported that the administration of RT twice a day, using 6-hour interfractional intervals at 1.1 Gy per fraction (hyperfractionated schedule), 5 days per week, was feasible, did not improve local control, and was associated with increased acute toxicity. [31]

Thus, conventional RT remains the standard for treating patients who have rhabdomyosarcoma with gross residual disease.[32]

Brachytherapy

Brachytherapy, using either intracavitary or interstitial implants, is another method of local control that has been used in selected situations for children with rhabdomyosarcoma, especially for patients with primary tumors at a vaginal site [33-38] and selected bladder/prostate sites.[39][Level of evidence: 3iiiA] This technique requires specialized technical skill and expertise and is limited to only a few providing institutions. 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.[34,40]; [41][Level of evidence: 3iiDii] Other sites, especially head and neck, have also been treated with brachytherapy.[42]

Patients with initial Group III disease, who subsequently have microscopic residual disease after chemotherapy with or without delayed surgery, require external-beam RT at doses of 36 Gy to 40 Gy for durable local control.[43]

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.[8] Reduced radiation doses have been used when delayed surgery can provide negative margins. However, for most patients and those in whom surgical resection is not appropriate, higher doses of RT are given.[44] Radiation techniques are designed to maximize normal tissue sparing and should include conformal approaches, often with intensity-modulation or protons. When radiation is omitted, even in those with Stage 1 disease, there is a high risk of recurrence, with local recurrence being the most common, confirming the need for RT.[45-47]

Delayed primary excision may allow for a radiation dose reduction and has been studied in select patients.[7] However, the youngest patients frequently do not get appropriate RT because of concerns about normal tissue toxicity, and these are the best 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. Local control rates from delayed primary excision and RT are equivalent to that with RT alone.[7]

Studies of infants younger than 1 or 2 years included 77 patients with nonmetastatic rhabdomyosarcoma and showed a 5-year failure-free survival (FFS) rate of 57% to 68% and an OS rate of 76% to 82%.[48] 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.[49] This experience has been confirmed for children up to age 2 years.[48]

Surgery and RT by Primary Site of Disease (Local Control Management)

Head and neck sites

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.

For patients with head and neck primary tumors that are considered unresectable, chemotherapy and RT with organ preservation are the mainstay of primary management.[50-55] 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.[56-58]; [59][Level of evidence: 3iiiA]

  1. Orbit.
    Rhabdomyosarcomas of the orbit should not undergo exenteration, but biopsy is needed for diagnosis.[60,61] Biopsy is followed by chemotherapy and RT, with orbital exenteration reserved for the small number of patients with locally persistent or recurrent disease.[52,62] RT and chemotherapy are the standard of care, with survival in excess of 90% to 95%. When RT is omitted, there is risk of local relapse. For patients with orbital tumors, precaution should be taken to limit the RT dose to the lens, conjunctiva, and cornea.
    The COG studied administering a lower dose of cyclophosphamide to reduce the risk of infertility. In the COG ARST0331 (NCT00075582) trial, only four cycles of therapy contained cyclophosphamide, for a total cyclophosphamide exposure of 4.8 g/m2. Sixty-two patients with Group III orbital embryonal rhabdomyosarcoma were treated. None of the 15 patients with radiographic complete response (CR) had local recurrences, compared with 6 of the 38 patients who had less than a CR after 12 weeks of vincristine, dactinomycin, and cyclophosphamide (VAC) chemotherapy (P = .11). The authors concluded that for patients with Group III orbital embryonal rhabdomyosarcoma achieving a CR after VAC chemotherapy that includes modest-dose cyclophosphamide, 45 Gy of radiation may be sufficient for durable FFS. However, for patients with less than a CR who were treated with the ARST0331 systemic therapy, a radiation dose of 50.4 Gy or a higher dose of cyclophosphamide may be needed to achieve the control rate reported in the IRS-IV trial.[63][Level of evidence: 2Di]
  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.[53,64,65] 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 patients with high-risk parameningeal tumors. Because complete removal of these tumors is not feasible, 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.[64] 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.[65]
    Evidence (timing of RT for nonorbital and cranial parameningeal tumors):
    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.[65]
      • When no signs of meningeal impingement were present, delay of RT for more than 10 weeks did not impact local failure rates.
    2. A comparison of local control, FFS, and OS rates showed no statistical difference between early irradiation (day 0) for Group III patients in the IRS-IV study with cranial nerve palsy and/or cranial base erosion versus later initiation of RT (week 12) for Group III patients in the D9803 study who had similar evidence of meningeal involvement. This suggested that early RT for this group of patients is not necessary.[66][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.[67][Level of evidence: 3iiDii]
    4. A single-institution retrospective review identified 14 patients with head and neck alveolar rhabdomyosarcoma. All patients were treated with multiagent chemotherapy and RT to the primary site and clinically involved nodes.[68][Level of evidence: 3iiiDiii]
      • There were ten relapses in the cohort: seven regional nodal, one combination local and regional nodal, and two leptomeningeal.
      • In six of eight patients (75%) with no nodal disease at diagnosis, isolated regional nodal relapse developed.
      • The authors recommended elective nodal irradiation to treat at-risk draining lymph node stations relative to the primary tumor site for patients who present with head and neck alveolar rhabdomyosarcoma.
    5. 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.[69][Level of evidence: 3iiiA]
      • 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.
    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 patients without other distant metastases were alive at 6 to 16 years after diagnosis, as was one of the four patients who had concomitant metastases elsewhere.[70]
    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.[71,72]
  3. Nonparameningeal, nonorbital head and neck.
    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.[73]; [74][Level of evidence: 3iiA] 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 be considered, however, only in children with recurrent locoregional disease or residual disease after chemotherapy and RT.

