General Information About Childhood Rhabdomyosarcoma

Continual improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[1,2,3] Between 1975 and 2017, the 5-year relative survival rate for patients with rhabdomyosarcoma increased from 53% to 71% for children younger than 15 years and from 30% to 52% for adolescents aged 15 to 19 years.[1,2] In more recent years, improvements in outcome have plateaued.

Childhood and adolescent cancer survivors require close monitoring because side effects of cancer and its therapy may persist or develop months to years later. For specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Incidence

Childhood rhabdomyosarcoma is a soft tissue malignant tumor of mesenchymal origin. It accounts for approximately 2.7% of cancer cases among children aged 0 to 14 years and 1.4% of the cases among adolescents and young adults aged 15 to 19 years.[2] The incidence is 4.6 cases per 1 million children younger than 20 years, which translates into about 350 new cases per year. Fifty percent of these cases are seen in the first decade of life.[2,4]

The 2020 World Health Organization classification distinguishes four histological subtypes of rhabdomyosarcoma, including embryonal, alveolar, spindle cell/sclerosing, and pleomorphic.[5] While these subtypes classify rhabdomyosarcoma into prognostically useful histological categories, FOXO1 gene fusions uniquely occur in alveolar histology tumors; however, not all tumors that have been classified as alveolar histology have a FOXO1 fusion. Molecular characterization has replaced histopathological assessment for treatment risk assignment. Male patients have a higher incidence of embryonal tumors, and Black patients have a slightly higher incidence of alveolar tumors.[4] For more information, see the sections on Cellular Classification for Childhood Rhabdomyosarcoma and Molecular Characteristics of Rhabdomyosarcoma.

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

• Embryonal: Patients with embryonal rhabdomyosarcoma are predominantly male (male-to-female ratio, 1.5). The peak incidence is in children between the ages of 0 and 4 years, with approximately 4 cases per 1 million children. The incidence rate is lower in adolescents, with approximately 1.5 cases per 1 million adolescents. This subtype constitutes 57% of patients in the Surveillance, Epidemiology, and End Results (SEER) Program 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]
• Spindle cell/sclerosing: Spindle cell and sclerosing rhabdomyosarcoma are considered in the same diagnostic category. This uncommon variant accounts for 3% to 10% of all cases.[5]
• Pleomorphic: Pleomorphic rhabdomyosarcoma is a high-grade pleomorphic sarcoma seen in adults. Childhood cases are considered to be rhabdomyosarcoma with diffuse anaplasia.[5]

Rhabdomyosarcoma may occur anywhere in the body. The most common primary sites include the following:[6,7]

• 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 usually have an alveolar histology.[8]

Other less common primary sites include the trunk, chest wall, perineal/anal region, and abdomen, including the retroperitoneum and biliary tract.[7]

Risk Factors

Most cases of rhabdomyosarcoma occur sporadically, with no recognized predisposing risk factor.

Predisposition factors reported for rhabdomyosarcoma include the following:

• Genetic factors:
  • Li-Fraumeni cancer susceptibility syndrome (with germline TP53 variants).[9,10,11]
  • DICER1 syndrome.[12,13]
  • Neurofibromatosis type I (NF1).[14,15]
  • Costello syndrome (with germline HRAS variants).[16,17,18,19]
  • 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]

The Children's Oncology Group (COG) performed retrospective exome sequencing on germline DNA to determine the prevalence of 63 autosomal dominant cancer-predisposing genes in 615 patients with newly diagnosed rhabdomyosarcoma.[25] They identified germline cancer-predisposition variants in 45 patients with rhabdomyosarcoma (7.3%; all FOXO1 fusion negative) across 15 autosomal dominant genes. Specifically, 73.3% of the predisposition variants were found in predisposition syndrome genes previously associated with pediatric rhabdomyosarcoma risk, such as Li-Fraumeni syndrome (TP53, n = 11) and NF1 (NF1, n = 9). Notably, five patients had well-described oncogenic missense variants in HRAS (p.G12V and p.G12S) associated with Costello syndrome, and two patients each had variants in DICER1 and CBL, respectively. Germline variants were more frequent in patients with embryonal rhabdomyosarcoma than in those with alveolar rhabdomyosarcoma (10% vs. 3%, P = .02), but all of the patients with alveolar rhabdomyosarcoma were FOXO1 negative, and no germline variants were identified in patients with FOXO1 translocations. Although patients with a cancer-predisposition variant tended to be younger at diagnosis (P = .00099), 40% of germline variants were identified in patients older than 3 years.

The COG reviewed the correlation between anaplastic histology and germline TP53 pathogenic variants in 239 patients with rhabdomyosarcoma. Among the 46 patients with anaplastic rhabdomyosarcoma, 11% (n = 5) carried a germline TP53 pathogenic variant, compared with 1% (n = 2) of the patients without anaplasia (P = .003). The rates of TP53 pathogenic variants in those with diffuse anaplasia and focal anaplasia were 9% (n = 3) and 17% (n = 2), respectively. Among the seven patients with TP53 pathogenic variants, 71% (5 of 7) had tumors with anaplastic histology.[26]

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.[6,7,27] 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 in patients who have unresectable disease, tumor in an unfavorable site at diagnosis, or metastatic disease at diagnosis.[28]

The prognosis for children or adolescents with rhabdomyosarcoma is related to many clinical and biological factors, including the following:

• Age.
• Site of origin.
• Tumor size.
• Resectability.
• Histopathological subtype.
• PAX3::FOXO1 or PAX7::FOXO1 gene fusion status.
• Metastases at diagnosis.
• Lymph node involvement at diagnosis.
• Biological characteristics.
• Response to therapy.
• Circulating tumor DNA and RNA.

Because treatment and prognosis partly depend on the histology and molecular characterization of the tumor, it is necessary that the tumor tissue be reviewed by expert pathologists with experience in the evaluation and diagnosis of tumors in children. Typically, accurate diagnosis requires additional molecular characterization. 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 than 1 year and older than 10 years fare less well. In Intergroup Rhabdomyosarcoma Study Group (IRSG) and COG 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. The 5-year overall survival (OS) rates were 76% for patients younger than 1 year, 87% for patients aged 1 to 9 years, and 76% for patients older than 10 years.[29] Historical data show that adults have fared less well than children (5-year OS rates, 27% ± 1.4% vs. 61% ± 1.4%; P < .0001).[30,31,32,33]

• Young age: Infants tend to do poorly, often because of treatment modifications to reduce toxicity. Typically, chemotherapy doses are reduced by 50% on the basis of reports that infants have higher death rates related to chemotherapy toxicity when compared with older patients; therefore, young patients may be underdosed.[34] In addition, infants younger than 1 year are less likely to receive radiation therapy for local control because of the high incidence of late effects in this age group.[27,35,36]

  The 5-year FFS rate was 67% for infants, compared with 81% in a matched group of older patients treated by the COG.[29,37] This inferior FFS rate was largely the result 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.[37]

  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; and 32 patients presented with alveolar rhabdomyosarcoma pathology. The following results were reported:[38][Level of evidence C1]

  • Of the 144 patients with localized disease, 129 had a complete response.
  • Fifty-one infants had a recurrence of their disease; 63% of patients with alveolar rhabdomyosarcoma had a relapse, and 28% of patients with embryonal rhabdomyosarcoma had a relapse.
  • The 5-year OS rates were 69% for patients with localized disease, 14% for patients with metastatic disease, and 41% for patients with relapsed disease.

  A retrospective analysis of five consecutive studies from the CWS group examined infants and older children with localized rhabdomyosarcoma of the female genitourinary tract.[39] Among 67 patients treated from 1981 to 2019, age of 12 months or younger at diagnosis was the only significant negative prognostic factor that influenced EFS.

  The European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) enrolled 490 children younger than 36 months in their prospective RMS2005 study. The study included 110 patients younger than 12 months and 380 patients aged 12 to 36 months. Chemotherapy was given according to the risk group. Radiation therapy (22% received brachytherapy) was administered to 33.6% of the infants and 63.5% of the children aged 12 to 36 months. The 5-year OS rate was 88.4% for the infants, which was significantly better than the 72.5% rate observed in children aged 12 to 36 months. The treatment protocol in this trial, which used an increased application of adequate local therapy, may have contributed to these improved outcomes.[40][Level of evidence B4]

  The EpSSG analyzed neonates with congenital rhabdomyosarcoma, which they defined as infants younger than 2 months at diagnosis who were enrolled in EpSSG trials.[41] Twenty-four patients with congenital rhabdomyosarcoma were registered. All patients had favorable histology and localized disease, except for one patient with PAX3::FOXO1 fusion–positive metastatic rhabdomyosarcoma. Three patients had VGLL2::CITED2 or VGLL2::NCOA2 fusions. Complete tumor resection was achieved in ten patients. No radiation therapy was given. Chemotherapy doses were adjusted to age and weight. Only two patients required further dose reduction for toxicity. The 5-year EFS rate was 75.0% (95% confidence interval [CI], 52.6%–87.9%), and the OS rate was 87.3% (95% CI, 65.6%–95.7%).

  An international consortium identified 40 infants with spindle cell rhabdomyosarcoma.[42] The 5-year EFS rate for these infants with localized disease was 86% (± 11%; 95% CI), and the OS rate was 91% (± 9%; 95% CI). These outcomes compare favorably with those of all infants with localized rhabdomyosarcoma, for whom the 5-year failure-free survival rates range from 42% to 72% and the 5-year OS rates range from 61% to 88%. This finding suggests that infants with congenital spindle cell rhabdomyosarcoma have a favorable outcome compared with infants with other subtypes of rhabdomyosarcoma.

• 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.[36,43]
• Adolescents: A report from the Associazione Italiana Ematologia Oncologia Pediatrica 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.[44]

  Two reports from the COG have documented inferior 5-year EFS rates in patients older than 10 years.[36,43] 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.

  Adolescent and young adult (AYA) patients were more likely to have worse survival outcomes than children.[45]

  • AYA patients were more likely to have metastatic tumors (61 of 257 [23.7%] vs. 197 of 1,720 [11.5%]; P < .0001), unfavorable histological subtypes (119 [46.3%] vs. 451 [26.2%]; P < .0001), tumors larger than 5 cm (177 [68.9%] vs. 891 [51.8%]; P < .0001), and regional lymph node involvement (109 [42.4%] vs. 339 [19.7%]; P < .0001) than children.
  • AYA patients had lower 5-year EFS rates (52.6% [95% CI, 46.3%–58.6%] vs. 67.8% [95% CI, 65.5%–70.0%]; P < .0001) and OS rates (57.1% [95% CI, 50.4%–63.1%] vs. 77.9% [95% CI, 75.8%–79.8%]; P < .0001) than children.
  • The multivariable analysis confirmed the inferior prognosis of patients aged 15 to 21 years (hazard ratio [HR], 1.48 [95% CI, 1.20–1.83; P = .0002] for poorer EFS; HR, 1.73 [95% CI, 1.37–2.19; P < .0001] for poorer OS).
• 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.[30]

Site of origin

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

Tumor size

Children with tumors 5 cm or smaller have improved survival, compared with children with tumors larger than 5 cm.[6] Both tumor volume and maximum tumor diameter are associated with outcome.[53][Level of evidence C1]

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.[54] This was not confirmed by a COG study of patients with intermediate-risk rhabdomyosarcoma.[55] 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.[6] 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).[6,56] Groups I and II represent a minority of patients; approximately 50% of patients have unresectable Group III disease at time of diagnosis.[6]

Resectability without functional impairment is related to the tumor's initial size and site 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%.[57] Two intermediate-risk COG rhabdomyosarcoma studies (D9803 and ARST0531 [NCT00354835]) were pooled to assess the benefit of delayed primary excision. In the D9803 study, local control with radiation therapy after either a partial or complete excision was completed at week 12. In the ARST0531 study, radiation was administered upfront at week 4. Patients with bladder or prostate rhabdomyosarcoma who received a delayed primary excision had no difference in survival, whereas patients with extremity rhabdomyosarcoma or nonbladder/nonprostate nonextremity rhabdomyosarcoma had an improved OS with delayed primary excision. Delayed primary excision strategy with a reduction in radiation dose resulted in superior OS for those sites.[58,59]

Histopathological subtype

The alveolar subtype of childhood rhabdomyosarcoma 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). It 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).[60]
• A statistically significant difference in 5-year survival by histopathological subtype (82% for embryonal rhabdomyosarcoma vs. 65% for alveolar rhabdomyosarcoma) was noted when 1,258 IRS-III and IRS-IV patients with rhabdomyosarcoma were analyzed.[61]
• In the IRS-III study, the 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.[6]
• Patients with alveolar rhabdomyosarcoma who have regional lymph node involvement have significantly worse outcomes than patients who do not have regional lymph node involvement (5-year FFS rates, 43% vs. 73%).[62]
• Local-control rates after radiation therapy are similar among patients with alveolar and embryonal tumors. However, patients who present with tumors 5 cm or larger have a significantly higher local failure rate.[63]

Anaplasia has been observed in 13% of embryonal rhabdomyosarcoma cases, with some studies suggesting the presence of anaplasia adversely influenced clinical outcome in patients with intermediate-risk disease. However, anaplasia has not been shown to be an independent prognostic variable.[64,65]

PAX3::FOXO1orPAX7::FOXO1gene fusion status

Approximately 80% of rhabdomyosarcoma cases morphologically defined as alveolar rhabdomyosarcoma express a FOXO1 fusion. FOXO1 gene fusions occur only in alveolar histology tumors.[66] Several retrospective studies found that fusion status is an independent prognostic factor. Patients with translocation-negative alveolar rhabdomyosarcoma have tumors with genetic and molecular profiles and outcomes similar to patients with embryonal rhabdomyosarcoma, and they fare better than patients with fusion-positive alveolar rhabdomyosarcoma.[67,68] Early retrospective studies relied on convenience samples of available tumor tissue.[67,68] A subsequent prospective study from the Soft Tissue Sarcoma Committee of the COG that examined 434 cases of intermediate-risk rhabdomyosarcoma treated on a single intermediate protocol (D9803) confirmed these observations.[69] Analysis of 38 patients enrolled in the COG D9802 (NCT00003955) low-risk study determined that fusion-positive, low-risk patients should be treated as intermediate risk.[70]

The specific fusion partner may have prognostic impact. In a COG study, fusion-positive patients with Stage 2 or 3, Group III, and PAX3-positive tumors had a lower EFS rate (54%) than those with PAX7-positive tumors (65%). Both fusion-positive groups did worse than those with embryonal rhabdomyosarcoma (EFS rate, 77%; P < .001). Patients with alveolar rhabdomyosarcoma and PAX3 fusions had a poorer OS rate (64%) than patients with alveolar rhabdomyosarcoma and PAX7 fusions (87%), patients with alveolar rhabdomyosarcoma who were fusion negative (89%), and patients with embryonal rhabdomyosarcoma (82%; P = .006).[69] Comparable results were observed in the U.K. study; patients with PAX7-positive tumors and patients with fusion-negative tumors had similar outcomes.[71]

Using data from six consecutive COG studies, a retrospective analysis of 1,727 patients with rhabdomyosarcoma refined the risk stratification for childhood rhabdomyosarcoma. The study reported that after metastatic status, FOXO1 status was the most important prognostic factor and improved the risk stratification of patients with localized rhabdomyosarcoma.[68]

The COG performed a retrospective analysis of 269 patients with confirmed FOXO1 fusion–positive rhabdomyosarcoma who were enrolled in three completed clinical trials for localized rhabdomyosarcoma.[72] The estimated 4-year EFS rate was 53% (95% CI, 47%–59%), and the OS rate was 69% (95% CI, 63%–74%). Multivariate analysis identified older age (≥10 years) and larger tumor size (>5 cm) as independent, adverse prognostic factors for EFS within this population. Patients who had both of these adverse features experienced substantially inferior outcomes.

