Continual improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. 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.
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.)
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. Males have a higher incidence of embryonal tumors, and blacks have a slightly higher incidence of alveolar tumors.
Incidence may depend on the histologic subtype of rhabdomyosarcoma, as follows:
Other less common primary sites include the trunk, chest wall, perineal/anal region, and abdomen, including the retroperitoneum and biliary tract.
Most cases of rhabdomyosarcoma occur sporadically, with no recognized predisposing risk factor, with the exception of the following:
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.
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.
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. Historical data show that adults fare less well than children (5-year overall survival [OS] rates, 27% ± 1.4% and 61% ± 1.4%, respectively; P < .0001).[28,29,30,31]
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.
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:[Level of evidence: 3iiA]
Two reports from the COG have documented inferior 5-year EFS rates in patients older than 10 years.[34,37] When compared with younger patients, this group of older patients was more likely to present with advanced-stage, large, and invasive alveolar tumors with nodal involvement arising in the extremity and paratesticular sites. Older patients experienced less myelosuppression and more peripheral nervous system toxicity, suggesting that dose modifications during therapy cannot account for the age-related differences in EFS.
Site of origin
Prognosis for childhood rhabdomyosarcoma varies according to the primary tumor site (refer to Table 1).
|Primary Site||Number of Patients||Survival at 5 Years (%)|
|a Patients treated on the ARST0331 study.|
|b Patients treated on Intergroup Rhabdomyosarcoma Studies III–IV.|
|c Pooled analysis of European and North American groups.|
|d Combined result from the Children's Oncology Group, German Cooperative Soft Tissue Sarcoma Study, Italian Cooperative Group, and International Society of Pediatric Oncology groups.|
|e Pooled analysis of European and North American groups.|
|f Patients treated on Intergroup Rhabdomyosarcoma Study III.|
|g Patients treated on Intergroup Rhabdomyosarcoma Studies I–IV.|
|Head and neck (nonparameningeal)b||164||83|
|Genitourinary (excluding bladder/prostate)b||158||89|
|Trunk, abdomen, perineum, etc.f||147||67|
Children with tumors 5 cm or less have improved survival compared with children with tumors larger than 5 cm. Both tumor volume and maximum tumor diameter are associated with outcome.[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. This was not confirmed by a COG study of patients with intermediate-risk rhabdomyosarcoma. This relationship requires prospective study to determine the therapeutic implications of the observation.
The extent of disease after the primary surgical procedure (i.e., the Surgical-pathologic Group, also called the Clinical Group) is correlated with outcome. 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).[5,48] Group I and Group II represent a minority of patients; approximately 50% of patients have unresectable Group III disease at time of diagnosis.
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%.
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.
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).
PAX3-FOXO1orPAX7-FOXO1gene 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.[55,56,57] 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. Comparable results were observed in another study; patients with PAX7-positive tumors and patients with fusion-negative tumors had similar outcomes.
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.[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:
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.[Level of evidence: 1iiDi]
Lymph node involvement at diagnosis
Lymph node involvement at diagnosis is seen in about 23% of patients with rhabdomyosarcoma and is associated with an inferior prognosis.[51,66] Clinical and/or imaging evaluation is performed before treatment and preoperatively; these findings are incorporated into the initial staging and grouping of a patient with rhabdomyosarcoma. 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.
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.[69,70,71,72]
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.; [Level of evidence: 3iiDi]; [Level of evidence: 3iiiA] However, an Italian study did find that patient response correlated with likelihood of survival.[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.[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.[77,78,79,80,81,82]
Response as judged by sequential functional imaging studies with fluorine F 18-fludeoxyglucose positron emission tomography (PET) may be an early indicator of outcome  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. 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.[Level of evidence: 3iiiDiii]
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. 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).
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.
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%). 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.
Approximately 30% of children with rhabdomyosarcoma have the alveolar subtype, when histology alone is used to determine subtype. An increased frequency of this subtype is noted in adolescents and in patients with primary sites involving the extremities, trunk, and perineum/perianal region. 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.[7,8,9] Patients without a fusion have outcomes that are similar to those for patients with embryonal rhabdomyosarcoma.[10,11,12]
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. 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%). 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. There are at least two distinct molecular subtypes of spindle cell/sclerosing rhabdomyosarcoma in pediatrics.
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.[16,17]
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.[7,18,19,20,21]
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.[3,26] Rhabdomyosarcoma with nonalveolar anaplastic morphology may be a presenting feature for children with Li-Fraumeni syndrome and germline TP53 mutations. 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).
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.