Extremity sites

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 5-year OS 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.[75]

Primary re-excision before initiation of 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 without loss of cosmesis or function.[4] Chemotherapy or delayed primary excision does not improve outcome over chemotherapy and RT.[7]

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.

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.[76][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.[77][Level of evidence: 3iiiA] Definitive RT and chemotherapy for Group III tumors resulted in 90% to 95% local control in the IRS-IV trial.[31]

Regional and in-transit lymph nodes for extremity tumors

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.[78-82]; [83][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.[83]

Positron emission tomography (PET) scanning is recommended for evaluation and staging of extremity primary tumors before initiation of therapy [83] and is useful in RT treatment planning.

For patients enrolled in clinical trials, the COG-STS recommends biopsy of all enlarged or clinically suspicious lymph nodes, if possible, without delay in therapy or adverse functional outcome. If biopsy is not feasible, clinically abnormal nodes need to be included in the RT treatment plan.

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 than random lymph node sampling. Techniques for sentinel lymph node biopsy are standardized and should be completed by an experienced surgeon.[81,84-90]

In a single-institution study of 28 patients aged 6 months to 32 years with soft tissue sarcomas, but not confined to rhabdomyosarcoma, sentinel lymph node biopsy was prospectively compared with PET-CT scan for detection of lymph node metastases. Forty-three percent of patients (3 of 7) with proven malignant sentinel lymph nodes had negative cross-sectional and functional imaging (PET-CT). Also, PET-CT suggested nodal involvement in 14 patients, whereas only 4 of those were proven to have metastatic disease. The study does not address relapse rate or follow-up in these patients. Therefore, the use of PET-CT staging to diagnose lymph node disease in soft tissue sarcomas is of uncertain utility.[91]

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 follows 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).[92] 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 is unresectable at diagnosis but may become amenable to resection with negative margins after preoperative chemoradiation therapy; such patients may have excellent long-term survival.[92-95]
    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 RT.[95] Aggressive resections at diagnosis before chemotherapy are not necessary because rhabdomyosarcoma is very chemosensitive and radiosensitive.
  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.[96]
    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).[96]
    Evidence (chemotherapy with or without RT followed by surgery):
    1. 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.[97][Level of evidence: 2A]
      • Age older than 10 years and lymph node involvement were unfavorable prognostic factors.
    2. A German study reported on 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.[98][Level of evidence: 3iiA]
      • The EFS rate was 52% (± 10%), and the OS rate 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).
    3. A small series of seven patients with rhabdomyosarcoma who had peritoneal dissemination and/or malignant ascites achieved good outcomes with whole-abdomen irradiation using IMRT with dose painting.[99][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. Outcomes for patients with this primary site are good despite residual disease after surgery. External biliary drains significantly increase the risk of postoperative infectious complications. Thus, external biliary drainage is not warranted.[100]
  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.[101] The high frequency of nodal involvement and the prognostic association between nodal involvement and poorer outcome support the recommendation to sample the regional lymph nodes.[102] 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.[102]
    • 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.[103][Level of evidence: 3iiiA]