An EpSSG study evaluated the role of clinical factors together with FOXO1 fusion status in patients with nonmetastatic rhabdomyosarcoma, using data from the EpSSG RMS2005 study. The multivariable analysis of 1,661 evaluable patients retained five prognostic variables: age at diagnosis, tumor size, primary site, IRS Group, and FOXO1 status. A nomogram was created, stratifying patients into four risk groups. The 5-year EFS rates were 94.1% for patients in the low-risk group, 78.4% for patients in the intermediate-risk group, 65.2% for patients in the high-risk group, and 52.1% for patients in the very high-risk group.[73]

These studies demonstrated that fusion status was a better predictor of outcome than histology. Similar conclusions were reached in a retrospective study of three consecutive trials in the United Kingdom. Fusion status has now been incorporated into the risk stratification of patients in the current COG ARST1431 (NCT02567435) study for patients with intermediate-risk rhabdomyosarcoma, in subsequent COG trials, and in the new international EpSSG trial.[73] 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.[74][Level of evidence C1]

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). Patients with localized alveolar histology and regional node disease have a similar prognosis as patients with a single site of metastatic disease, provided that the regional disease is treated with radiation therapy.[62]
• Age at diagnosis (<10 years for children with embryonal rhabdomyosarcoma).
• The site of primary disease. Patients with metastatic genitourinary (nonbladder, nonprostate) primary tumors have a more favorable outcome than patients with metastatic disease from other primary sites.[75]
• The number of metastatic sites.[76,77,78,79]

The COG performed a retrospective analysis of 179 patients who were diagnosed with rhabdomyosarcoma that was metastatic to the bone marrow. These patients were enrolled in one of four COG rhabdomyosarcoma clinical trials (D9802, D9803, ARST0431, and ARST08P1) between 1997 and 2013.[80] Patients were a median age of 14.8 years and 58% were male. Alveolar histology was the predominant type (76%), the extremity was the most common primary site (32%), and most patients had metastatic disease to additional sites (87%). The 3-year EFS rate was 9.4%, and the 5-year EFS rate was 8.2%. The 3-year OS rate was 26.1%, and the 5-year OS rate was 12.6%.

The COG performed a retrospective review of patients enrolled in high-risk protocols for rhabdomyosarcoma. FOXO1 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.[81][Level of evidence B1]

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.[61,82] 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. The updated TNM staging defines clinical node involvement as larger than 1 cm.[83]

Pathological assessment of nodal disease is determined by biopsy and incorporated in the Surgical/Pathologic Clinical Group classification. Core-needle or open biopsy of clinically enlarged nodes is appropriate to confirm the presence of disease. Approximately 25% of enlarged nodes will be pathologically negative. Suspicious nodes are sampled surgically with open biopsy, preferred to needle aspiration, although needle aspiration may occasionally be appropriate. Pathological evaluation of clinically uninvolved nodes is site specific. In COG studies, it is required for extremity sites and for boys older than 10 years with paratesticular primary tumors.[84] Given the poorer outcomes, pathological node evaluation is required for patients with fusion-positive disease in current European and North American clinical trials.

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.[85]

In the extremities and select truncal sites, sentinel lymph node evaluation is a more accurate form of diagnosis than 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.[86,87,88,89] Lymph node removal does not improve outcome, and it is useful for staging but not treatment.

The EpSSG performed a retrospective analysis of 109 patients with rhabdomyosarcoma with extremity primary tumors distal to the elbow or knee who were treated in the EpSSG RMS-2005 (NCT00379457) trial (2005–2016).[90] Thirty-seven of 109 patients (34%) had lymph node metastases at diagnosis. Of the 37 patients, 19 (51%) had in-transit metastases (ITM), especially in lower extremity rhabdomyosarcoma. The 5-year EFS rates were 88.9% for patients with ITM, 21.4% for patients with proximal lymph node involvement, and 20% for combined proximal lymph node involvement and ITM (P = .01). The 5-year OS rates were 100% for patients with ITM, 25.2% for patients with proximal lymph node involvement, and 15% for patients with combined proximal lymph node involvement and ITM (P =. 003). The authors concluded that popliteal and epitrochlear nodes should be considered as true (distal) regional nodes, instead of ITM. The authors recommended biopsy of these nodes, especially for distal extremity rhabdomyosarcoma of the lower limb.

The EpSSG reported a retrospective analysis of 1,294 children with embryonal rhabdomyosarcoma enrolled in the RMS-2005 protocol.[91] Of these patients, 143 had nodal involvement (N1). Patients with N1 disease were older and presented with tumors of unfavorable size, invasiveness, site, and resectability. Unlike alveolar rhabdomyosarcoma, nodal involvement was more frequent in the head and neck area and rare in extremity sites. The 5-year EFS rate was 75.5%, and the OS rate was 86.3% for patients with N0 disease. The 5-year EFS rate was 65.2%, and the OS rate was 70.7% for patients with N1 disease. Nodal involvement and the result of surgery at diagnosis (Intergroup Rhabdomyosarcoma Study group) were independent prognostic factors on multivariate analysis. Investigators concluded that regional nodal involvement is an independent prognostic factor in patients with embryonal rhabdomyosarcoma; therefore, it is appropriate to include this population in the high-risk category.

Biological characteristics

For more information, see the Molecular Characteristics of Rhabdomyosarcoma section.

Response to therapy

It is unlikely that response to induction chemotherapy or best tumor response during therapy, assessed by anatomic imaging, correlates with the likelihood of survival in patients with rhabdomyosarcoma. This finding was based on the IRSG, COG, and International Society of Pediatric Oncology (SIOP) studies that found no association.[92,93]; [94][Level of evidence C2]; [95][Level of evidence C1] However, an Italian study did find that patient response correlated with likelihood of survival.[53][Level of evidence C1] 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.[96][Level of evidence C1] The 5-year survival rate 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. Thus the situation is not as clear as the COG data suggest.[97,98,99,100,101,102]

Response as judged by sequential functional imaging studies with fluorine F 18-fludeoxyglucose positron emission tomography (18F-FDG PET) may be an early indicator of outcome [103] 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.[103] 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. The COG evaluated the relationship between complete metabolic response, as assessed by 18F-FDG PET imaging, and EFS in patients with intermediate- or high-risk rhabdomyosarcoma.[104][Level of evidence B4] The maximum standard uptake values (SUVmax) at study entry did not correlate with EFS for intermediate-risk (P = .32) or high-risk (P = .86) patients. Compared with patients who did not achieve a complete metabolic response, EFS was not superior for intermediate-risk patients who achieved a complete metabolic response at weeks 4 (P = .66) or 15 (P = .46), or for high-risk patients who achieved a complete metabolic response at weeks 6 (P = .75) or 19 (P = .28). Change in SUVmax at weeks 4 (P = .21) or 15 (P = .91) for intermediate-risk patients and at weeks 6 (P = .75) or 19 (P = .61) for high-risk patients did not correlate with EFS.

PET scans have been shown to be useful in understanding patterns of spread, particularly in patients with extremity disease.[105][Level of evidence C2]

Circulating tumor DNA (ctDNA) and RNA

A retrospective study of 99 children with rhabdomyosarcoma used reverse transcription–polymerase chain reaction to analyze an 11-gene panel in peripheral blood and bone marrow samples at the time of initial diagnosis.[106] The 5-year EFS rate was 35.5% (95% CI, 17.5%–53.5%) for the 33 patients who were RNA positive, compared with 88.0% (95% CI, 78.9%–97.2%) for the 66 patients who were RNA negative (P < .0001). The predictive power of the assay was maintained in a multivariate analysis, which included the usual clinical characteristics that correlate with prognosis such as the presence of metastatic disease. These investigators also studied the diagnostic potential of ctDNA in 57 patients enrolled in the EpSSG RMS-2005 (NCT00379457) study. ctDNA was detected using both shallow whole-genome sequencing (WGS) and cell-free reduced representation bisulfite sequencing (cfRRBS). Of the 25 samples tested, 21 were correctly classified as embryonal histology by cfRRBS. The presence of methylated RASSF1A correlated with a poor outcome.[107]

The COG analyzed ctDNA in 124 patients with newly diagnosed, intermediate-risk rhabdomyosarcoma from the COG biorepository, which included 75 patients with fusion-negative rhabdomyosarcoma and 49 patients with fusion-positive rhabdomyosarcoma.[108] Ultralow passage WGS was used to detect copy number alterations. Rhabdo-Seq, a new custom sequencing assay, was used to detect rearrangements and single-nucleotide variants (SNVs).

• The authors reported that ultralow passage WGS was a method that could detect ctDNA in all patients with fusion-negative rhabdomyosarcoma. ctDNA was detected in 13 of 75 serum samples (17%).
• However, the use of Rhabdo-Seq in fusion-negative rhabdomyosarcoma samples also identified SNVs, such as the L122R variant in the MYOD1 gene. This variant was previously associated with a poor prognosis.
• Identification of pathognomonic translocations between PAX3 or PAX7 and FOXO1 by Rhabdo-Seq was the best method for measuring ctDNA in fusion-positive rhabdomyosarcoma tumors. It detected ctDNA in 27 of 49 cases (55%).
• Patients with fusion-negative rhabdomyosarcoma with detectable ctDNA at diagnosis had significantly worse outcomes than patients without detectable ctDNA (EFS rates, 33.3% vs. 68.9%; P = .0028; OS rates, 33.3% vs. 83.2%; P < .0001).
• Patients with fusion-positive rhabdomyosarcoma with detectable ctDNA at diagnosis had significantly worse outcomes than patients without detectable ctDNA (EFS rates, 37% vs. 70%; P = .045; OS rates, 39.2% vs. 75%; P = .023).
• In a multivariate analysis, ctDNA was independently associated with poor prognoses in patients with fusion-negative rhabdomyosarcoma but not in the smaller cohort of patients with fusion-positive rhabdomyosarcoma.

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107. Lak NSM, van Zogchel LMJ, Zappeij-Kannegieter L, et al.: Cell-Free DNA as a Diagnostic and Prognostic Biomarker in Pediatric Rhabdomyosarcoma. JCO Precis Oncol 7: e2200113, 2023.
108. Abbou S, Klega K, Tsuji J, et al.: Circulating Tumor DNA Is Prognostic in Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol 41 (13): 2382-2393, 2023.

Cellular Classification for Childhood Rhabdomyosarcoma

Histological Subtypes

The 5th edition of the World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone recognizes the following four categories of rhabdomyosarcoma:[1]

• Embryonal rhabdomyosarcoma.
• Alveolar rhabdomyosarcoma.
• Spindle cell/sclerosing rhabdomyosarcoma.
• Pleomorphic rhabdomyosarcoma.

Embryonal rhabdomyosarcoma

The embryonal subtype, which includes classic, dense, and botryoid variants, is the most frequently observed subtype in children, accounting for 70% to 75% of childhood rhabdomyosarcomas.[1,2] 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, with some studies suggesting the presence of anaplasia adversely influenced clinical outcome in patients with intermediate-risk disease. However, anaplasia has not been shown to be an independent prognostic variable.[3,4]

Botryoid tumors, which represent about 10% of all rhabdomyosarcoma cases, 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 and 5th editions) and the Children's Oncology Group (COG) eliminated botryoid rhabdomyosarcoma as a separate entity, with these cases classified as typical embryonal rhabdomyosarcoma.[1,5]

A COG study of 2,192 children with embryonal rhabdomyosarcoma (including botryoid and spindle cell variants) enrolled in clinical trials showed improved event-free survival (EFS) rates for patients with botryoid tumors (80%; 95% confidence interval [CI], 74%–84%), compared with typical embryonal rhabdomyosarcoma (73%; 95% CI, 71%–75%).[6] However, after adjusting for primary site, resection, and metastatic status, there was no difference in EFS by histological subtype. In this COG report, botryoid tumors accounted for 14% of intermediate-risk patients and 15% of low-risk patients. The botryoid histology retained prognostic significance in only a small proportion of patients with low-risk head and neck tumors, who are known to have excellent outcomes. For these reasons, the COG concluded that the addition of this histological classification of rhabdomyosarcoma has limited clinical utility and endorsed the recommendations of the WHO to remove this subtype from the current COG pathology classification.

One study analyzed the clinical and variant spectrum of 24 pediatric fusion-negative rhabdomyosarcoma tumors with high levels of myogenic differentiation. The analysis revealed that most tumors arose in the head and neck or genitourinary region. The overall survival rate was 100% for these patients (median follow-up, 4.6 years).[7]

Alveolar rhabdomyosarcoma

Approximately 20% to 25% of children with rhabdomyosarcoma have the alveolar subtype, when histology alone is used to determine subtype.[1] An increased frequency of this subtype is noted in adolescents and in patients with primary sites involving the extremities, trunk, and perineum/perianal region.[2] Eighty percent of patients with alveolar histology tumors will have one of two gene fusions, PAX3 on chromosome 2 or PAX7 on chromosome 1, with the FOXO1 gene on chromosome 13.[8,9,10] Patients without a fusion have outcomes that are similar to those for patients with embryonal rhabdomyosarcoma.[11,12,13]

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.[5] The 5th edition of the WHO Classification of Tumors of Soft Tissue and Bone continues to identify this separate subtype.[1] The spindle cell variant of embryonal rhabdomyosarcoma is most frequently observed at the paratesticular site.[6,14]

A COG study of 2,192 children with embryonal rhabdomyosarcoma (including botryoid and spindle cell variants) and enrolled in clinical trials showed improved EFS rates for patients with spindle cell rhabdomyosarcoma (83%; 95% CI, 77%–87%) compared with typical embryonal rhabdomyosarcoma (73%; 95% CI, 71%–75%).[6] 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 rate of 28% (compared with >70% 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 children:

• One subtype affects patients in their first year of life, with a median age at presentation of 3 months. The tumors usually arise in the trunk and morphologically resemble infantile fibrosarcoma. This variant is characterized by fusions involving the VGLL2 gene with the CITED2 or NCOA2 genes. In a series of six patients with long-term follow-up data, two patients developed a local recurrence, but all were alive at a median of 7 years.[15,16] For more information on spindle cell/sclerosing histology, see the Molecular Characteristics of Rhabdomyosarcoma section.
• Another subtype is characterized by MYOD1 (p.L122R) variants, and about one-third of this subset have coexistent PIK3CA variants.[17] These tumors can affect children, adolescents, and adults. They more frequently arise in the head and neck region and are characterized by an aggressive clinical course. In one series, 10 of 12 pediatric patients with follow-up data died of disease.[17]

Pleomorphic rhabdomyosarcoma

Pleomorphic rhabdomyosarcoma occurs in adults in their sixth and seventh decades, most commonly involves the extremities, and is associated with a poor prognosis. This histological variant is extremely rare and not well characterized in the pediatric population.[18,19] In children, tumors with extensive pleomorphism are considered anaplastic embryonal rhabdomyosarcoma.[1]

Machine learning of rhabdomyosarcoma histopathology can potentially provide predictive models for identifying the histological subtypes of rhabdomyosarcoma.[20,21] Digital whole-slide hematoxylin and eosin (H&E) images were collected from a cohort of 321 patients with rhabdomyosarcoma enrolled in COG trials from 1998 to 2017. These images were fed into deep learning convolutional neural networks (CNNs) to learn features associated with driver variants and patient outcomes.[22]

• The trained CNNs accurately classified alveolar rhabdomyosarcoma (subtype associated with PAX3 or PAX7 fused with FOXO1) with a receiver operating characteristic (ROC) curve of 0.85.
• CNN models identified tumors with RAS pathway variants with an ROC of 0.67. These models also identified high-risk variants in MYOD1 or TP53 with an ROC of 0.97 and 0.63, respectively.
• CNN models were superior at predicting EFS and OS when compared with current molecular–clinical risk stratification models.