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.[30,31,32,33,34,35] 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.[21,28]
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.[24,25]BCOR and PIK3CA mutations and amplification of MYCN, MIR17HG, and CDK4 have also been described.
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. 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. 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.[14,37,38,39] Activating PIK3CA mutations are seen in about one-half of the cases, and 60% of these cases have pure sclerosing morphology. The presence of the MYOD1 mutation is associated with an increased risk of local and distant failure.[14,37,38] In one study that included 15 children with MYOD1-mutant tumors, the most common primary site was the head and neck region. 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.[11,12,21,40,41] 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.
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:
The European Pediatric Soft Tissue Sarcoma Study Group reviewed 367 patients enrolled in the CCLG-EPSSG-RMS-2005 (NCT00379457) study.[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.
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. The International Society of Paediatric Oncology Malignant Mesenchymal Tumour Group has confirmed this is a necessary approach. (Refer to the Regional and in-transit lymph nodes for extremity tumors section of this summary for more information.)
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.
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.
Staging of rhabdomyosarcoma is complex. The process includes the following steps:
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.[14,15]
Terms defining the TNM criteria are described in Table 2.
|T = primary tumor; N = regional lymph node; M = distant metastasis.|
|Favorable site||Orbit; nonparameningeal head and neck; genitourinary tract other than kidney, bladder, and prostate; biliary tract.|
|Unfavorable site||Any site other than a favorable site.|
|T1||Tumor confined to organ or tissue of origin (noninvasive).|
|T2||Tumor extension beyond the organ or tissue of origin (invasive).|
|a||Tumor ≤5 cm in maximum dimension.|
|b||Tumor >5 cm in maximum dimension.|
|N0||No clinical regional lymph node involvement.|
|N1||Clinical regional lymph node involvement.|
|NX||Regional lymph nodes not examined; no information.|
|M0||No metastatic disease.|
|Stage||Sites of Primary Tumor||T Stagea||Tumor Size||Regional Lymph Nodesa||Distant Metastasisa|
|a Refer to Table 2for the definitions of the TNM criteria.|
|1||Favorable sites||T1 or T2||Any size||N0 or N1 or NX||M0|
|2||Unfavorable sites||T1 or T2||a, ≤5 cm||N0 or NX||M0|
|3||Unfavorable sites||T1 or T2||a, ≤5 cm||N1||M0|
|b, >5 cm||N0 or N1 or NX|
|4||Any site||T1 or T2||Any size||N0 or N1 or NX||M1|
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.[16,17,18]
|I||Approximately 13%||Localized tumor, completely removed with microscopically clear margins and no regional lymph node involvement.|
|II||Approximately 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.|
|III||Approximately 48%||Localized tumor, incompletely removed with gross, residual disease after: (a) biopsy onlyor(b) subtotal resection.|
|IV||Approximately 18%||Distant metastases present at diagnosis. This category includes: (a) radiographically identified evidence of tumor spreador(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.[19,20] Treatment assignment is based on Risk Group, as shown in Table 5.
|Low risk||Embryonal||1||I, II, III (orbit only)|
|Intermediate risk||Embryonal||1||III (nonorbit)|
|4||IV (age <10 years)|
|Alveolar||1, 2, 3||I, II, III|
|Embryonal||4||IV (age ≥10 years)|
The most recent COG protocol uses fusion status, as opposed to histology, to define Risk Groups.
All children with rhabdomyosarcoma require multimodality therapy with systemic chemotherapy, in conjunction with either surgery, radiation therapy (RT), or both modalities to maximize local tumor control.[1,2,3] Surgical resection is performed before chemotherapy if it will not result in disfigurement, functional compromise, or organ dysfunction. If this is not possible, only an initial biopsy is performed.
Most patients (about 50%) have Group III (gross residual) disease; the remaining patients have Group I (about 15%), Group II (about 20%), and Group IV (about 15%) disease. After initial chemotherapy, Group III patients receive definitive RT for control of the primary tumor. Some patients with initially unresected tumors may undergo delayed primary excision to remove residual tumor before the initiation of RT. This is appropriate only if the delayed excision is deemed feasible with acceptable functional/cosmetic outcome and if a grossly complete resection is anticipated. If a delayed primary excision results in complete resection or microscopic residual disease, a modest reduction in RT could be utilized.
RT is given to clinically suspicious lymph nodes (detected by palpation or imaging) unless the suspicious lymph nodes are biopsied and shown to be free of rhabdomyosarcoma. RT is also administered to lymph node basins where a sentinel lymph node biopsy has identified microscopic disease.
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:
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. The overall impression is that survival for most patient subsets is superior with the use of early local therapy, including RT.[1,2,3]
Special Considerations for the Treatment of Children With Cancer
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 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:
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. 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.