Genitourinary system sites

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.[104]

  1. Testis or spermatic cord (paratesticular).
    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).[105] 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. In 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 alkylating agent, and other agents.[106][Level of evidence: 3iiiDi]
    In a retrospective study of 842 patients with localized paratesticular rhabdomyosarcoma who were enrolled in COG, CWS, European Pediatric Soft Tissue Sarcoma Study Group (EpSSG), Italian Cooperative Group, and MMT studies from 1988 to 2013, 7.7% of patients had a transscrotal resection; however, this surgical factor did not contribute to an inferior EFS in stratified univariable and multivariable analysis.[107]
    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.[108][Level of evidence: 3iiiC] A retrospective review of 49 patients with paratestis rhabdomyosarcoma referred to Memorial Sloan Kettering Cancer Center found that 20 patients had scrotal violation as a part of their original surgery. Fifteen of these patients underwent salvage surgery or RT; 11 of these patients had continuous progression-free survival, whereas four of the five patients who were treated without a salvage procedure developed recurrent disease.[109][Level of evidence: 3iiiDiii]
    Paratesticular tumors have a relatively high incidence of lymphatic spread (26% in IRS-I and IRS-II),[78] and all patients with paratesticular primary tumors should have thin-cut abdominal and pelvic CT scans with intravenous 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.[110,111] 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.[3,32,112] Patients with suspicious or documented retroperitoneal/pelvic lymph nodes require nodal RT.
    Patients older than 10 years without clinical or radiologic evidence of retroperitoneal node enlargement should have an ipsilateral, nerve sparing retroperitoneal node dissection.[113] 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.[105,110]
    Evidence (lymph node sampling):
    1. In the SIOP-MMT-89 and -95 studies, patients with paratesticular rhabdomyosarcoma were evaluated with imaging but did not undergo routine ipsilateral lymph node sampling.[114][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. The North American and European cooperative groups performed a pooled analysis of 12 studies from five cooperative groups.[107][Level of evidence: 3iiA]
      • For patients with paratesticular rhabdomyosarcoma (N = 842), age 10 years and older at diagnosis and tumor size larger than 5 cm were unfavorable prognostic features.
      • At 7.5 years of median follow-up, the EFS rate was 87.7%, and the OS rate was 94.8% at 5 years.
      • The only treatment variable that was associated with EFS in patients aged 10 years or older was surgical assessment of regional nodes and this may most accurately identify those patients who can benefit from RT.
    Surgical resection, in the form of ipsilateral retroperitoneal lymph node sampling of clinically normal nodes (not enlarged by CT or MRI), in patients aged 10 years and older with paratesticular rhabdomyosarcoma, is now recommended by both SIOP and COG because of the high relapse rate and worse EFS in Stage N0 patients.[107] RT should be considered for patients whose nodes are biopsy positive.
  2. Bladder or prostate.
    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.
    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.[115,116]
    In rare cases, the tumor is confined to the dome of the bladder and can be completely resected, leaving functional bladder intact. 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,[117,118] sometimes followed, when necessary, by a more limited surgical procedure such as partial cystectomy.[119] 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).[119,120] The later experience from the IRS-III and IRS-IV studies, 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%.[118,121,122]
    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.
    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.[39][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.[123]
    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%.[124][Level of evidence: 3iiA]
    Another alternative strategy in highly selected patients is to perform conservative surgery followed by brachytherapy at a specialized center.[125]; [126][Level of evidence: 3iiDiii]; [127][Level of evidence: 3iiiA] A prospective, nonrandomized analysis of this strategy reported the outcomes of 100 children. The 5-year disease-free survival rate was 84%, and the OS rate was 91%. At last follow-up, most survivors presented with only mild to moderate genitourinary sequelae and a normal diurnal urinary continence. Five patients required a secondary total cystectomy, three patients for a nonfunctional bladder and two patients for relapse.
    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.[121,128,129] 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.[121] 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 aged 5.8 and 6.1 years at diagnosis. This very limited experience concluded that the kidney is an unfavorable site for primary sarcoma.[130]
  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 radiation (external beam or brachytherapy) for residual disease (Group II or III), results in excellent 5-year survival rates.[45,131,132][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.[45][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 FFS rate was 57%, compared with an FFS rate of 77% in the other 45 patients with non–female genitourinary primary tumors (P = .02).[46][Level of evidence: 2Dii] Therefore, the COG-STS recommended that RT be administered to patients with residual viable vaginal tumor, beginning at week 12.[47][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.[131,133] Twelve of 14 girls with primary cervical embryonal (mainly botryoid) rhabdomyosarcoma were disease-free after VAC chemotherapy and conservative surgery. Of note, two girls also had a pleuropulmonary blastoma and another had Sertoli-Leydig cell tumor.[134] 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.
    Four cooperative groups in the United States and Europe evaluated patients with localized vaginal/uterine tumors (N = 427). Some patients received initial RT for local control of residual disease after induction chemotherapy, while others had it later, or not at all if no demonstrable disease was found. The 10-year EFS rate was 74%, and the 10-year OS rate was 92%. Unfavorable factors were positive lymph node disease and uterine corpus primary site. There was no statistical difference in outcomes between patients who received early RT and patients who received later RT. About one-half of these patients were cured without radical surgery or systematic RT.[38][Level of evidence: 3iiA]
    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.[135] Alternatively, ovarian tissue preservation is under investigation and can be considered.[136]