Molecular Characteristics of Rhabdomyosarcoma

Genomics of rhabdomyosarcoma

The four histological categories recognized in the 5th edition of the World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone have distinctive genomic alterations and are briefly summarized below.[1,2,23]

• Embryonal rhabdosarcoma: Characterized by loss of heterozygosity at 11p15 and by a high frequency of variants in genes in the RAS pathway. For the purposes of this section, patients with embryonal rhabdomyosarcoma are considered negative for PAX3::FOXO1 and PAX7::FOXO1 gene fusions (i.e., fusion-negative rhabdomyosarcoma).
• Alveolar rhabdomyosarcoma: Characterized by gene fusions involving FOXO1 with either PAX3 or PAX7 (i.e., FOXO1 fusion–positive rhabdomyosarcoma). Cases with alveolar rhabdomyosarcoma histology without FOXO1 gene fusions have clinical behavior, gene alteration patterns, and transcriptomic profiles like cases with embryonal rhabdomyosarcoma. Therefore, the discussion below focuses only on alveolar rhabdomyosarcoma with FOXO1 gene fusions.[12,13,24,25,26]
• Spindle cell/sclerosing rhabdomyosarcoma: Characterized by variants of MYOD1 in older patients and by VGLL2 and NCOA2 gene rearrangements in young children.
• Pleomorphic rhabdomyosarcoma: Characterized by complex karyotypes with numerical and unbalanced structural changes that are indistinguishable from those of undifferentiated pleomorphic sarcomas.

The distribution of gene variants and gene amplifications (for CDK4 and MYCN) differs between patients with embryonal histology lacking a PAX::FOXO1 gene fusion (fusion-negative rhabdomyosarcoma) and patients with PAX::FOXO1 gene fusions (fusion-positive rhabdomyosarcoma). See Table 2 below and the text that follows. These frequencies are derived from a combined cohort of the Children's Oncology Group (COG) and United Kingdom rhabdomyosarcoma patients (n = 641).[27]

Details of the genomic alterations that predominate within each of the WHO histological categories are as follows.

1. Fusion-negative rhabdomyosarcoma (embryonal histology): Embryonal rhabdomyosarcoma tumors often show loss of heterozygosity at 11p15 and gains on chromosome 8.[9,28,29,30] Embryonal tumors have a higher background variant rate and a higher single-nucleotide variant rate than do alveolar rhabdomyosarcoma tumors, and the number of somatic variants increases with older age at diagnosis.[30,31] The most common recurring variants include those in the RAS pathway (e.g., NRAS, KRAS, HRAS, and NF1), which together are observed in approximately one-half of cases.[27] Variants in NRAS are the most frequent RAS pathway gene variants beyond infancy, while variants in HRAS predominate during infancy.[27] The presence of a RAS variant does not confer prognostic significance.

   Among the RAS pathway genes, germline variants in NF1 and HRAS predispose to rhabdomyosarcoma. In a study of 615 children with rhabdomyosarcoma, 347 had tumors with embryonal histology. Of these, nine patients had NF1 germline variants, and five patients had HRAS germline variants, representing 2.6% and 1.4% of embryonal histology cases, respectively.[32]

   Other genes with recurring variants in fusion-negative rhabdomyosarcoma tumors include FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR, all of which are present in fewer than 15% of cases.[27,30,31]

   TP53 variants: TP53 variants are observed in 10% to 15% of patients with fusion-negative rhabdomyosarcoma and occur less commonly (about 4%) in patients with alveolar rhabdomyosarcoma.[27] In other childhood cancers (e.g., Wilms tumor), TP53 variants are associated with anaplastic histology,[33] and the same is true for embryonal rhabdomyosarcoma. In a study of 146 rhabdomyosarcoma patients with known TP53 status, approximately two-thirds of tumors with TP53 variants showed anaplasia (69%), but only one-quarter of tumors with anaplasia had TP53 variants.[4]

   The presence of TP53 variants was associated with reduced EFS in both nonrisk-stratified and risk-stratified analyses for both a COG and a U.K. rhabdomyosarcoma cohort.[27] The poor prognosis associated with TP53 variants was observed for both embryonal and alveolar patients. Based on these results, the COG plans to consider TP53 variant as a high-risk defining characteristic in its upcoming trials.[34]

   Rhabdomyosarcoma is one of the childhood cancers associated with Li-Fraumeni syndrome. In a study of 614 pediatric patients with rhabdomyosarcoma, 11 patients (1.7%) had TP53 germline variants. Variants were less common in patients with alveolar histology (0.6%), compared with patients with nonalveolar histologies (2.2%).[32] Rhabdomyosarcoma with nonalveolar anaplastic morphology may be a presenting feature for children with Li-Fraumeni syndrome and germline TP53 variants.[35]

   • Among eight consecutively presenting children with rhabdomyosarcoma and TP53 germline variants, all showed anaplastic morphology. Among an additional seven children with anaplastic rhabdomyosarcoma and unknown TP53 germline variant status, three of the seven children had functionally relevant TP53 germline variants. The median age at diagnosis of the 11 children with TP53 germline variant status was 40 months (range, 19–67 months).[35]
   • In another series, 26 of 31 patients with germline TP53 variants had tumors with embryonal histology. Of the 16 tumors that were submitted for central pathology review, 12 had focal or diffuse anaplasia. The median age of patients in this group was 2.3 years.[36]

   DICER1 variants in embryonal rhabdomyosarcoma: DICER1 variants are observed in a small subset of patients with embryonal rhabdomyosarcoma, most commonly arising in tumors of the female genitourinary tract.[27] More specifically, most cases of cervical embryonal rhabdomyosarcoma,[37,38,39] which most commonly occurs in adolescents and young adults,[40,41] have DICER1 variants. In contrast, DICER1 variants are rarely observed in patients with vaginal primary sites, an entity occurring primarily in girls younger than 2 or 3 years.[38,40]DICER1 variants are also common in embryonal rhabdomyosarcoma arising in the uterine corpus, but this presentation is primarily observed in adults.[38,42] Cervical rhabdomyosarcoma generally shows a sarcoma botryoides histological pattern, and many cases show areas of cartilaginous differentiation, a feature also observed in other tumor types with DICER1 variants.[40,41,43] In support of the distinctive biology of embryonal rhabdomyosarcoma with DICER1 variants, these cases have a DNA methylation pattern that is distinctive from that of other embryonal rhabdomyosarcoma cases.[39] A diagnosis of cervical rhabdomyosarcoma is an indication for genetic testing for DICER1 syndrome.[38,44]

2. Fusion-positive rhabdomyosarcoma (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)).[8,9,10] Other rare fusions include PAX3::NCOA1 and PAX3::INO80D.[30] Translocations involving the PAX3 gene occur in approximately 60% of alveolar rhabdomyosarcoma cases, while the PAX7 gene appears to be involved in about 20% of cases.[8] Patients with solid-variant alveolar histology have a lower incidence of PAX::FOXO1 gene fusions than do patients showing classical alveolar histology.[45] 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 EFS rates than those associated with PAX3 gene rearrangements.[46,47,48,49,50,51] Patients with alveolar histology and the PAX3 gene are older and have a higher incidence of invasive tumor (T2). Around 20% of cases showing alveolar histology have no detectable PAX gene translocation.[25,45] These patients have clinical behaviors, gene alteration patterns, and transcriptomic profiles that align with patients who have embryonal rhabdomyosarcoma and are now classified together with embryonal rhabdomyosarcoma, as fusion-negative rhabdomyosarcoma.[12,13,24,25,26]

   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.[52]

   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.[30,31] The most frequently observed alterations in fusion-positive tumors are focal amplification of CDK4 (13%) or MYCN (10%), with small numbers of patients having recurring mutations in other genes (e.g., BCOR, 6%; NF1, 4%; TP53, 4%; and PIK3CA, 2%).[27]TP53 mutations in alveolar rhabdomyosarcoma appear to connote a high risk of treatment failure.[27]

3. Spindle cell/sclerosing histology: Spindle cell/sclerosing rhabdomyosarcoma has been proposed as a separate entity in the WHO Classification of Tumors of Soft Tissue and Bone.[53] Within the spindle cell/sclerosing rhabdomyosarcoma category, several entities have distinctive molecular and clinical characteristics, described below.

   Congenital/infantile spindle cell rhabdomyosarcoma: Several reports have described cases of congenital or infantile spindle cell rhabdomyosarcoma with gene fusions involving VGLL2 and NCOA2 (e.g., VGLL2::CITED2, TEAD1::NCOA2, VGLL2::NCOA2, SRF::NCOA2).[15,54]

   • 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 there were no paratesticular tumors. 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.[15] Three patients (27%) harbored different NCOA2 gene fusions, including TEAD1::NCOA2 in two patients and SRF::NCOA2 in one patient. In this report, all fusion-positive congenital/infantile spindle cell rhabdomyosarcoma patients with long-term follow-up data were alive and well, and no patients developed distant metastases.[15]
   • While most studies of congenital/infantile spindle cell rhabdomyosarcoma have shown favorable outcomes, it was reported that four patients developed metastatic disease and two patients had fatal outcomes. Disease progression occurred a median of 3.5 years from diagnosis (range, 1–8 years).[55] All four patients had unresectable tumors and were treated with chemotherapy. However, most literature reported cases in which surgical resection was achieved. At disease progression, a tumor from one patient had a TP53 variant, and a tumor from another patient showed a homozygous CDKN2A and CDKN2B deletion.
   • A study of 40 patients with congenital/infantile spindle cell rhabdomyosarcoma (defined by diagnosis at age ≤12 months) found that almost all patients had localized disease (n = 39) and that one-half of patients who underwent molecular testing (13 of 26) had rearrangements of NCOA2 and/or VGLL2.[16] Because testing was limited to NCOA2 and VGLL2, it is possible that more comprehensive genomic analysis would identify a higher proportion of patients with relevant gene fusions. The 5-year EFS rate for the 13 patients with either a VGLL2 and/or a NCOA2 fusion was 90% (95% CI, ±19%), and the overall survival (OS) rate was 100% (95% CI, ±9%).
   • Further study is needed to better define the prevalence and prognostic significance of gene rearrangements in VGLL2, NCOA2, and other relevant genes in young children with congenital/infantile spindle cell rhabdomyosarcoma.

   MYOD1-altered spindle cell/sclerosing rhabdomyosarcoma: In older children and adults with spindle cell/sclerosing rhabdomyosarcoma, a specific MYOD1 variant (p.L122R) has been observed in a large proportion of patients.[15,56,57,58] In the combined cohort of COG and U.K. rhabdomyosarcoma patients (n = 641), variants in MYOD1 were found in 3% (17 of 515) of all fusion-negative rhabdomyosarcoma cases and in no fusion-positive cases. The presenting age of patients with MYOD1 variants was 10.8 years.[27] Most cases in this cohort showed spindle or sclerosing features, but cases with densely packed cells that mimicked the dense pattern of embryonal rhabdomyosarcoma were also observed. Most cases in this cohort (15 of 17, 88%) had either head and neck or parameningeal region primary sites. Activating PIK3CA variants are seen in about one-half of cases with MYOD1 variants.[17,27] The presence of the MYOD1 variant is associated with a markedly increased risk of local and distant failure.[15,27,56,57]

   Intraosseous spindle cell rhabdomyosarcoma: Primary intraosseous rhabdomyosarcoma is a very uncommon presentation for rhabdomyosarcoma. Most cases present with gene rearrangements involving TFCP2, with either FUS or EWSR1.[59,60,61,62,63] Rhabdomyosarcoma with a FUS::TFCP2 or EWSR1::TFCP2 gene fusion most commonly presents in young adults, although cases in older children and adolescents have been reported.[59,62,63] Craniofacial bones are the most common primary tumor location, and positivity for ALK and cytokeratins by immunohistochemistry is commonly observed. Other characteristics of this entity include a complex genomic profile, with most cases showing deletion of the CDKN2A tumor suppressor gene.[62] Intraosseous spindle cell rhabdomyosarcoma with a FUS::TFCP2 or EWSR1::TFCP2 gene fusion shows an aggressive clinical course. In one study, the median OS was only 8 months.[62]

Recurrent and refractory rhabdomyosarcomas from pediatric (n = 105) and young-adult patients (n = 15) underwent tumor sequencing in the National Cancer Institute–Children's Oncology Group (NCI-COG) Pediatric MATCH trial. Actionable genomic alterations were found in 53 of 120 tumors (44.2%), and patients with these alterations qualified for treatment on MATCH study arms.[64] Variants of MAPK pathway genes (HRAS, KRAS, NRAS, NF1) were most frequent and were reported in 32 of 120 tumors (26.7%). Amplifications of cyclin-dependent kinase genes (CDK4, CDK6) were detected in 15 of 120 tumors (12.5%).

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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 Paediatric Soft Tissue Sarcoma Study Group reviewed 367 patients enrolled in the CCLG-EPSSG-RMS-2005 (NCT00379457) study.[1][Level of evidence B4] 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.[2,3,4,5,6,7]

     Pathological 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 sampling (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] The International Society of Paediatric Oncology Malignant Mesenchymal Tumour Group has confirmed this is a necessary approach.[9] For more information, see the Regional and in-transit lymph nodes for extremity tumors section.