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. 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.
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.[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). 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. 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. 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). 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.
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.
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.
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. 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.[Level of evidence: 3iiiDii]
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.
As with the surgical management of patients with rhabdomyosarcoma, recommendations for RT depend on the following:
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.[15,16,17,18,19,20]
Evidence (radiation delivery techniques):
The radiation doses according to Group, histology, and disease site for children with rhabdomyosarcoma are described in Table 6:
|N = regional lymph node.|
|Embryonal, fusion negative||No RT required.|
|FOXO1positive||36 Gy to involved (prechemotherapy) site.|
|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.|
|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 COGARST1431 [NCT02567435]) protocol.|
|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.|
In the COG ARST1431 (NCT02567435) study, risk group is in part determined by fusion status. The recommended dose of radiation therapy depends on the amount of residual disease, if any, after the initial primary surgical procedure and fusion status. For patients with fusion-positive rhabdomyosarcoma who have had an initial complete resection (group 1), radiation therapy with 36 Gy is recommended.
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. 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).[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. 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.
Thus, conventional RT remains the standard for treating patients who have rhabdomyosarcoma with gross residual disease.
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 [34,35,36,37,38,39] and selected bladder/prostate sites.[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.[35,41]; [Level of evidence: 3iiDii] Other sites, especially head and neck, have also been treated with brachytherapy.
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.
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. 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. 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.[46,47,48]
Delayed primary excision may allow for a radiation dose reduction and has been studied in select patients. 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.
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%. 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. This experience has been confirmed for children up to age 2 years.
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.[51,52,53,54,55,56] 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.[57,58,59]; [Level of evidence: 3iiiA]
Rhabdomyosarcomas of the orbit should not undergo exenteration, but biopsy is needed for diagnosis.[61,62] Biopsy is followed by chemotherapy and RT, with orbital exenteration reserved for the small number of patients with locally persistent or recurrent disease.[53,63] 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 investigators have shown that patients with embryonal rhabdomyosarcoma of the orbit who achieve a complete response to induction chemotherapy have improved local control following radiation therapy of 45 Gy compared with those patients who fail to achieve a complete response.[Level of evidence: 2Div] For those patients in whom a complete response has not been achieved with induction chemotherapy, 50.4 Gy is recommended by the investigators.
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.[Level of evidence: 2Di]
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.[54,65,66] 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. 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.
Evidence (timing of RT for nonorbital and cranial parameningeal tumors):
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.
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.[72,73]
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.; [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.
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.
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. Chemotherapy or delayed primary excision does not improve outcome over chemotherapy and RT.
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.[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.[Level of evidence: 3iiiA] Definitive RT and chemotherapy for Group III tumors resulted in 90% to 95% local control in the IRS-IV trial.
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.[79,80,81,82,83]; [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.
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.[82,86,87,88,89,90,91,92]
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.
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.
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). 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.[94,95,96,97]
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. Aggressive resections at diagnosis before chemotherapy are not necessary because rhabdomyosarcoma is very chemosensitive and radiosensitive.
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.
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).
Evidence (chemotherapy with or without RT followed by surgery):
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.
Evidence (chemotherapy, surgery, and RT):
Patients with rhabdomyosarcoma arising from tissue around the perineum or anus often present with advanced disease. These patients have a high likelihood of regional lymph node involvement, and about half of the tumors have alveolar histology. 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. When feasible and without unacceptable morbidity, removing all gross tumor before chemotherapy may improve the likelihood of cure; however, chemotherapy and RT remain standard of care. With the goal of organ preservation, patients with tumors of the perineum or anus are preferentially managed with chemotherapy and RT without aggressive surgery, as aggressive surgery may result in the loss of sphincter control. Very aggressive surgery is not indicated because of multiple critical structures that limit the ability to achieve negative margins near the anus and urethra.
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.
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). 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.[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.
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.[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.[Level of evidence: 3iiiDiii]
Paratesticular tumors have a relatively high incidence of lymphatic spread (26% in IRS-I and IRS-II), 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.[113,114] 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.[3,33,115] 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. 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.[108,113]
Evidence (lymph node sampling):
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. RT should be considered for patients whose nodes are biopsy positive.
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.[119,120]
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,[121,122] sometimes followed, when necessary, by a more limited surgical procedure such as partial cystectomy. 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).[123,124] 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%.[122,125,126]
In a prospective registry study of 19 patients (median age, 1.8 years at diagnosis; range, 0.5–5.0) who were treated with proton therapy, the 5-year OS and progression-free survival (PFS) rates were 76%. The 5-year local-control rate was 76%. Tumor size predicted the local-control rate, with 5-year local-control rates of 43% for patients whose tumors were larger than 5 cm versus 100% for patients whose tumors were 5 cm or smaller (P = .006). The four patients who relapsed all died.