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.[137][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.[138]
  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.[139]
  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.[140][Level of evidence: 3iiiDiii] Treatment with combination chemotherapy followed by removal of the residual mass or masses can sometimes be successful.[140]

Metastatic sites

Primary resection of metastatic disease at diagnosis (Stage 4, M1, Group IV) is rarely indicated. A site of gross disease is rarely cured with chemotherapy alone; thus, RT to sites of gross disease is recommended by COG.

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.[141][Level of evidence: 3iiiA]
    • They reported a 5-year EFS rate 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 nonlung metastatic sites or multiple other sites of metastases. The lung-only patients were more likely to have embryonal rhabdomyosarcoma and parameningeal primary tumors than the larger group of 234 patients, and were less likely to have regional lymph node disease at diagnosis.[142][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. Patients who received lung irradiation had better FFS and OS at 4 years than those who did not receive lung irradiation (P = .01 and P = .039, respectively).

Chemotherapy

All children with rhabdomyosarcoma should receive chemotherapy. The intensity and duration of the chemotherapy are dependent on the Risk Group assignment.[143] (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.[144]

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.) 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 of vincristine and dactinomycin (VA) plus RT for residual tumor. (Refer to Table 7 below.)

Table 7. Characteristics of Low-Risk Patients With High Survival Rates Using Two-Drug Therapy With Vincristine and Dactinomycin With or Without Radiation Therapy (Subset A)

Tumor SiteTumor SizeSurgical-pathologic GroupNodes
FavorableAnyI, IIAN0
OrbitalAnyI, II, IIIN0
Unfavorable≤5 cmIN0

N0 = absence of nodal spread.

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.[145] 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 COG clinical trial COG-ARST0331 for subset 2 low-risk patients was designed to test the safety of reducing the total cumulative cyclophosphamide dose to decrease the risk of permanent infertility.[46][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. These patients (Stage I, Group III nonorbit and Stage 3, Group I/II) are now being treated in the intermediate-risk ARST1431 (NCT02567435) trial.
      • For patients with an orbital primary tumor who achieved only a partial response or stability after 12 weeks induction chemotherapy, the 5-year FFS rate was only 84%, compared with 100% for patients who achieved a CR.[63][Level of evidence: 3iiiDiii]
  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)

    Tumor SiteTumor SizeSurgical-pathologic GroupNodes
    Favorable (orbital or nonorbital)AnyIIB, IIC, IIIN0, N1
    Unfavorable≤5 cmII N0
    Unfavorable>5 cmI, IIN0, N1

    N0 = absence of nodal spread; N1 = presence of regional nodal spread beyond the primary site.