   • Positron emission tomography (PET): PET with fluorine F 18-fludeoxyglucose scans can identify areas of possible metastatic disease not seen by other imaging modalities.[10,11,12]

   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.[13]

Assessment of Extent of Disease

Assessing extent of disease of rhabdomyosarcoma is complex. The process includes the following steps:

1. Assignment of Stage: Stage is a clinical assessment determined by primary site, tumor size (longest diameter), and clinical (imaging) presence or absence of regional lymph node and/or distant metastases (TNM criteria).
2. Assignment of Group: Group is determined by status of the initial surgical procedure (resection/biopsy), with pathological 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 fusion status.

Prognosis for children with rhabdomyosarcoma depends predominantly on the primary tumor site, tumor size, surgical-pathological Group, presence or absence of nodal disease and distant metastasis, and fusion status. Favorable prognostic groups were identified in previous IRSG studies, and treatment plans were designed on the basis of patient assignment to different treatment protocols according to prognosis.

Assignment of clinical 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, clinical (imaging) assessment of regional lymph node status, and the presence or absence of metastases. This staging system is described in Table 4 below.[14,15,16]

Terms defining the TNM criteria are described in Table 3.

Assignment of Group

The IRS-I, IRS-II, IRS-III, and IRS-IV studies prescribed treatment plans on the basis of the surgical-pathological Group system. In this system, Groups are defined by the extent of disease and by the completeness or extent of initial surgical resection after pathological review of the tumor specimen(s). The definitions for these Groups are shown in Table 5 below.[16,17,18,19]

Assignment of Risk Group

After patients are categorized by Stage and surgical-pathological Group, a Risk Group is assigned on the basis of the Stage, Group, and FOXO1 fusion status. The planned COG low-risk study will also use TP53 and MYOD1 variant status to assign risk group. Patients are classified for protocol purposes as having a low risk, intermediate risk, or high risk of disease recurrence.[20,21,22] Treatment assignment is based on Risk Group, as shown in Table 6.

The most recent COG protocols use fusion status and molecular findings, 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.
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.
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.
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.
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.
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.
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.
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.
9. Rogers T, Minard-Colin V, Cozic N, et al.: Paratesticular rhabdomyosarcoma in children and adolescents-Outcome and patterns of relapse when utilizing a nonsurgical strategy for lymph node staging: Report from the International Society of Paediatric Oncology (SIOP) Malignant Mesenchymal Tumour 89 and 95 studies. Pediatr Blood Cancer 64 (9): , 2017.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. Crane JN, Xue W, Qumseya A, et al.: Clinical group and modified TNM stage for rhabdomyosarcoma: A review from the Children's Oncology Group. Pediatr Blood Cancer 69 (6): e29644, 2022.
17. 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.
18. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995.
19. 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.
20. 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.
21. 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.
22. HaDuong JH, Martin AA, Skapek SX, et al.: Sarcomas. Pediatr Clin North Am 62 (1): 179-200, 2015.

Treatment Option Overview for Childhood Rhabdomyosarcoma

Multimodality Therapy

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

Low-risk Group I (complete tumor resection, about 15% of patients) patients are treated with multiagent chemotherapy after surgical resection. Group II patients typically require chemotherapy and local tumor bed irradiation (about 20% of patients). Most patients (about 50%) have Group III (gross residual) disease.[4] After initial chemotherapy, Group III patients receive definitive RT for local control of the primary tumor. Some patients with initially unresected tumors may undergo delayed primary excision after induction chemotherapy to remove residual tumor before the initiation of RT. This is appropriate only if the delayed excision is deemed feasible with acceptable functional and 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 (15%–30%) reduction in RT could be utilized.[5] Patients with Group IV disease (about 15%) receive chemotherapy and RT to the primary tumor and metastatic disease sites when feasible.

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 sections:

• Surgery (local control management).
• RT (local control management).
• Surgery and RT by primary site of disease (local control management).
• Chemotherapy.

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

• The primary objective of the COG-STS, after the initial surgical resection or biopsy and induction chemotherapy, has been to use additional local control therapy, predominantly with RT or surgical resection when appropriate . Event-free survival is the target end point, attempting to avoid relapse and subsequent salvage therapy.[3]
• In the MMT trials, the main objective has been to reduce the use of local therapies using initial front-line chemotherapy, followed by second-line therapy in the presence of poor response. Subsequent surgical resection is preferred over RT, which is used only after incomplete resection, documented regional lymph node involvement, or a poor clinical response to initial chemotherapy. This approach is designed to avoid major surgical procedures and long-term damaging effects from RT. Some patients have been spared aggressive local therapy, which may reduce the potential for morbidities associated with such therapy.[1,2,3]

  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 outcomes 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.[1,2,3]

• The EpSSG RMS-2005 (NCT00379457) study reported comprehensive outcome data for 1,733 children and adolescents with nonmetastatic rhabdomyosarcoma. These patients were enrolled in two phase III randomized trials for high-risk patients and observational trials for low-risk, standard-risk, and very-high risk patients. Eighty percent of children with localized rhabdomyosarcoma were long-term survivors. This study established the standard of care across EpSSG countries, including the following:[7]
  • A 22-week vincristine/dactinomycin regimen for patients with low-risk rhabdomyosarcoma.
  • The reduction of the cumulative ifosfamide dose for patients with standard-risk disease.
  • The omission of doxorubicin and the addition of maintenance chemotherapy for patients with high-risk disease.

References:

1. Donaldson SS, Meza J, Breneman JC, et al.: Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma--a report from the IRSG. Int J Radiat Oncol Biol Phys 51 (3): 718-28, 2001.
2. Stevens MC, Rey A, Bouvet N, et al.: Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology--SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol 23 (12): 2618-28, 2005.
3. Donaldson SS, Anderson JR: Rhabdomyosarcoma: many similarities, a few philosophical differences. J Clin Oncol 23 (12): 2586-7, 2005.
4. Wexler LH, Skapek SX, Helman LJ: Rhabdomyosarcoma. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 7th ed. 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.
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.
7. Bisogno G, Minard-Colin V, Zanetti I, et al.: Nonmetastatic Rhabdomyosarcoma in Children and Adolescents: Overall Results of the European Pediatric Soft Tissue Sarcoma Study Group RMS2005 Study. J Clin Oncol 41 (13): 2342-2349, 2023.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[1] 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 pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

• Primary care physicians.
• Pediatric surgeons.
• Transplant surgeons.
• Pathologists.
• Pediatric radiation oncologists.
• Pediatric medical oncologists and hematologists.
• Ophthalmologists.
• Rehabilitation specialists.
• Pediatric oncology nurses.
• Social workers.
• Child-life professionals.
• Psychologists.
• Nutritionists.

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress 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. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed December 15, 2023.

Treatment of Childhood Rhabdomyosarcoma

Optimizing care for patients with rhabdomyosarcoma requires a multidisciplinary team approach. All patients require chemotherapy and effective local tumor control. 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 ideally occur at the time of diagnosis, either before or after the diagnostic biopsy and before the initiation of therapy.

Local control remains a significant problem in children with rhabdomyosarcoma. The predominant site of treatment failure in patients with initially localized rhabdomyosarcoma has been local recurrence. In the Intergroup Rhabdomyosarcoma Study Group (IRS)-II trial, 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.[1]

Both surgery and radiation therapy (RT) are procedures primarily focused on local tumor control, but each treatment has risks and benefits.

For more information about surgical and radiotherapeutic management of the more common primary sites, see the Surgery and RT by Primary Site of Disease (Local Control Management) section.

Treatment options for childhood rhabdomyosarcoma include the following:

1. Surgery (local control management).
2. RT (local control management).
3. Surgery and RT by primary site of disease (local control management).
4. Chemotherapy.

Surgery (Local Control Management)

Surgical removal of the entire tumor should be considered initially, but only if functional and cosmetic impairment will not result.[2] With that stipulation, complete gross resection of the primary tumor, with a surrounding margin of normal tissue, and biopsy are recommended by the authors of one study. For some tumor sites, sampling of regional draining lymph nodes is necessary. Children's Oncology Group (COG) protocols require regional draining node sampling in extremity tumors and paratesticular tumors in patients older than 10 years. Important exceptions to achieving an R0 resection (negative margins) are in tumors of the orbit and the genitourinary region.[3,4] Additionally, the principle of wide and complete resection of the primary tumor is less applicable for patients known to have metastatic disease at the initial operation, but it is an appropriate approach if easily accomplished without loss of form (cosmesis) and function.

Patients with microscopic residual tumor after their initial surgery appear to have improved prognoses if a second operation (primary re-excision) to resect the primary tumor bed before beginning chemotherapy can completely remove the tumor without loss of form and function.[5]

There is no evidence that debulking surgery (i.e., surgery that is expected to leave macroscopic residual tumor) improves outcomes, compared with biopsy alone; therefore, debulking surgery is not recommended for patients with rhabdomyosarcoma.[6][Level of evidence B4] Rather than debulking a tumor at the time of initial biopsy, it is preferable to delay definitive surgery until after induction chemotherapy (delayed primary excision). In a retrospective study of 73 selected patients, delayed primary excision allowed for the identification of viable tumor that remained after initial chemotherapy. Of the 73 patients, 65 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).[7] There is also no evidence that performing surgical resection on residual masses detected by imaging at completion of all planned therapy improves outcomes.[8] 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.[9] Subsequently, delayed primary excision was evaluated by the Soft Tissue Sarcoma Committee of the COG (COG-STS) in the D9602 and D9803 studies.[8] Delayed primary excision at week 12 after induction chemotherapy was completed in 45% to 54% of patients with Group III rhabdomyosarcoma tumors when appropriate (anticipated complete resection with no loss of form or function at select sites such as bladder, prostrate, extremity, trunk, retroperitoneum, intrathoracic, perineum, or perianal). Of these patients, 81% to 84% were eligible for modest RT dose reduction. Approximately 50% of these patients had an R0 resection (negative margins) and received a reduced RT dose of 36 Gy, and 30% of patients had an R1 resection (margins were microscopically involved) and received a reduced RT dose of 41.4 Gy (from the standard 50.4-Gy dose). Local control and survival outcomes were similar to those of patients who received full-dose RT alone in the IRS-IV study.[7]

A retrospective analysis compared patients with clinical Group III rhabdomyosarcoma treated on consecutive COG protocols D9803 (encouraged delayed primary excision) and ARST0531 (NCT00354835) (discouraged delayed primary excision).[10] Among 369 patients in an adjusted-regression analysis, the risk of death (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.43–1.16) was similar for patients who did or did not undergo delayed primary excision. A subset of patients who had tumors of the trunk and retroperitoneum did have a reduced risk of death with delayed primary excision (HR, 0.44; 95% CI, 0.20–0.97).

RT (Local Control Management)

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 at diagnosis before initiation of chemotherapy do well without RT. However, because approximately 75% of embryonal rhabdomyosarcoma patients are Groups II to IV, RT is used in most patients.[11]

  A study of Group I patients with alveolar rhabdomyosarcoma and undifferentiated soft tissue sarcoma found that omission of RT was followed by decreased local control.[12] 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.[13][Level of evidence C2] COG recommends the use of RT for all patients with FOXO1 fusion–positive disease (previously called alveolar rhabdomyosarcoma).

• Group II: In more than 50% of Group II rhabdomyosarcoma patients, local recurrence was the result of noncompliance with guidelines or omission of RT.[14]

  The German Cooperative Weichteilsarkom Studiengruppe (CWS) conducted a review of European trials 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.[15]

• 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.[16]

The CWS performed a retrospective analysis of 395 children with parameningeal rhabdomyosarcoma. Patients had IRS Groups II (n = 15) and III (n = 380) disease. Delayed resection was performed in 88 of 395 patients (22%), and RT was also given to 79 of the 88 patients (90%) who underwent resections. RT was the predominant local treatment for 355 of 395 patients (90%), which included hyperfractionated accelerated photon RT (HART) (n = 77), conventionally fractionated photon RT (n = 91) or proton-beam RT (n = 126), brachytherapy (n = 4), and heavy ions (n = 1). Details of the RT received were not available for 56 patients.[17]

• In the subgroup of patients who received RT as the only local treatment (n = 278), significant positive prognostic factors included no intracranial tumor extension and complete remission at the end of treatment.
• No significant differences in tumor outcomes were seen between the different RT concepts.

Investigators performed a retrospective analysis of 1,470 patients (aged 21 years or younger) with localized rhabdomyosarcoma. These patients were enrolled in the CWS-96, CWS-2002P, and Soft Tissue Sarcoma Registry (SoTiSaR) trials. The study analyzed and compared the indications, doses, and application methods of RT and their influence on prognosis.[18] The authors concluded the following:

• RT can be omitted in patients with IRS Group I embryonal rhabdomyosarcoma (fusion-negative rhabdomyosarcoma).
• RT improves EFS and local control survival (LCS) in patients with IRS Groups II and III disease.
• Patients with tumors in the head and neck region (orbital, parameningeal, and nonparameningeal) and in other sites who received proton RT had EFS and LCS that were comparable with those of patients who received photon RT. Patients with parameningeal tumors had an improved OS with proton RT.
• The efficacy of low RT doses of 32 Gy (HART) and 36 Gy to 41.4 Gy (conventional fractionated RT [CFRT]) in the favorable-risk groups of patients and higher doses of 44.8 Gy (HART) and 50.4 Gy to 55.4 Gy (CFRT) in the unfavorable-risk group of patients was comparable.

External-beam RT

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

• Site of primary tumor.
• Histological 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 therapists, 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, proton-beam therapy [charged-particle radiation therapy], or brachytherapy) are appropriate.[19,20,21,22,23,24]

Dosimetric comparison of proton-beam RT and photon IMRT treatment plans has shown that proton-beam treatment plans may spare more normal tissue adjacent to the targeted volume than IMRT plans, but with no difference in local control using photon RT. Late effects data are lacking.[25,26]

Evidence (radiation delivery techniques):

1. A prospective, phase II trial compared proton-beam therapy with IMRT in pediatric rhabdomyosarcoma.[27]
   • 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.[28][Level of evidence B4]
   • 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 results were observed:[29]
   • The 2-year local control rate was 88%.
   • All 11 children with local recurrences were Group III (gross residual disease) and experienced relapse 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. The COG ARST1431 (NCT02567435) protocol is testing escalated doses to 59.4 Gy for these patients.
   • This study did not delineate whether the recurrence was in the 41.4 Gy or 50.4 Gy irradiated volumes.
4. In the COG ARST0531 (NCT00354835) trial, local failure rates were similar among patients who were treated with proton and photon radiation therapy.[30]

The radiation doses according to Group, histology, and disease site for children with rhabdomyosarcoma are described in Table 7:

In the COG ARST1431 (NCT02567435) study, risk group is in part determined by fusion status. The recommended dose of RT 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 I), radiation therapy with 36 Gy is recommended.