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.[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.
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%.[Level of evidence: 3iiA]
Another alternative strategy in highly selected patients is to perform conservative surgery followed by brachytherapy at a specialized center.; [Level of evidence: 3iiDiii]; [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.[125,133,134] 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. 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.
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.
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. 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.[46,136,137][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.[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).[Level of evidence: 2Dii] Therefore, the COG-STS recommended that RT be administered to patients with residual viable vaginal tumor, beginning at week 12.[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.[136,138] 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. 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.[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. Alternatively, ovarian tissue preservation is under investigation and can be considered.
Unusual primary sites
Rhabdomyosarcoma occasionally arises in sites other than those previously discussed.
Patients with localized primary rhabdomyosarcoma of the brain can occasionally be cured using a combination of tumor excision, RT, and chemotherapy.[Level of evidence: 3iiiDiii]
Patients with laryngeal rhabdomyosarcoma will usually be treated with chemotherapy and RT after biopsy in an attempt to preserve the larynx.
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.
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.[Level of evidence: 3iiiDiii] Treatment with combination chemotherapy followed by removal of the residual mass or masses can sometimes be successful.
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):
All children with rhabdomyosarcoma should receive chemotherapy. The intensity and duration of the chemotherapy are dependent on the Risk Group assignment. (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.
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.)
|Tumor Site||Tumor Size||Surgical-pathologic Group||Nodes|
|N0 = absence of nodal spread.|
|Orbital||Any||I, II, III||N0|
Evidence (chemotherapy for low-risk Group patients):
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.)
|Tumor Site||Tumor Size||Surgical-pathologic Group||Nodes|
|N0 = absence of nodal spread; N1 = presence of regional nodal spread beyond the primary site.|
|Favorable (orbital or nonorbital)||Any||IIB, IIC, III||N0, N1|
|Unfavorable||>5 cm||I, II||N0, N1|
The COG-ARST0331 trial evaluated a refinement of therapy for two subsets of low-risk patients.
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):
The patients classified as high risk by the EpSSG were nonmetastatic, incompletely resected embryonal rhabdomyosarcoma at unfavorable sites, aged 10 years or older, or with a tumor larger than 5 cm, or both; embryonal rhabdomyosarcoma with nodal involvement; or alveolar rhabdomyosarcoma without nodal involvement. These patients would be classified as intermediate risk by the COG.
Patients received initial treatment with cycles of ifosfamide (6 g/m2), dactinomycin (1.5 mg/m2), and vincristine (1.5 mg/m2) for 7 weeks (IVA) followed by randomization to continue IVA or to continue IVA with the addition of doxorubicin (60 mg/m2). IVA represents a lower alkylating agent dose than the cyclophosphamide dose of 2.2 g/m2 used in COG rhabdomyosarcoma studies. Patients assessed to be in complete remission at the end of initial therapy were randomly assigned to either observation or the addition of six 4-week cycles of maintenance chemotherapy with vinorelbine (25 mg/m2) on days 1, 8, and 15 of each cycle with continuous daily cyclophosphamide (25 mg/m2 /day).
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.[162,163] 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. 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.
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.[Level of evidence: 3iiA]
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.[147,166,167] Two retrospective studies have examined patients who present with metastases limited to the lungs;[146,147] 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):
Analysis identified several adverse prognostic factors (Oberlin risk factors):
The EFS rate at 3 years depended on the number of adverse prognostic factors:[Level of evidence: 3iiiA]
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:
Results with VAC chemotherapy for Stage IV rhabdomyosarcoma in the North American experience are similar.
The following results were observed:
The following results were observed:
Other Therapeutic Approaches
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:
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.
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.
The following studies reported on the prognostic factors associated with progressive or recurrent disease:
Treatment Options for Progressive or Recurrent Childhood Rhabdomyosarcoma
The selection of further treatment depends on many factors, including the site(s) of progression or recurrence, previous treatment, and individual patient considerations.
Treatment options for progressive or recurrent childhood rhabdomyosarcoma include the following:
The following chemotherapy regimens have been used to treat progressive or recurrent rhabdomyosarcoma:
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.[39,40,41]
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 Progressive or 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:
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.
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.
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.
Editorial changes were made to this summary.
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.
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
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Rhabdomyosarcoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/soft-tissue-sarcoma/hp/rhabdomyosarcoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389243]
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Last Revised: 2020-12-07
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