  3. Treatment duration.
    The 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.[47] 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).[32]
    • Intermediate-risk patients had survival rates at 3 years from 84% to 88%.[32]
    • There was no difference in outcome between these three treatments; the VAC regimen was easier to administer, confirming VAC as the standard chemotherapy combination for children with intermediate-risk rhabdomyosarcoma.[32]
    • 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.[146] For other groups of intermediate-risk patients, an intensification of cyclophosphamide was feasible but did not improve outcome.[147]
  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.[148,149] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity both in patients with recurrent disease and in newly diagnosed patients with metastatic disease.[150,151]
    1. 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; the 4-year FFS rate was 73% with VAC and 68% with VAC plus vincristine, topotecan, and cyclophosphamide (VTC).[150][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.[152][Level of evidence: 3iiiA]
    • The relative efficacy of this approach versus the standard approach requires further investigation.
  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.[153]
    • 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.
  5. The COG reported a prospective randomized trial of two treatment strategies for patients with intermediate-risk rhabdomyosarcoma.[154][Level of evidence: 1iiA] Patients were randomly assigned to receive treatment with either VAC or VAC with half of the cyclophosphamide cycles replaced with vincristine/irinotecan (VAC/VI). All patients received a lower cumulative dose of cyclophosphamide and earlier introduction of RT than did patients who were treated in previous COG studies. Patients who were treated with VAC/VI received half as much cumulative cyclophosphamide than did patients who were treated with VAC.
    • At a median follow-up of 4.8 years, the 4-year EFS was 63% with VAC and 59% with VAC/VI (P = .51), and the 4-year OS was 73% for VAC and 72% for VAC/VI (P = .80). The COG concluded that the addition of VI to VAC did not improve EFS or OS for patients with intermediate-risk rhabdomyosarcoma.
    • Among patients with Group III embryonal tumors, local failure was higher in the ARST0531 (NCT00354835) trial than in the D9803 (NCT00003958) trial (27.9% vs. 19.4%) and was similar for the VAC and VAC/VI arms.
    • After adjusting for other prognostic factors, OS was inferior in the ARST0531 trial.
    • VAC/VI produced less hematologic toxicity, had a lower cumulative cyclophosphamide dose, and continues to be the backbone for the ARST1431 (NCT02567435) study.

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.[155,156] Aggressive alternative therapy is not warranted for patients with rhabdomyosarcoma who have 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.[156] 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.[157]

Members of the EpSSG evaluated the role of indeterminate pulmonary nodules at diagnosis in patients with rhabdomyosarcoma. The criteria for indeterminate pulmonary nodules were one to four nodules smaller than 5 mm or one nodule measuring 5 mm to 10 mm. Of 316 patients, 67 patients had nodules and 249 patients did not have nodules. At a median follow-up of 75 months, the 5-year EFS was 77% for patients with nodules and 73.2% for patients without nodules (P = .68). The 5-year OS was 82% for patients with nodules and 80.8% for patients without nodules (P = .76). The authors concluded that there was no need to perform a biopsy on or upstage the patients with indeterminate pulmonary nodules at diagnosis.[158][Level of evidence: 3iiA]