• 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 41.4 Gy in the presence of involved nodes.[12,31] Low-risk patients (embryonal histology and favorable sites with microscopic residual disease) treated in a COG study had excellent local control with 36 Gy, which was comparable to historical controls who received 41.4 Gy.[9] For Group II patients, 36 Gy of RT is recommended to the prechemotherapy involved site, and 41.4 Gy to involved nodes.
• 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.[32,33] Group III patients on the standard treatment arm of the IRS-IV study received 50.4 Gy to 59.4 Gy, with 5-year progression-free survival (PFS) rates of 55% to 75% and local control rates of 85% to 88%.[34]

  Select COG subgroups with Group III disease received somewhat reduced radiation doses of 36 Gy after delayed gross-total resection with negative margins (R0 resection), and 41.4 Gy if the margins were microscopically involved (R1 resection) 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.[9] Similarly, the intermediate-risk studies for patients with Group III disease investigated the paradigm of delayed resection in amenable patients (anticipated complete resection with no loss of form or function at select sites such as bladder, prostate, extremity, trunk, peritoneum, intrathoracic, perineum, and perianal), with a subsequent reduced dose of RT (36 Gy for R0 resections or 41.4 Gy for R1 resections). The study demonstrated that patients who received reduced doses of RT had outcomes equivalent to patients who were treated with full-dose RT of 50.4 Gy.[8,10]

• Group IV. Radiation therapy is appropriate treatment for sites of metastatic disease (technique, timing, and volume discussed below). The European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) examined 102 patients with metastatic rhabdomyosarcoma (97 analyzed). Patients received radical RT (all metastatic sites except those completely resected), partial RT, or no RT. The OS was superior in patients treated with radical RT than partial RT (HR, 0.245; P = .039); however, it should be noted that some component of the difference in survival likely relates to the patients selected to receive radical versus partial RT rather than the type of RT administered. The 3-year OS rate was 84% for patients who received radical RT, 54% for patients who received partial RT, and 23% for patients who received no RT.[35]

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 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).[36][Level of evidence C2]

Treatment volume

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.[12] This clinical tumor volume can be modified on the basis of anatomical constraints, especially in situations where the tumor was pushing, rather than invading, the adjacent normal tissues, or when adjacent normal tissues are functionally critical (e.g., head and neck rhabdomyosarcoma). Thus, while the volume irradiated may be modified because of considerations for normal tissue tolerance, gross residual disease at the time of RT should receive full-dose RT. 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). Gross residual disease still receives the full RT dose (50.4–59.4 Gy, the higher dose if >5 cm at diagnosis).

For involved nodal sites, the treated volume is defined as the extent of nodal involvement at diagnosis, factoring in changes in anatomy, plus a 3-cm margin superiorly and inferiorly in the direction of lymphatic drainage, or inclusion of the entire nodal chain where there is uncertainty.

For metastatic disease, the treated volume is the extent of metastases at diagnosis, with the exception of the lung or extensive brain metastases where the whole organ is irradiated, or diffuse peritoneal metastases where the entire peritoneal cavity is included. The use of novel techniques, such as stereotactic body RT to appropriate sites (e.g., bone or small volume soft tissue metastases), can be considered.

Timing of RT

The timing of RT generally allows for chemotherapy to be given for up 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, doxorubicin, and temsirolimus. Another consideration is the administration of RT before a planned second surgical excision that will be R0 or R1, particularly if RT might facilitate surgical resection to decrease the chances of loss of form or function. This approach is protocol dependent.

• The randomized IRS-IV trial 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.[37] The 5-year local control rate was 87% for all patients on this study.

For metastatic sites, RT is usually given after 16 to 20 weeks of chemotherapy or, rarely, as consolidation at the completion of planned chemotherapy.

Thus, conventional RT remains the standard for treating patients who have rhabdomyosarcoma with gross residual disease.[38]

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 [39,40,41,42,43,44] and selected bladder/prostate sites.[45][Level of evidence C1] This technique requires specialized technical skill and expertise and is limited to only a few institutions. In small series from one or two institutions, this treatment approach was associated with a high survival rate and retention of a functional organ or tissue in most patients.[40,46]; [47][Level of evidence C2] Other sites, especially head and neck, have also been treated with brachytherapy.[48]

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.[9] 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.[49] 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.[50,51,52]

Delayed primary excision may allow for a radiation dose reduction and has been studied in select patients.[8] 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. Both treatments are optimal, but at least one approach is necessary in addition to chemotherapy. Local control rates from delayed primary excision and reduced-dose RT are equivalent to that from RT alone.[8]

In studies of infants younger than 1 or 2 years, 77 patients with nonmetastatic rhabdomyosarcoma were included. These studies showed 5-year failure-free survival (FFS) rates of 57% to 68% and OS rates of 76% to 82%.[53] 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.[54] This experience has been confirmed for children up to age 2 years.[53] Consequently, the COG recommends treating children aged 2 years or younger with the same guidelines as recommended for children older than 2 years.

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

Local control of primary disease in rhabdomyosarcoma has evolved with the use of more effective chemotherapy protocols, improved surgical approaches and techniques, and improvements in RT, including better definition of therapy fields, tailored dosing, and new techniques such as IMRT, brachytherapy, and proton therapy. Data are predominantly derived from retrospective reviews of primary tumor sites from cooperative group studies, including the IRSG, COG, EpSSG, CWS, Gesellschaft für Pädiatrische Onkologie und Hämatologie, International Society for Pediatric Oncology (SIOP) Malignant Mesenchymal Tumour (MMT), and the Associazione Italiana di Ematologia e Oncologia Pediatrica Soft Tissue Sarcoma Committee. These groups created the International Soft Tissue Sarcoma Consortium (INSTRuCT) and agreed to form a single data commons by merging multiple cooperative group databases. Leaders of INSTRuCT have initiated efforts to define international consensus statements for approaches to several primary tumor sites, predominantly through their expert review of published data, sometimes enhanced with new analyses of merged data.

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.[55,56,57,58,59,60] 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.[61,62,63]; [64][Level of evidence C1]

1. Orbit.

   Rhabdomyosarcomas of the orbit should not undergo exenteration, but biopsy is needed for diagnosis.[65,66] Biopsy is followed by chemotherapy and RT, with orbital exenteration reserved for the small number of patients with locally persistent or recurrent disease.[57,67] RT and chemotherapy are the standard of care, with survival rates exceeding 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 after radiation therapy of 45 Gy, compared with patients who fail to achieve a complete response.[68][Level of evidence B4] For patients in whom a complete response has not been achieved with induction chemotherapy, 50.4 Gy of RT is recommended by the investigators.

   The COG studied 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 RT 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.[68][Level of evidence B4]

   Long-term outcomes were evaluated in 218 patients with orbital rhabdomyosarcoma enrolled in COG clinical trials between 1997 and 2013. The 192 patients with low-risk orbital rhabdomyosarcoma (clinical groups I–III with mostly embryonal histology treated on the low-risk D9602 and ARST0331 studies) had 10-year EFS and OS rates of 85.5% (95% CI, 77.0%–94.0%) and 95.6% (95% CI, 90.8%–100.0%), respectively. The 26 patients with non–low-risk orbital rhabdomyosarcoma (mostly tumors with alveolar histology that were treated with more intensive intermediate-risk protocols [D9802, D9803 and ARST0531]), had 5-year EFS and OS rates of 88.5% (95% CI, 75.6%–100.0%) and 95.8% (95% CI, 87.7%–100.0%), respectively. Twenty-eight patients experienced a recurrence, including 25 who were treated in low-risk trials (6 patients did not receive radiation therapy during initial therapy). Twenty-seven recurrences were local. One metastatic recurrence occurred in a patient with Group III, PAX3::FOXO1 fusion–positive alveolar rhabdomyosarcoma. Patients with recurrent orbital rhabdomyosarcoma had a 10-year OS rate of 69.4% (95% CI, 50.0%–88.8%) from time of recurrence, showing that a significant number of patients with recurrent orbital rhabdomyosarcoma may achieve long-term survival.[69]

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.[58,70,71] 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 bordering 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.[70] 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.[71]

   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.[71]
      • 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.[72][Level of evidence B4]
   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.[73][Level of evidence C2]
   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.[74][Level of evidence C2]
      • 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 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.[75][Level of evidence C1]
      • 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%.
      • Patients with two adverse factors had a 10-year OS rate of 68.4%.
      • Patients with three or four adverse 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. This finding establishes RT as a necessary component of initial treatment.
   6. A single-institution prospective registry identified 25 patients with head and neck parameningeal rhabdomyosarcoma who were treated with proton-beam RT.[76]
      • Of 25 total patients, 11 had intracranial extension at baseline, 6 of whom experienced a local recurrence.
      • This recurrence rate is similar to the rate reported in the IRS-IV and D9803 trials for patients with high-risk parameningeal rhabdomyosarcoma.[72]
   7. A study included 15 children and adolescents with intermediate- and high-risk parameningeal rhabdomyosarcoma who were treated with proton RT during cycle 1 or 2 of chemotherapy.[77]
      • At 3 weeks from RT simulation, most patients demonstrated a significant reduction in initial tumor volume.
      • This finding suggests that for patients who receive early RT after the initiation of chemotherapy, on-treatment imaging should be performed approximately 4 weeks from the initiation of chemotherapy.

   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.[78]

   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.[79,80]

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.[81]; [82][Level of evidence C1] Narrow resection margins (<1 mm) are acceptable because of anatomical restrictions. Cosmetic and functional factors should always be considered, but with modern techniques, complete resection in patients with superficial tumors is consistent with good cosmetic and functional results.

   The EpSSG RMS-2005 (NCT00379457) study prospectively enrolled 165 patients with localized head and neck, nonparameningeal rhabdomyosarcoma. Local therapy included surgery (58%) and/or RT (72%). Chemotherapy was given according to the patient's risk group. Low-risk patients received vincristine and dactinomycin (VA) therapy. High-risk patients were randomly assigned to receive either neoadjuvant therapy with ifosfamide, vincristine, and dactinomycin (IVA) or IVA and doxorubicin for four courses followed by five courses of IVA. The 5-year EFS rate was 75% (95% CI, 67.3%–81.2%), and the OS rate was 84.9% (95% CI, 77.5%–89.7%). Favorable histology was associated with a better EFS rate (82.3% vs. 64.6%, P = .02), and nodal spread was associated with a worse OS rate (88.6% vs. 76.1%, P = .04). Locoregional relapse/progression was the main tumor failure event (84% of events).[83][Level of evidence B4]

   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. However, these procedures should be considered 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 invasive disease and N1 nodal 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.[84]

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.[5] Chemotherapy or delayed primary excision does not improve outcome over chemotherapy and RT.[8]

Delayed primary excision has been studied in patients with extremity tumors enrolled in the COG intermediate-risk rhabdomyosarcoma trials. Two COG studies (D9803 and ARST0531 [NCT00354835]) were pooled to assess the benefit of delayed primary excision. In the D9803 study, local control with RT after a partial or complete excision was completed at week 12. In the ARST0531 study, RT was done upfront at week 4. Patients with bladder or prostate rhabdomyosarcoma who received a delayed primary excision had no difference in survival, whereas patients with extremity rhabdomyosarcoma had an improved OS with delayed primary excision. The delayed primary excision strategy with a reduction in RT dose resulted in superior OS for those sites.[8,10] Delayed primary excision may be most appropriate for infants because the late effects of RT are more severe than in older patients; thus, even a moderate reduction in radiation dose is desirable. For more information, see the Surgery (Local Control Management) section.

IMRT can be used to spare the bone yet provide optimal soft tissue coverage in extremity rhabdomyosarcoma. Complete primary tumor removal from the hand or foot is not feasible in most cases because of functional impairment.[85][Level of evidence C1] For children presenting with a primary tumor of the hands or feet, COG studies have shown a 10-year local control rate of 100% using RT along with chemotherapy, avoiding amputation in these children.[86][Level of evidence C1] Definitive RT and chemotherapy for Group III tumors resulted in a local control rate of 90% to 95% in the IRS-IV trial.[37]

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 in-transit nodes is warranted.[87,88,89,90,91]; [92][Level of evidence C2] 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. 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.[92]

Positron emission tomography (PET) scanning is recommended for evaluation and staging of extremity primary tumors before initiation of therapy [92] and is useful in RT treatment planning.[93]

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 type of biopsy 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.[90,94,95,96,97,98,99,100]

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.[101]

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).[102] These resections may require use of prosthetic materials for subsequent reconstruction.

   Initial primary resection is performed if there is a realistic expectation of achieving negative margins (R0 resection). 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. These patients may have excellent long-term survival.[102,103,104,105]

   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.[105] Aggressive resections at diagnosis before chemotherapy are not necessary because rhabdomyosarcoma is 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.[106]

   For patients with initially unresectable retroperitoneal/pelvic tumors, complete surgical removal after induction chemotherapy, with or without RT, offers a significant survival advantage (73% vs. 34%–44% without removal).[106]

   Evidence (chemotherapy with or without RT followed by surgery):

   1. The 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.[107][Level of evidence B4]
      • 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.[108][Level of evidence C1]
      • 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 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.[109][Level of evidence C1] 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 at diagnosis is rarely feasible. The standard treatment includes chemotherapy and RT. Outcomes for patients with this primary tumor site were considered favorable despite residual disease after surgery;[110] however, an analysis of COG low-risk studies found that patients with this site had suboptimal outcomes.[111] The CWS also reported poorer outcomes,[112] confirmed by a systematic review and meta-analysis.[113] The COG now recommends that this site be classified as unfavorable. External biliary drains significantly increase the risk of postoperative infectious complications. Thus, external biliary drainage is not warranted.[110]

   Evidence (chemotherapy, surgery, and RT):

   1. A retrospective review by the CWS identified 17 patients with rhabdomyosarcoma of the biliary tree.[112]
      • The 5-year OS rate was 58% (45%–71%), and the EFS rate was 47% (34%–50%).
      • Patients older than 10 years and those with alveolar histology had the worst prognosis (OS rate, 0%).
      • Patients with botryoid histology had an excellent survival (OS rate, 100%) compared with those with nonbotryoid histology (OS rate, 38%; 22%–54%; P = .047).
      • Microscopic complete tumor resection was achieved in five of six patients who received initial tumor biopsy followed by chemotherapy and delayed surgery.
   2. A COG analysis of 17 patients enrolled in two consecutive low-risk studies (D9602 and ARST0331) reported the following results:[111]
      • The 5-year EFS rate was 76.5% (95% CI, 54.6%–98.4%), and the OS rate was 70.6% (95% CI, 46.9%–94.3%).
      • Most patients (80%) who received RT did not have disease recurrence.
      • Of 14 patients with Group III disease, 5 underwent delayed primary excision, 2 of whom had local relapses.
      • Of the nine patients without delayed primary excision, two developed local relapses.
4. Perineum or anus.