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.[142,159,160] Two retrospective studies have examined patients who present with metastases limited to the lungs;[141,142] 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 patients with high-risk rhabdomyosarcoma who were 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.[161][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 on the number of adverse prognostic factors:[161][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 outcomes 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),[162] and ifosfamide/doxorubicin (ID).[163] 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%).[163]
      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.[150,151]
    • 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.[149]
  3. Irinotecan and the combination of irinotecan with vincristine have also been evaluated as up-front window trials by the COG-STS.[164]
    • 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.[165]
    • 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.[166]
    • 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 outcomes of 109 patients with the disease.[161] 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 zero or one and 60% for patients younger than 10 years with embryonal rhabdomyosarcoma.[167][Level of evidence: 3iiDi]
    • However, patients with more than two Oberlin risk factors had a 3-year EFS of 20%, comparable to historic outcomes. This intensive protocol did not appear to improve outcome for the highest-risk patients.
  7. The EpSSG performed a randomized prospective phase III trial of patients with high-risk rhabdomyosarcoma. They compared a standard arm comprising nine cycles of ifosfamide, vincristine, and dactinomycin (IVA) with an investigational arm comprising four cycles of IVA plus doxorubicin followed by five cycles of IVA.[168][Level of evidence: 3iiA]
    • The investigational therapy was associated with increased toxicity, including treatment-related mortality, and was not associated with improvement in either EFS or OS.
  8. The COG performed two nonrandomized pilot trials in patients with high-risk rhabdomyosarcoma. All patients received 54 weeks of chemotherapy, including vincristine/irinotecan, interval-compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide.[169][Level of evidence: 3iiDi]
    1. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. Cixutumumab is a monoclonal antibody against the insulin-like growth factor 1 receptor.
    2. In pilot 2, patients received oral temozolomide (100 mg/m2) daily for 5 days with irinotecan.
    The following results were observed:
    • With a median follow-up of 2.9 years, the 3-year EFS rate was 16% (95% CI, 7%–25%) with cixutumumab and 18% (95% CI, 2%–35%) with temozolomide.
    • These results did not differ from the results observed in the ARST0431 (NCT00354744) trial that used the same chemotherapy regimen.

Other Therapeutic Approaches

  • High-dose chemotherapy with autologous and allogeneic stem cell rescue has been evaluated in a limited number of patients with rhabdomyosarcoma.[170-172] The use of this modality has failed to improve the outcomes of patients with newly diagnosed or recurrent rhabdomyosarcoma.[172]
  • The National Cancer Institute's (NCI) 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.[173][Level of evidence: 3iiiA]

Treatment Options Under Clinical Evaluation For Childhood Rhabdomyosarcoma

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

  • ARST1431 (NCT02567435) (Combination Chemotherapy With or Without Temsirolimus in Treating Patients With Intermediate-Risk Rhabdomyosarcoma): This trial consists of three basic treatment regimens. Patients are randomly assigned to receive either regimen A or regimen B, in which the only difference is the addition of temsirolimus. Regimen C is for patients with alveolar rhabdomyosarcoma who are fusion-negative with Stage 1, Group III (orbit) disease, or Stage 2, Group I/II disease. These patients will receive three cycles of VAC plus four cycles of VA.
  • ADVL1622 (NCT02867592) (Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors): This phase II trial studies how well cabozantinib-s-malate works in treating younger patients with sarcomas, Wilms tumor, or other rare tumors that have come back, do not respond to therapy, or are newly diagnosed. Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for tumor growth and tumor blood vessel growth.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  150. Saylors RL, 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]
  151. 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]
  152. 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]
  153. 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]
  154. Hawkins DS, Chi YY, Anderson JR, et al.: Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol 36 (27): 2770-2777, 2018. [PMC free article: PMC6145831] [PubMed: 30091945]
  155. 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]
  156. 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]
  157. 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]
  158. Vaarwerk B, Bisogno G, McHugh K, et al.: Indeterminate Pulmonary Nodules at Diagnosis in Rhabdomyosarcoma: Are They Clinically Significant? A Report From the European Paediatric Soft Tissue Sarcoma Study Group. J Clin Oncol 37 (9): 723-730, 2019. [PubMed: 30702969]
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Treatment of Progressive or Recurrent Childhood Rhabdomyosarcoma

Prognosis and Prognostic Factors

Although patients with progressive or recurrent rhabdomyosarcoma sometimes achieve complete remission with secondary therapy, the long-term prognosis is usually poor.[1,2] Rhabdomyosarcoma may relapse locally or in the lung, bone, or bone marrow. Less commonly, the site of first recurrence can be the breast in adolescent females or the liver.[3]

The following studies reported on the prognostic factors associated with progressive or recurrent 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.[4][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 (RT).[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 RT.[5]
  • 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 RT.[6][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) RT, 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.[7]
  • 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 RT. 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%.[8][Level of evidence: 3iiA]
  • A single-institution, retrospective review identified 23 patients with central nervous system (CNS) relapse after initial treatment for rhabdomyosarcoma.[9][Level of evidence: 3iiA] High-risk features at initial presentation included 16 alveolar patients, 13 Stage 4 patients, and 13 patients with primary tumor in parameningeal locations. All of the patients died. Twenty-one patients died of CNS disease and two died of metastatic disease at other sites. Median survival post-CNS relapse was 5 months (range, 0.1–49 months).