   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.[114] 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.[115] When feasible and without unacceptable morbidity, removing all gross tumor before chemotherapy may improve the likelihood of cure; however, chemotherapy and RT remain the 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.[115]

   • 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.[115]
   • In a subsequent report from the German CWS trials, 32 patients had an EFS and OS rate of 47% at 5 years. In addition, patients with embryonal histology fared significantly better than did patients with alveolar histology.[116][Level of evidence C1]
   • A retrospective review examined 50 patients with nonmetastatic perianal/perineal rhabdomyosarcoma treated in the SIOP-MMT-95 (NCT00002898), Italian RMS-96, and EpSSG RMS-2005 trials. The study found a 5-year EFS rate of 47.8% and an OS rate of 52.6%. Eighty-seven percent of patients with relapse or disease progression died. Older patients and those with large tumors had the worst outcomes.[117][Level of evidence C1]

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.[118]

1. Testis or spermatic cord (paratesticular).

   Recommendations for paratesticular primary tumors are primarily based on the results from cooperative group trials and a recent INSTRuCT consensus opinion.[119]

   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, using an inguinal incision with proximal vascular control (i.e., radical orchiectomy).[120] Resection of hemiscrotal skin is required when there is tumor fixation or invasion.

   Hemiscrotectomy had been recommended by the COG, German groups, and Italian groups when a previous transscrotal biopsy had been performed. 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 rate was 93.8% in 16 patients without subsequent hemiscrotectomy. All of these patients also received chemotherapy with vincristine, dactinomycin, an alkylating agent, and other agents.[121][Level of evidence C2]

   A retrospective study examined 842 patients with localized paratesticular rhabdomyosarcoma who were enrolled in COG, CWS, EpSSG, Italian Cooperative Group, and MMT studies from 1988 to 2013. Of all patients, 7.7% had a transscrotal resection; however, this surgical factor did not contribute to an inferior EFS in stratified univariable and multivariable analysis.[122] A COG study evaluated 279 patients with paratesticular rhabdomyosarcoma. The study also found that hemiscrotectomy did not improve outcome after transscrotal violation.[123][Level of evidence C1] These findings support the consensus statement from INSTRuCT that hemiscrotectomy is no longer recommended for scrotal violation.[119]

   The EpSSG RMS-2005 (NCT00379457) study enrolled 237 patients with paratesticular tumors. Seventy-five patients (32%) had an inappropriate first surgery, defined as tumorectomy without orchidectomy, transscrotal orchidectomy without an inguinal approach, or biopsy in a resectable tumor. These patients required intensified therapy to maintain excellent OS and EFS. Ten patients required additional local surgery and intensified chemotherapy.[124]

   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; however, more data are needed.[125][Level of evidence C1] 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. Eleven of these patients had continuous PFS, whereas four of the five patients who were treated without a salvage procedure developed recurrent disease.[126][Level of evidence C2]

   Paratesticular tumors have a relatively high incidence of lymphatic spread (26% in IRS-I and IRS-II).[87] 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.[127,128] For patients with suggestive or positive CT scans, retroperitoneal, ipsilateral, infra-renal vein lymph node sampling of 10 to 12 nodes (but not formal node dissection) is recommended, and treatment is based on the findings of this procedure.[4,38,129] Patients with suspicious or documented retroperitoneal/pelvic lymph nodes require nodal RT.

   In patients aged 10 years and older, only 9% will have clinical or radiological evidence of retroperitoneal node enlargement. However, pathological evaluation has shown that imaging alone will miss 50% of nodal disease. Therefore, patients aged 10 years and older should have an ipsilateral, nerve-sparing retroperitoneal node dissection, regardless of imaging findings.[130] Staging ipsilateral retroperitoneal lymph node sampling is currently required for all children aged 10 years and older with paratesticular rhabdomyosarcoma on COG-STS studies.

   Many European investigators relied on radiographic, rather than surgical-pathological assessment, for retroperitoneal lymph node involvement.[120,127] European studies, as well as an international pooled data analysis, demonstrated worse outcomes in this patient population when surgical lymph node evaluation was not performed.[122,124,131] On the basis of these results and with the high relapse rate and worse EFS in Stage N0 patients, investigators from SIOP, EpSSG, and COG recommended 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.[122] A consensus document regarding paratesticular rhabdomyosarcoma from all North American and European cooperative groups concurred that all patients aged 10 years or older should undergo ipsilateral, infra-renal vein, retroperitoneal surgical lymph node evaluation by sampling 7 to 12 nodes or a nerve-sparing dissection.[119]

   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.[132][Level of evidence B4]
      • 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.[122][Level of evidence C1]
      • 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, which may most accurately identify patients who can benefit from RT.
   3. In the EpSSG RMS-2005 (NCT00379457) cooperative group study (n = 237) of patients with paratesticular rhabdomyosarcoma, retroperitoneal lymph node staging was based on conventional imaging with ultrasonography, CT, or MRI, not systematic surgical staging.[124][Level of evidence B4]
      • Twenty-one of 26 recurrences were in patients older than 10 years and were mainly locoregional in 16 of the 26 patients.
      • The 5-year OS and EFS rates were both significantly worse in patients older than 10 years, compared with those younger than 10 years (OS rates, 86.7% vs. 98.1%, respectively; P = .0013; EFS rates, 79.6% vs. 95.8%, respectively; P = .0004).
      • Eight of ten nodal relapses were in patients older than 10 years.
      • The EpSSG group advocates surgical staging for patients aged 10 years and older.
   4. The COG reviewed 279 patients with localized paratesticular rhabdomyosarcoma enrolled in one of four COG studies (D9602, ARST0331, D9803, or ARST0531 [NCT00354835]). Surgical resection of the primary tumor before chemotherapy and RT was encouraged, when possible, with retroperitoneal lymph node dissection (RPLND) recommended for patients aged 10 years and older. Most tumors were resected with negative margins (78.5%), and most patients did not have radiographic enlargement of regional lymph nodes (90.3%). Of 270 analyzed patients, 121 were older than 10 years. Of these patients, 25 (20.9%) underwent template RPLND, 35 (28.9%) had RPLN sampling, and for 12 of the patients (9.9%), the RPLN technique was unknown.[123][Level of evidence B4]
      • In patients older than 10 years, imaging alone will miss over 51.5% of nodal disease.
      • Sampling of ≥7 to 12 nodes appeared optimal.
      • The 5-year EFS rate was 92%.
      • There was a trend toward improved EFS among those who underwent template RPLND (P = .068).
      • Reliance on imaging alone to detect nodal involvement will miss pathological node involvement and may result in undertreatment.

   RT should be considered for patients whose nodes are biopsy positive.

2. Bladder or prostate.

   Bladder preservation is a major goal of therapy for patients with tumors arising in the bladder and/or prostate. Two reviews provide information about the historical, current, and future treatment approaches for patients with bladder and prostate rhabdomyosarcomas.[133,134]

   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.[135]

   In rare cases, the tumor is confined to the dome of the bladder and can be completely resected, leaving a 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.[136,137] This is sometimes followed, when necessary, by a more limited surgical procedure such as partial cystectomy.[138] 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 rate was 70% in IRS-II).[138,139] The later experience from the IRS-III and IRS-IV studies, which used more intensive chemotherapy and RT and had a greater emphasis on bladder preservation, showed 55% of patients alive with functional bladders at 3 years postdiagnosis, with 3-year OS rates exceeding 80%.[137,140,141]

   In a prospective registry study of 19 patients (median age, 1.8 years at diagnosis; range, 0.5–5.0 years) who were treated with proton therapy, the 5-year OS and 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 had a relapse all died.[142]

   Patients with a primary tumor of the bladder or prostate who present with a large pelvic mass, resulting from a distended bladder caused by outlet obstruction at diagnosis, receive RT. The RT volume is 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.

   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 report objective long-term assessment of bladder function. Urodynamic studies can accurately evaluate bladder function.[143]

   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 enrolled 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%.[144][Level of evidence C1]

   Another alternative strategy in highly selected patients is to perform conservative surgery, followed by brachytherapy at a specialized center.[145]; [146][Level of evidence C2]; [147][Level of evidence C1] 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 another series, bladder-conserving surgery plus brachytherapy for boys with prostate or bladder-neck rhabdomyosarcoma led to excellent survival rates, bladder preservation, and short-term functional results.[45][Level of evidence C1]

   In patients who have been treated with chemotherapy and RT for rhabdomyosarcoma arising in the bladder or 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.[140,148,149] One study suggested that in patients with residual bladder tumors with histological evidence of maturation, additional courses of chemotherapy should be given before cystectomy is considered.[140] Surgery should be considered if malignant tumor cells do not disappear over time after initial chemotherapy and RT. Because of 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 among 5,746 eligible patients enrolled in 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 limited experience concluded that the kidney is an unfavorable site for primary sarcoma.[150]

4. Vulva, vagina, or uterus.

   For patients with genitourinary primary tumors of the vulva, vagina, or uterus, the initial surgical procedure is usually a vulvar or transvaginal biopsy. Initial radical surgery is not indicated for rhabdomyosarcoma of the vulva, vagina, or uterus.[4] Conservative surgical intervention for vaginal rhabdomyosarcoma, with primary chemotherapy and radiation (external beam or brachytherapy) for Group II or III disease results in excellent 5-year survival rates.[50,151,152][Level of evidence C1]

   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.[50][Level of evidence C2] In 21 girls with genitourinary tract disease who were not treated with RT (mostly Group III vaginal primary tumors), the 3-year FFS rate was 57%, compared with 77% in the other 45 patients with non–female genitourinary primary tumors (P = .02).[51][Level of evidence B4] Therefore, the COG-STS recommended that RT be administered to patients with residual viable vaginal tumor, beginning at week 12.[52][Level of evidence C1]

   Because of the small number of patients with uterine rhabdomyosarcoma, it is difficult to make a definitive treatment decision, but chemotherapy with or without RT is effective.[151,153] 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 a Sertoli-Leydig cell tumor.[154] Exenteration is usually not required for primary tumors at these sites, but may be done if needed, with rectal preservation possible in most cases.

   Four cooperative groups in the United States and Europe evaluated patients with localized vaginal or 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.[44][Level of evidence C1]

   A study of five CWS trials (and one registry) included 67 patients with localized vaginal or uterine rhabdomyosarcoma diagnosed at a median age of 2.89 years (0.09–18.08). Multimodality treatment consisted of chemotherapy (n = 66), secondary surgery (n = 32), and RT (n = 11). The study reported the following results:[155][Level of evidence C1]

   • Diagnosis at age 12 months or younger was the only significant negative prognostic factor influencing EFS.
   • The 10-year EFS rate for infants aged 12 months or younger was 50%, and the OS rate was 81%.
   • In contrast, children with local disease older than 1 year to age 10 years had a 10-year EFS rate of 78% and an OS rate of 94% (P = .038). Children older than 10 years had a 10-year EFS rate of 82% and an OS rate of 88% (P = .53).
   • Metastatic disease was observed in four patients, three of whom are alive.
   • Relapsed disease occurred in 5 of 12 infants aged 1 year or younger and 10 of 55 children at a median of 1.38 years (0.53–2.97) after initial diagnosis.
   • Treatment of patients with relapsed disease consisted of multimodality treatment (n = 13) or resection only (n = 2). Nine patients (60%) were alive in clinical remission at a median of 7.02 years (1.23–16.72) after diagnosis of relapsed disease.

   The INSTRuCT group summarized its consensus expert opinion about local treatment of female genital tract tumors as follows:[156]

   • Prognosis for female genital tract tumors is favorable, with an excellent response to chemotherapy.
   • Definitive local control can often be achieved by chemotherapy alone.
   • Adequate biopsy is required and should provide sufficient tissue to establish the diagnosis and for further molecular or genetic analysis.
   • Initial complete surgical resection before chemotherapy can be avoided in most cases:
     • Vaginal: Vaginectomy is unnecessary.
     • Cervix: Up-front vaginectomy/hysterectomy is usually not indicated.
     • Uterus: Up-front hysterectomy is usually not indicated.
   • Primary re-excision to achieve complete resection is usually not indicated.
   • Patients with tumors that are localized to the vagina or cervix and who demonstrate incomplete response after induction chemotherapy receive local RT (brachytherapy).
   • Hysterectomy is indicated for patients with tumors of the corpus uteri who have persistent tumor after definitive initial therapy.
   • Fertility preservation is a consideration for all patients.[156]

   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.[157] Alternatively, ovarian tissue preservation is under investigation and can be considered.[158]

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.[159][Level of evidence C2]

2. Larynx.

   Patients with laryngeal rhabdomyosarcoma will usually be treated with chemotherapy and RT after biopsy in an attempt to preserve the larynx.[160]

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 could be considered.[161]

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.[162][Level of evidence C2] Treatment with combination chemotherapy, followed by removal of the residual mass or masses, can sometimes be successful.[162]

Unknown primary sites

The EpSSG reported a retrospective analysis of ten patients with rhabdomyosarcoma and unknown primary sites, most of whom were adolescents (median age, 15.8 years; range, 4.6–20.4 years).[163] Nine patients had fusion-positive alveolar rhabdomyosarcoma. Seven patients had multiple organ involvement, two patients had only bone marrow disease, and one patient had only leptomeningeal dissemination. All patients received chemotherapy, four received radiation therapy, and none underwent surgery. Three patients underwent allogeneic bone marrow transplant. At the time of this analysis, only two patients were alive in complete remission: one who was treated with radiation therapy, and one who was treated with a bone marrow transplant.

Metastatic disease

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, the COG recommends RT to sites of gross disease.

In the COG protocols, resection of the primary tumor in patients with metastatic disease may be considered before initiating chemotherapy if a complete resection is anticipated without the loss of form or function. After induction chemotherapy, delayed resection can be performed, with the same caveat regarding complete resection without loss of form or function, followed by RT of the primary tumor. The paradigm of aggressive local control of primary tumors in patients with metastases is supported by a European evaluation of 101 patients treated from 1998 to 2011 using MMT protocols. OS rates were best when both surgical resection and RT were combined (44%) versus surgical resection alone (19%) or RT alone (16%) (P < .006).[164][Level of evidence C1] Outcome also correlated with completeness of the surgical resection (R0, 41%; R1, 56%; R2, 20%; P < .03). Primary resection of metastatic disease at diagnosis (Stage 4, M1, Group IV) is rarely indicated. Treatment of metastatic disease occurs near the end of therapy using RT and, rarely, resection or other ablative techniques. The primary treatment for bony metastatic disease is 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 rate was 77% for patients with nodules and 73.2% for patients without nodules (P = .68). The 5-year OS rate 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.[165][Level of evidence C1]

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.[166][Level of evidence C1]
   • They reported a 5-year EFS rate of approximately 38% for the cohort.
   • The study 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 they were less likely to have regional lymph node disease at diagnosis.[167][Level of evidence C1]
   • 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.[168] For more information about Risk Groups, see Table 6.

Adolescents treated with chemotherapy for rhabdomyosarcoma experience less hematologic toxicity and more peripheral nerve toxicity than do younger patients.[169]

Low-risk Group

Cooperative group studies have defined low-risk patient populations who have better outcomes. The specific definition of the low-risk group is protocol dependent, and while outcomes have typically been excellent, some subgroups of low-risk patients have received relatively aggressive therapy. In the COG D9602 and ARST0331 studies, low-risk patients had localized (nonmetastatic) embryonal histology tumors in favorable sites that were grossly resected (Groups I and II), embryonal tumors in the orbit that were not completely resected (Group III), and localized tumors in unfavorable sites that were grossly resected (Groups I and II). Approximately 25% of newly diagnosed patients are low risk. For more information, see Table 5 in the Stage Information for Childhood Rhabdomyosarcoma section.

COG and EpSSG studies have evaluated two- and three-drug chemotherapy schedules with varying intensity of alkylator therapy and variations in length of therapy. The goals are to maximize cure rates while attempting to mitigate late effects of chemotherapy. These cooperative groups have evaluated different approaches in different patient subsets.

Evidence (chemotherapy for low-risk Group patients):

1. The COG-D9602 study stratified 388 patients with low-risk embryonal rhabdomyosarcoma into two groups.[170] 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%.

   Table 8. D9602 Risk Assignment for Low-Risk Patients

   Subset	Tumor Site	Tumor Size	Surgical-Pathological Group	Nodes
   N0 = absence of nodal spread; N1 = presence of regional nodal spread beyond the primary site.
   A	Favorable	Any	I, IIA	N0
   	Orbital	Any	I, II, III	N0
   	Unfavorable	≤5 cm	I	N0
   B	Favorable (orbital or nonorbital)	Any	IIB, IIC, III	N0, N1
   	Unfavorable	<5 cm	II	N0
   	Unfavorable	>5 cm	I, II	N0, N1

2. The COG-ARST0331 trial evaluated a refinement of therapy for two subsets of low-risk patients.[52] For subset 1 patients, this study reduced the length of therapy by using only four cycles of VAC (cumulative cyclophosphamide dose of 4.8 g/m²) followed by four VA cycles over 22 weeks. Group II and III patients received local RT. For subset 2 patients, the goal of this study was to reduce the total cumulative cyclophosphamide dose, compared with the previous IRS-IV study, without compromising FFS, and to decrease the risk of permanent infertility. Patients received four cycles of VAC (equivalent cyclophosphamide dose as subset 1) followed by VA over 46 weeks.[51][Level of evidence B4]
   1. Subset 1 enrolled 271 newly diagnosed patients with low-risk embryonal rhabdomyosarcoma, defined as patients who presented with Stage 1 or Stage 2 tumors; Group I or Group II tumors; or Stage 1, Group III orbital tumors. This noninferiority trial used a fixed outcome on the basis of expected FFS for similar patients treated in the D9602 trial.[52]
      • There were 35 treatment failures observed (48.8 expected).
      • 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.
   2. Subset 2 included patients with Stage 1, Group III nonorbital tumors or Stage 3, Group I/II embryonal tumors. Treatment consisted of four cycles of VAC chemotherapy followed by 12 cycles of VA therapy.[50,51]
      • Among 66 eligible patients, there were 20 failures, with an estimated 3-year FFS rate of 70% and an OS rate of 92%.
      • FFS rates at 3 years were even worse (57%) for girls with genital tract tumors.
      • 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.
   3. For patients with an orbital primary tumor who achieved only a partial response or stability after 12 weeks of induction chemotherapy, the 5-year FFS rate was only 84%, compared with 100% for patients who achieved a CR.[68][Level of evidence C2]

   Table 9. ARST0331 Risk Assignment for Low-Risk Patients

   Subset	Tumor Site	Tumor Size	Surgical-Pathological Group	Nodes
   N0 = absence of nodal spread; N1 = presence of regional nodal spread beyond the primary site.
   1	Favorable	Any	I	N0
   			II	N0, N1
   	Orbital	Any	III	N0
   	Unfavorable	<5 cm	I, II	N0
   2	Favorable (nonorbital)	Any	III	N0, N1
   	Unfavorable	>5 cm	I, II	N0, N1

3. The EpSSG RMS-2005 study prospectively evaluated the reduction in chemotherapy for patients with low-risk embryonal histology rhabdomyosarcoma. Between October 2005 and December 2016, 178 patients with Group I N0 disease were enrolled.[171][Level of evidence B4]
   • The 5-year EFS rate was 90.8% (95% CI, 85.0%–94.4%), and the OS rate was 95.7% (95% CI, 90.5%–98.1%).
   • Subgroup A: Patients younger than 10 years with tumors smaller than 5 cm received eight courses of VA therapy for 22 weeks. The EFS rate for this subgroup of 70 patients was 95.5% (95% CI, 86.6%–98.5%), and the OS rate was 100%.
   • Subgroup B: Patients who were older than 10 years or had tumors larger than 5 cm received four courses of IVA (VA plus ifosfamide) and five courses of VA for 25 weeks. The EFS rate for this subgroup was 87.8% (95% CI, 79.3%–93.0%), and the OS rate was 93% (95% CI, 84.8%–96.8%).
   • Treatment with VA for eight courses was effective and well tolerated by subgroup A patients with low-risk embryonal rhabdomyosarcoma. A reduction from nine courses of IVA in previous studies to four courses of IVA plus five courses of VA also produced good results.
4. The COG and EpSSG studies defined low-risk patient populations, largely based on histology. Genomic classification refined the risk classification for rhabdomyosarcoma and will be used in future COG studies.[172] Tumor samples from patients enrolled in COG trials (1988–2017), U.K. MMT, and RMS-2005 studies (1995–2016) were subjected to custom-capture sequencing. DNA from 641 patients was suitable for analysis. Variants, indels, gene deletions, and amplifications were identified, and survival analysis was performed.
   • A median of one variant per tumor was found.
   • In FOXO1 fusion–negative cases, any variant of RAS pathway members was found in more than 50% of cases. In 21% of cases, no putative driver variant was identified.
   • Variants in BCOR (15%), NF1 (15%), and TP53 (13%) were found at a higher incidence than previously reported.
   • TP53 variants were associated with worse outcomes in both fusion-negative and fusion-positive cases.
   • Variants of MYOD1 were associated with a dismal survival.
5. The COG and European investigators pooled the results of patients with rhabdomyosarcoma who had definitive surgery of the primary tumor before the initiation of systemic chemotherapy.[173] A total of 113 patients aged 0 to 18 years were identified and enrolled from January 1995 to December 2016 in COG (n = 64) and European protocols. Patients with genitourinary nonbladder and prostate rhabdomyosarcomas were excluded. The recommended chemotherapy in the European protocols was VA for 24 weeks or ifosfamide plus VA. The COG protocols recommended VA for 48 weeks or VA plus cyclophosphamide.
   • With a median follow-up of 97.5 months, the 5-year PFS rate was 80.0% (71.2%–86.4%), and the OS rate was 92.5% (85.6%–96.2%). There were no significant differences in outcomes between the chemotherapy regimens.
   • Tumor size (<5 cm vs. >5 cm) significantly influenced OS (96.2% [88.6%–98.8%] vs. 80.6% [59.5%–91.4%]; P = .01).
   • The authors suggested that to reduce the burden of treatment, VA for 24 weeks may be considered in children with tumors smaller than 5 cm.

Intermediate-risk Group

Approximately 50% of newly diagnosed patients are in the intermediate-risk category. In North America, VAC is the standard multiagent chemotherapy regimen used for intermediate-risk patients. In Europe, ifosfamide is typically used in place of cyclophosphamide. COG studies for intermediate-risk rhabdomyosarcoma use VAC plus vincristine and irinotecan (VI).

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).[38]
   • At 3 years, intermediate-risk patients had survival rates from 84% to 88%.[38]
   • 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.[38]
   • Survival in patients with tumors of embryonal histology treated in the IRS-IV trial (who received higher doses of alkylating agents) was compared with similar patients treated in the IRS-III trial (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.[174] For other groups of intermediate-risk patients, an intensification of cyclophosphamide was feasible but did not improve outcome.[175] A single-institution retrospective review of patients with head and neck rhabdomyosarcoma identified an increased risk of local failure with the use of reduced-dose cyclophosphamide.[176]
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.[177,178] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity, both in patients with recurrent disease and in newly diagnosed patients with metastatic disease.[179,180]
   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.[181][Level of evidence A1]
      • 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.
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.[182][Level of evidence C1]
   • The relative efficacy of this approach versus the standard approach requires further investigation.
4. A European trial (SIOP-MMT-95) included 457 patients with incompletely resected embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, undifferentiated sarcoma, or soft tissue primitive neuroectodermal tumor. In this study, carboplatin, epirubicin, and etoposide was added to standard IVA therapy.[183]
   • The addition of carboplatin, epirubicin, and etoposide did not improve outcome. The 3-year OS rate was 82% for patients who received IVA and 80% for patients who received IVA plus carboplatin, epirubicin, and etoposide.
   • Toxicity was significantly worse for patients in the six-drug arm.
5. The COG reported a prospective randomized trial of two treatment strategies for patients with intermediate-risk rhabdomyosarcoma.[184][Level of evidence A1] 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.
6. The EpSSG performed a randomized phase III trial to test the addition of vinorelbine and low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma.[185]

   The patients classified as high risk by the EpSSG had:

   • Nonmetastatic incompletely resected embryonal rhabdomyosarcoma at unfavorable sites with unfavorable age (aged 10 years or older) or 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 IVA—ifosfamide (6 g/m²), dactinomycin (1.5 mg/m²), and vincristine (1.5 mg/m²)—for 7 weeks, followed by randomization to continue IVA or IVA with 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).

   • The 5-year DFS rate was 69.8% for patients in the observation group and 77.6% for patients in the maintenance chemotherapy group (P = .061).
   • The 5-year OS rate was 73.7% for patients in the observation group and 86.5% for patients in the maintenance chemotherapy group (P = .0097).
   • The addition of doxorubicin did not appear to confer any improvement in outcomes.[186]
7. The CWS conducted a phase III trial (RMS-96) in patients with high-risk nonmetastatic rhabdomyosarcoma and Ewing sarcoma recruited between 1995 to 2004 from the CWS and Italian Soft Tissue Sarcoma Committee institutions.[187] There were 557 evaluable patients with localized rhabdomyosarcoma. Patients were randomly assigned to receive either a four-drug regimen (vincristine, ifosfamide, doxorubicin, dactinomycin; 284 rhabdomyosarcoma patients) or six-drug regimen (carboplatin, epirubicin, vincristine, dactinomycin, ifosfamide, and etoposide; 273 rhabdomyosarcoma patients).
   • The addition of etoposide and carboplatin and increased single-dose ifosfamide did not improve the EFS and overall outcome.
   • Toxicities and secondary malignancies were identical in both treatment arms.

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.[181,188] 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. A 2009 analysis by the COG reported that for Group III patients, best response (complete resolution versus partial response or no response) to initial chemotherapy had no impact on overall outcome.[188] In 2020, the COG reported a retrospective analysis of 601 patients with clinical Group III disease. The patients were enrolled in two COG studies (ARST0531 [n = 285] and D9803 [n = 316]) and completed all protocol therapy without developing progressive disease.[189] Response was defined radiographically: 393 patients had complete resolution (65.4%), and 208 patients had partial response/no response (34.6%). The overall 5-year FFS rate was 75% for patients who achieved complete resolution and 66.5% for those who had a partial response/no response (adjusted [adj.] P = .094). Radiographic response was not associated with OS at any site of disease (adj. P = .21). Resection of the end-of-therapy mass did not improve FFS (P = .12) or OS (P = .37). Patients with parameningeal primary sites who achieved complete resolution had significantly improved FFS (adj. P = .037), while those with nonparameningeal primary sites had similar outcomes (adj. P = .47). In conclusion, complete resolution status at the end of protocol therapy in patients with parameningeal clinical Group III rhabdomyosarcoma was associated with improved FFS but not OS.

While induction chemotherapy is commonly administered for 9 to 12 weeks, 2.2% of patients with intermediate-risk rhabdomyosarcoma in the IRS-IV and D9803 studies were found to have early disease progression and did not receive their planned local control therapy.[184][Level of evidence A1]

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.[167,190,191] Two retrospective studies have examined patients who present with metastases limited to the lungs;[166,167] results are summarized in the Metastatic disease 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.[192][Level of evidence C1]

   The 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:[192][Level of evidence C1]

   • 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).

Many clinical trials have tried 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: IE, vincristine/melphalan (VM),[193] and ifosfamide/doxorubicin (ID).[194] 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%).[194]
   • 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.[179,180]
   • 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.[178]
3. Irinotecan and the VI combination have also been evaluated as up-front window trials by the COG-STS.[195]
   • The response rates were better when irinotecan was administered with vincristine than without it.
   • 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.[196]
   • Thirteen of 20 patients responded to therapy, and four patients had progressive disease.
5. A study from the SIOP demonstrated continued poor outcomes for patients with high-risk features such as age 10 years and older or bone/bone marrow involvement. This study compared a standard six-drug combination followed by vincristine/doxorubicin/cyclophosphamide (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.[197]
   • 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.[192] Several treatment strategies, all given over 54 planned weeks, were used:
   1. A period of compressed (every 2 weeks) schedule of chemotherapy using VDC alternating with IE.
   2. The addition of VI, including during RT.
   3. A period of VDC 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 historical controls for patients with lower-risk disease. The 3-year EFS rates were 69% for those with an Oberlin risk factor score of zero or one and 60% for patients younger than 10 years with embryonal rhabdomyosarcoma.[198][Level of evidence C2]
   • However, patients with more than two Oberlin risk factors had a 3-year EFS rate of 20%, comparable to historical 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 IVA with an investigational arm comprising four cycles of IVA plus doxorubicin, followed by five cycles of IVA.[186][Level of evidence C1]
   • 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 VI, interval-compressed VDC alternating with IE, and vincristine/dactinomycin/cyclophosphamide.[199][Level of evidence C2]
   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%) for patients who received cixutumumab and 18% (95% CI, 2%–35%) for patients who received temozolomide.
   • These results did not differ from the results observed in the ARST0431 (NCT00354744) trial that used the same chemotherapy regimen.
9. A European multinational collaboration investigated an intensive induction regimen followed by 1 year of maintenance therapy for patients with high-risk rhabdomyosarcoma who were aged 21 years or younger. Induction therapy consisted of four cycles of ifosfamide, vincristine, dactinomycin, and doxorubicin followed by five cycles of ifosfamide, vincristine, and dactinomycin. Maintenance therapy comprised 48 weeks of low-dose intravenous vinorelbine and low-dose oral cyclophosphamide. There were 270 evaluable patients.[200]
   • The 3-year EFS rate was 34.9% (95% CI, 29.1%–40.8%), and the OS rate was 47.9% (95% CI, 41.6%–53.9%).
   • The investigators simultaneously conducted a prospective randomized trial that tested the addition of bevacizumab to chemotherapy. In a subset of 102 patients, 50 were assigned to receive bevacizumab. The addition of bevacizumab did not improve EFS or OS.