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.[10,11] Some survivors have also been reported after surgical removal of only one or a few metastases in the lung.[10] A review of 108 Italian children with bladder or prostate tumors who did not achieve tumor eradication after chemotherapy with or without RT found that only two factors correlated with inability to achieve progression-free survival (PFS) at 5 or more years: initial histology showing undifferentiated sarcoma (P = .008) and diameter of the surgically removed tumor exceeding 5 cm. Positive tumor margins at the salvage operation did not predict ultimate failure.[12][Level of evidence: 3iiiDiii]
  2. RT. RT should be considered for patients with rhabdomyosarcoma who have not already received RT in the area of recurrence, or selectively for those who have received previous RT but for whom surgical excision is not possible. RT techniques may include the following: external beam in fractionated or hypofractionated courses (e.g., stereotactic body radiation therapy, cyberknife, or brachytherapy).
  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%).[13] 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.[13]
  2. Ifosfamide, carboplatin, and etoposide.[14,15]
  3. Cyclophosphamide/topotecan.[16]
  4. Topotecan, carboplatin, cyclophosphamide, and etoposide.[17]
    1. In a 2018 Italian study, 38 patients with recurrent or refractory rhabdomyosarcoma were treated with topotecan, carboplatin, cyclophosphamide, and etoposide.[17][Level of evidence: 3iiA]
      • Nine of 32 patients had a complete or partial response, but the 5-year OS rate was 17%, and the PFS rate was 14%.
  5. Single-agent vinorelbine.[18,19]
    • In one phase II trial, four of eleven patients with recurrent rhabdomyosarcoma responded to single-agent vinorelbine.[18]
    • In another trial, 6 of 12 young patients (aged 9–29 years) had a partial response.[19]
  6. Vinorelbine and cyclophosphamide.[20,21]
    1. In a pilot study, three of nine patients with rhabdomyosarcoma had an objective response.[20]
    2. In a phase II study in France (N = 50), children with recurrent or refractory rhabdomyosarcoma were treated with vinorelbine and low-dose oral cyclophosphamide.[21][Level of evidence: 3iiiDiv]
      • Four complete responses and 14 partial responses were observed, for an objective response rate of 36%.
  7. Gemcitabine and docetaxel.[22]
    • In a single institution trial, two patients (N = 5) with recurrent rhabdomyosarcoma achieved an objective response.[22]
  8. Sirolimus.[23]
  9. Topotecan, vincristine, and doxorubicin.[24][Level of evidence: 3iiiDiv]
  10. Vincristine, irinotecan, and temozolomide.[25-27]
    1. One of four patients with recurrent alveolar rhabdomyosarcoma had a complete radiographic response sustained for 27 weeks with no grade 3 or 4 toxicities.[25]; [26][Level of evidence: 3iiiDiii]
    2. A group of 15 patients with relapsed rhabdomyosarcoma were treated with vincristine, irinotecan, and temozolomide. Many of the patients had received previous relapse therapy.[27][Level of evidence: 3iiiA]
      • There were no complete or partial remissions; 4 patients had stable disease, and 11 patients had progressive disease.
  11. Vincristine, irinotecan, doxorubicin, cyclophosphamide, etoposide, ifosfamide, and tirapazamine.[28]
    1. In 2019, the Children's Oncology Group (COG) reported three trials of patients with recurrent or refractory rhabdomyosarcoma with specific criteria for eligibility. Unfavorable-risk patients with measurable disease could undergo a 6-week phase II window study of VI. Patients with at least a partial response then received 44 weeks of assigned chemotherapy. Unfavorable-risk patients without measurable disease, no radiographic response, or refusal to go on window therapy received 31 weeks of multiagent chemotherapy plus tirapazamine.[28][Level of evidence: 3iiA]
      • Favorable-risk patients had a 3-year FFS rate of 79% and an OS rate of 84%.
      • Thirty patients with unfavorable-risk disease who were not treated with VI had a 3-year FFS rate of 21% and an OS rate of 39%.
  12. Irinotecan with or without vincristine and with or without temozolomide.[29-34]
    1. A COG prospective, randomized, up-front window trial, COG-ARST0121, compared 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.[33][Level of evidence: 1iiA]
      • 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.
      • At 1 year after initiation of treatment for recurrence, 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.
    2. In a European Soft Tissue Sarcoma Study Group (EpSSG) study, 120 patients with recurrent or refractory rhabdomyosarcoma were randomly assigned to receive either vincristine and irinotecan (VI) or vincristine, irinotecan, and temozolomide (VIT).[34]
      • The VIT arm was associated with higher response rates (44% vs. 31%), improved PFS (4.7 months vs. 3.2 months), improved OS (15 months vs. 10.3 months), and a higher incidence of grade 3 and grade 4 toxicities.
  13. Temsirolimus, irinotecan, and temozolomide.[35]
    1. In a phase I trial of these agents, four patients had rhabdomyosarcoma.[35]
      • The regimen was well tolerated.
      • One patient had a partial response, and another patient had stable disease.
  14. Temsirolimus, cyclophosphamide, and vinorelbine.[36]
    1. A COG randomized, phase II, selection-design study of patients with relapsed rhabdomyosarcoma compared bevacizumab with temsirolimus, both administered with cyclophosphamide and vinorelbine.[36]
      • The temsirolimus arm had a superior 6-month EFS (65%; 95% confidence interval [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%).