Other Therapeutic Approaches

• High-dose chemotherapy with autologous and allogeneic stem cell rescue has been evaluated in a limited number of patients with rhabdomyosarcoma.[201,202,203] The use of this modality has failed to improve the outcomes of patients with newly diagnosed or recurrent rhabdomyosarcoma.[203]
• 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.[204][Level of evidence C1]

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, see the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

• ARST2032 (NCT05304585) (Chemotherapy for the Treatment of Patients With Newly Diagnosed Very Low-Risk and Low-Risk, Fusion-Negative Rhabdomyosarcoma): The COG redefined low-risk rhabdomyosarcoma using both clinical and molecular criteria. The new criteria will be used in this study. Patients are required to enroll in the COG APEC14B1 trial and the Molecular Characterization Initiative. Low-risk patients have both fusion-negative and wild-type MYOD1 and TP53. In this trial, very low-risk patients will receive 24 weeks of VA therapy, and low-risk patients will receive four cycles of VAC followed by VA for a total of 24 weeks.

  Table ARST2032 Risk Assignment for Low-Risk Patients

  Subset	Fusion status	Tumor Site	Tumor Size	Surgical-pathological Group	MYOD1orTP53Status
  Very Low Risk	Negative	Favorable	Any	I	Wild-type
  Low Risk	Negative	Favorable	Any	II	Wild-type
  		Unfavorable	>5 cm	I, II
  		Orbit	Any	III

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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180. 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.
181. 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.
182. 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.
183. 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.
184. 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.
185. Bisogno G, De Salvo GL, Bergeron C, et al.: Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 20 (11): 1566-1575, 2019.
186. Bisogno G, Jenney M, Bergeron C, et al.: Addition of dose-intensified doxorubicin to standard chemotherapy for rhabdomyosarcoma (EpSSG RMS 2005): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet Oncol 19 (8): 1061-1071, 2018.
187. Sparber-Sauer M, Ferrari A, Kosztyla D, et al.: Long-term results from the multicentric European randomized phase 3 trial CWS/RMS-96 for localized high-risk soft tissue sarcoma in children, adolescents, and young adults. Pediatr Blood Cancer 69 (9): e29691, 2022.
188. 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.
189. Lautz TB, Chi YY, Tian J, et al.: Relationship between tumor response at therapy completion and prognosis in patients with Group III rhabdomyosarcoma: A report from the Children's Oncology Group. Int J Cancer 147 (5): 1419-1426, 2020.
190. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995.
191. 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.
192. 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.
193. Breitfeld PP, Lyden E, Raney RB, et al.: Ifosfamide and etoposide are superior to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when administered with irradiation and combination chemotherapy: a report from the Intergroup Rhabdomyosarcoma Study Group. J Pediatr Hematol Oncol 23 (4): 225-33, 2001.
194. Sandler E, Lyden E, Ruymann F, et al.: Efficacy of ifosfamide and doxorubicin given as a phase II "window" in children with newly diagnosed metastatic rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group. Med Pediatr Oncol 37 (5): 442-8, 2001.
195. 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.
196. Bergeron C, Thiesse P, Rey A, et al.: Revisiting the role of doxorubicin in the treatment of rhabdomyosarcoma: an up-front window study in newly diagnosed children with high-risk metastatic disease. Eur J Cancer 44 (3): 427-31, 2008.
197. McDowell HP, Foot AB, Ellershaw C, et al.: Outcomes in paediatric metastatic rhabdomyosarcoma: results of The International Society of Paediatric Oncology (SIOP) study MMT-98. Eur J Cancer 46 (9): 1588-95, 2010.
198. Weigel BJ, Lyden E, Anderson JR, et al.: Intensive Multiagent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide and Vincristine/Doxorubicin/Cyclophosphamide, Irinotecan, and Radiation, in Patients With High-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol 34 (2): 117-22, 2016.
199. Malempati S, Weigel BJ, Chi YY, et al.: The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy is feasible but does not improve outcome for patients with metastatic rhabdomyosarcoma: A report from the Children's Oncology Group. Cancer 125 (2): 290-297, 2019.
200. Schoot RA, Chisholm JC, Casanova M, et al.: Metastatic Rhabdomyosarcoma: Results of the European Paediatric Soft Tissue Sarcoma Study Group MTS 2008 Study and Pooled Analysis With the Concurrent BERNIE Study. J Clin Oncol 40 (32): 3730-3740, 2022.
201. Admiraal R, van der Paardt M, Kobes J, et al.: High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma. Cochrane Database Syst Rev (12): CD006669, 2010.
202. Peinemann F, Kröger N, Bartel C, et al.: High-dose chemotherapy followed by autologous stem cell transplantation for metastatic rhabdomyosarcoma--a systematic review. PLoS One 6 (2): e17127, 2011.
203. Thiel U, Koscielniak E, Blaeschke F, et al.: Allogeneic stem cell transplantation for patients with advanced rhabdomyosarcoma: a retrospective assessment. Br J Cancer 109 (10): 2523-32, 2013.
204. Mackall CL, Rhee EH, Read EJ, et al.: A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas. Clin Cancer Res 14 (15): 4850-8, 2008.

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 5-year overall survival (OS) rates of 40% to 50%. This population of patients with improved outcomes encompasses only 20% of all patients with a relapse.[1][Level of evidence C1]
• 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 C1]
• A 2005 study of 125 patients with nonmetastatic rhabdomyosarcoma whose disease 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 had a relapse after achieving complete remission and completing primary treatment, the favorable prognostic factors for 3-year OS were reported. These factors were favorable primary site, local relapse, time to relapse of more than 12 months, tumor size of 5 cm or smaller, and no previous RT.[6][Level of evidence C1]
• A 2011 study of 474 patients 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 of 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) and with or without RT. The four most important factors for survival after relapse were no lymph node involvement, no metastases, adequate local therapy, and a second complete remission. The OS rate at 5 years was 21%.[8][Level of evidence C1]
• A single-institution, retrospective review identified 23 patients with central nervous system (CNS) relapse after initial treatment for rhabdomyosarcoma.[9][Level of evidence C1] 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 Progressive or Recurrent Childhood Rhabdomyosarcoma

The selection of additional 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:

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 examined 108 Italian children with bladder or prostate tumors who did not achieve tumor eradication after chemotherapy, with or without RT. The study 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 C2]
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, particularly for those in whom surgical excision is not possible. RT techniques may include external beam in fractionated or hypofractionated courses (e.g., stereotactic body radiation therapy, CyberKnife, or brachytherapy). The rationale is primarily to improve local control that can translate into a better quality of life. An impact on OS is unlikely because of the metastatic disease that often occurs. Even a benefit on local control is difficult to unequivocally demonstrate because of small patient numbers in available reports. For example, in a multi-institutional study of 23 patients with local relapse only (n = 19) or local relapse with distant failure (n = 4) who were managed with (n = 12) or without (n = 11) re-irradiation, the local failure-free survival and OS in re-irradiated versus unirradiated patients was 19.6 months versus 12.4 months (P = .1) and 26.1 months versus 18.8 months (P = .46). In this report, patients with favorable site and Group 3 disease local (only) failure, and/or embryonal histology had improved 3-year local relapse-free survival rates with re-irradiation (62.3% vs. 40%; P = .11).[13]
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] rate, 41%), but it was less effective for patients with alveolar rhabdomyosarcoma (5-year EFS rate, 25%).[14] 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 progressive or recurrent rhabdomyosarcoma:

1. Carboplatin and etoposide.[14]
2. Ifosfamide, carboplatin, and etoposide.[15,16]
3. Cyclophosphamide and topotecan.[17]
4. Topotecan, carboplatin, cyclophosphamide, and etoposide.[18]
   1. In a 2018 Italian study, 38 patients with recurrent or refractory rhabdomyosarcoma were treated with topotecan, carboplatin, cyclophosphamide, and etoposide.[18][Level of evidence C1]
      • Nine of 32 patients had a complete or partial response. However, the 5-year OS rate was 17%, and the PFS rate was 14%.
5. Single-agent vinorelbine.[19,20]
   • In one phase II trial, 4 of 11 patients with recurrent rhabdomyosarcoma responded to single-agent vinorelbine.[19]
   • In another trial, 6 of 12 young patients (aged 9–29 years) had a partial response.[20]
   • In a meta-analysis of five studies, patients with relapsed alveolar rhabdomyosarcoma responded better to vinorelbine, either alone or in combination with other agents, than patients with relapsed embryonal and unclassified rhabdomyosarcoma.[21]
6. Vinorelbine and cyclophosphamide.[22,23]
   1. In a pilot study, three of nine patients with rhabdomyosarcoma had an objective response.[22]
   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.[23][Level of evidence C3]
      • Four complete responses and 14 partial responses were observed, for an objective response rate of 36%.
7. Gemcitabine and docetaxel.[24]
   • In a single-institution trial, two patients (N = 5) with recurrent rhabdomyosarcoma achieved an objective response.[24]
8. Sirolimus.[25]
9. Topotecan, vincristine, and doxorubicin.[26][Level of evidence C3]
10. Vincristine, irinotecan, and temozolomide.[27,28,29]
    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.[27]; [28][Level of evidence C2]
    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.[29][Level of evidence C1]
       • There were no complete or partial remissions; four patients had stable disease, and 11 patients had progressive disease.
11. Vincristine, irinotecan, doxorubicin, cyclophosphamide, etoposide, ifosfamide, and tirapazamine.[30]
    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 vincristine and irinotecan (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.[30][Level of evidence C1]
       • Favorable-risk patients had a 3-year failure-free survival (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.[31,32,33,34,35,36]
    1. A COG prospective, randomized, up-front window trial, COG-ARST0121, compared VI (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.[35][Level of evidence A1]
       • At 1 year after initiation of treatment for recurrence, the 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 study, 120 patients with recurrent or refractory rhabdomyosarcoma were randomly assigned to receive either VI or vincristine, irinotecan, and temozolomide (VIT).[37][Level of evidence A1]
       • The objective response rate was 44% (24 of 55 evaluable patients) for patients who received VIT, compared with 31% (18 of 58) for patients who received VI.
       • The patients in the VIT arm achieved significantly better OS (adjusted hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.35–0.84; P = .006), than patients on the VI arm, with consistent PFS results (adjusted HR, 0.68; 95% CI, 0.46–1.01; P = .059).
       • Overall, patients experienced grade 3 or greater adverse events more frequently with VIT than VI (98% vs. 78%, respectively; P = .009), including a significant excess of hematological toxicity (81% vs. 61%; P = .025).
13. Temsirolimus, irinotecan, and temozolomide.[38]
    1. In a phase I trial of these agents, four patients had rhabdomyosarcoma.[38]
       • The regimen was well tolerated.
       • One patient had a partial response, and another patient had stable disease.
14. Temsirolimus, cyclophosphamide, and vinorelbine.[39]
    1. A COG randomized, phase II, selection-design study of patients with relapsed rhabdomyosarcoma compared bevacizumab with temsirolimus, both administered with cyclophosphamide and vinorelbine.[40][Level of evidence C2]
       • Patients on the temsirolimus arm had improved EFS (P = .003). The 6-month and 12-month EFS rates in the temsirolimus arm were 65% (95% CI, 44%–79%) and 40.5% (95% CI, 25.6%–55.3%), respectively, compared with 50% (95% CI, 32%–66%) and 18.2% (95% CI, 6.8%–29.6%) in the bevacizumab arm.
       • The complete response rate (complete remission plus partial remission) was higher on the temsirolimus arm (47%) than on the bevacizumab arm (28%). The difference was not statistically significant at the 0.05 level (P = .12).
       • These results are the basis for the subsequent COG trial randomizing the use of temsirolimus for newly diagnosed patients with nonmetastatic rhabdomyosarcoma (ARST1431 [NCT02567435]).
15. Adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, and etoposide (ACCTTIVE) or topotecan, etoposide, carboplatin, and cyclophosphamide (TECC).
    1. The Cooperative Weichteilsarkom Studiengruppe (CWS) examined second-line treatment for patients who had recurrence of rhabdomyosarcoma after initial treatment. Second-line chemotherapy based on anthracyclines (ACCTTIVE) was recommended for patients in initial low-risk, standard-risk, and high-risk groups after their original treatment did not include anthracyclines. TECC was recommended for patients in the very high-risk group after their initial treatment included anthracycline-based regimens. The risk groups included low risk, standard risk, high risk, and very high risk.[41]
       • Initial risk stratification, pattern/time to relapse, and achievement of second complete remission were significant prognostic factors for postrelapse survival.
       • The 5-year OS rates were 80% (± 21%) for patients with relapsed disease in the standard-risk group, 20% (± 16%) for patients in the high-risk group, and 13% (± 23%) for patients in the very high-risk group (P = .008).

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.[42,43,44]

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.

Palliation of painful lesions in children with recurrent or progressive disease can be achieved using a short course (10 or fewer fractions) of radiation therapy. In a retrospective study of 213 children with various malignancies, who were treated with short course radiation therapy, 85% of patients had complete or partial pain relief, with low levels of toxicity.[45]

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, see the ClinicalTrials.gov website.

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

• 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 in pediatric participants who have either advanced melanoma or a programmed cell death ligand 1–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.
• 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 in a patient's tumor (refractory or recurrent). Children and adolescents aged 1 to 21 years are eligible for the trial.

  Patients with tumors that have molecular variants addressed by open treatment arms in the trial may be enrolled in 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.

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33. 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.
34. Furman WL, Stewart CF, Poquette CA, et al.: Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17 (6): 1815-24, 1999.
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Latest Updates to This Summary (06 / 17 / 2024)

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

General Information About Childhood Rhabdomyosarcoma

Added text about the results of a European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) study that evaluated the role of clinical factors together with FOXO1 fusion status in patients with nonmetastatic rhabdomyosarcoma, using data from the EpSSG RMS2005 study (cited De Salvo et al. as reference 73).

Revised text to state that fusion status has now been incorporated into the risk stratification of patients in the current Children's Oncology Group (COG) ARST1431 study for patients with intermediate-risk rhabdomyosarcoma, in subsequent COG trials, and in the new international EpSSG trial.

Treatment of Childhood Rhabdomyosarcoma

Added text to state that in a COG study of patients with orbital rhabdomyosarcoma, 28 patients experienced a recurrence, including 25 who were treated in low-risk trials. Twenty-seven recurrences were local. One metastatic recurrence occurred in a patient with Group III, PAX3::FOXO1 fusion–positive alveolar rhabdomyosarcoma.

Treatment of Progressive or Recurrent Childhood Rhabdomyosarcoma

Added adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, and etoposide (ACCTTIVE) and topotecan, etoposide, carboplatin, and cyclophosphamide (TECC) as chemotherapy regimens that have been used to treat progressive or recurrent rhabdomyosarcoma.

Added text about the results of a Cooperative Weichteilsarkom Studiengruppe study that examined second-line treatment using ACCTIVE or TECC for patients who had recurrence of rhabdomyosarcoma after initial treatment (cited Heinz et al. as reference 41).

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® Cancer Information for Health Professionals 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 in the care of their 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-Dixon, MD, FACS, FAAP (Howard University)
• William H. Meyer, MD
• 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)
• Malcolm A. Smith, MD, PhD (National Cancer Institute)

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

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The preferred citation for this PDQ summary is:

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

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Last Revised: 2024-06-17