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.[37-39]

Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches because no standard agents have demonstrated clinically significant activity.

Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.

Treatment Options Under Clinical Evaluation for Recurrent Childhood Rhabdomyosarcoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

  • 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. A rhabdomyosarcoma stratum is open in the phase II portion of this trial.
  • 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.
  • ADVL1622 (NCT02867592) (Cabozantinib-S-Malate in Treating Younger Patients with Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors): This is an open-label, two-stage, phase II trial of cabozantinib in selective solid tumors, including rhabdomyosarcoma. Cabozantinib is an oral small molecule inhibitor of multiple tyrosine kinases including MET, VEGFR2, and RET, which are potential therapeutic targets in many pediatric and adult solid tumors.
  • ADVL1921 (NCT03709680) (Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors): This study will evaluate palbociclib in combination with chemotherapy (temozolomide and irinotecan) in children, adolescents, and young adults with recurrent or refractory solid tumors. The main purpose of this study is to evaluate the safety of palbociclib in combination with chemotherapy to estimate the maximum tolerated dose. Pharmacokinetics and efficacy of palbociclib in combination with chemotherapy will be evaluated.
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
  • New agents under clinical evaluation in phase I and phase II trials should be considered for relapsed patients.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

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  26. 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. [PubMed: 22735885]
  27. Setty BA, Stanek JR, Mascarenhas L, et al.: VIncristine, irinotecan, and temozolomide in children and adolescents with relapsed rhabdomyosarcoma. Pediatr Blood Cancer 65 (1): , 2018. [PMC free article: PMC7497851] [PubMed: 28748602]
  28. Mascarenhas L, Lyden ER, Breitfeld PP, et al.: Risk-based treatment for patients with first relapse or progression of rhabdomyosarcoma: A report from the Children's Oncology Group. Cancer 125 (15): 2602-2609, 2019. [PMC free article: PMC7069123] [PubMed: 31067356]
  29. Cosetti M, Wexler LH, Calleja E, et al.: Irinotecan for pediatric solid tumors: the Memorial Sloan-Kettering experience. J Pediatr Hematol Oncol 24 (2): 101-5, 2002. [PubMed: 11990694]
  30. 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]
  31. Vassal G, Couanet D, Stockdale E, et al.: Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group. J Clin Oncol 25 (4): 356-61, 2007. [PubMed: 17264330]
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Changes to This Summary (01/14/2020)

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.

This summary was reformatted.

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
  • Andrea A. Hayes-Jordan, MD, FACS, FAAP (University of North Carolina - Chapel Hill School of Medicine)
  • Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
  • Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
  • 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: https://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.

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Bookshelf ID: NBK65802PMID: 26389243

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