Sarcoma, rhabdomyosarcoma, childhood: Treatment - Health Professional Information [NCI PDQ]

National Cancer Institute logo

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER

Childhood Rhabdomyosarcoma Treatment (PDQ®)

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood rhabdomyosarcoma. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

  • Cellular classification.
  • Stage information.
  • Treatment options.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

In the summary, treatments are described as “standard” or “conventional” and “under clinical evaluation.” These designations should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less-technical language, and in Spanish.

General Information

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Cancer in children and adolescents is rare. 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 primary care physician, pediatric surgical subspecialists, radiation oncologist, pediatric oncologist/hematologist, rehabilitation specialist, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[1] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ Late Effects of Treatment for Childhood Cancer summary for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Childhood rhabdomyosarcoma, a soft tissue malignant tumor of skeletal muscle origin, accounts for approximately 3.5% of the cases of cancer among children aged 0 to 14 years and 2% of the cases among adolescents and young adults aged 15 to 19 years.[2,3] It is usually a curable disease in most children with localized disease who receive combined modality therapy, with more than 70% surviving 5 years after diagnosis.[4,5,6] Relapses are uncommon after 5 years of disease-free survival, with a 9% late-event rate at 10 years. Relapses, however, are more common for patients who have gross residual disease in unfavorable sites following initial surgery and those who have metastatic disease at diagnosis.[7] The most common primary sites for rhabdomyosarcoma are the head and neck (e.g., parameningeal, orbit, pharyngeal, etc.), the genitourinary tract, and the extremities.[4,5] Other less common primary sites include the trunk, chest wall, the abdomen (including the retroperitoneum and biliary tract), and the perineal/anal region.

Most cases of rhabdomyosarcoma occur sporadically with no recognized predisposing factor or risk factor,[8] though a small proportion are associated with genetic conditions. These conditions include Li-Fraumeni cancer susceptibility syndrome (with germline p53 mutations),[9,10,11] neurofibromatosis type I,[12] Costello syndrome (with germline HRAS mutations),[13,14,15] and Beckwith-Wiedemann syndrome (Wilm tumor and hepatoblastoma are more commonly associated with the latter syndrome).[16,17]

The prognosis for a child or adolescent with rhabdomyosarcoma is related to the age of the patient, site of origin, resectability, presence of metastases, number of metastatic sites or tissues involved, presence or absence of lymph node involvement, histopathology,[4,5,18,19,20,21,22,23,24] and unique biological characteristics of rhabdomyosarcoma tumor cells. Examples of both clinical and biological factors with proven or possible prognostic significance are briefly described below.

  • Children younger than 1 year may pose a problem in terms of the ability to deliver aggressive therapy including full-dose radiation and appropriate chemotherapy on schedule; therefore, outcome may be adversely affected.[6,25] Children aged between 1 and 9 years have the best overall survival.[19]
  • Primary sites with more favorable prognoses include the orbit and nonparameningeal head and neck, paratestis and vagina (nonbladder, nonprostate genitourinary), and the biliary tract.[4,5,26,27,28]
  • Tumor burden at diagnosis has prognostic significance. Patients with smaller tumors (<5 cm) have improved survival compared with children with larger tumors; children with metastatic disease at diagnosis have the poorest prognosis.[4,26,29] The prognostic significance of metastatic disease is modified by tumor histology (embryonal is more favorable than other histologies) and by the number of metastatic sites.[20] Similarly, patients with metastatic genitourinary (nonbladder, nonprostate) primary tumors have a more favorable outcome compared with patients with metastatic disease and primary tumors at other sites.[30] In addition, patients with otherwise localized disease but with proven regional lymph node involvement have a poorer prognosis than patients without regional nodal involvement.[23,24]
  • The extent of disease following the primary surgical procedure (i.e., the Clinical Group) is also correlated with outcome.[4] In the Intergroup Rhabdomyosarcoma Study (IRS)-III, patients with gross residual disease after initial surgery (Clinical Group III) had a 5-year survival rate of approximately 70% compared with a greater than 90% 5-year survival rate for patients with no residual tumor after surgery (Clinical Group I) and an approximately 80% 5-year survival rate for patients with microscopic residual tumor following surgery (Clinical Group II).[4,18]
  • The alveolar subtype is more prevalent among patients with less favorable clinical features (e.g., younger than 1 year or older than 10 years, extremity primaries, and metastatic disease), and is generally associated with a worse outcome. 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 (Clinical Group I).[27] Statistically-significant differences in survival for histopathologic subtype were not, however, noted when all patients with rhabdomyosarcoma were analyzed,[31,32] nor were differences noted by histologic subtype in a large group of German children with rhabdomyosarcoma.[26] In the IRS-III study, outcome for patients with Clinical Group I alveolar subtype tumors was similar to those of other patients with Clinical Group I tumors, but the patients with alveolar subtype received more intensive therapy.[4]
  • Patients with undifferentiated sarcoma were eligible for participation in rhabdomyosarcoma trials coordinated by the Intergroup Rhabdomyosarcoma Study Group (IRSG) and the Children’s Oncology Group (COG) from 1972 until 2006. The rationale for this inclusion was the observation that patients with undifferentiated sarcoma have similar sites of disease and outcome to those with alveolar rhabdomyosarcoma (ARMS). The patients with undifferentiated sarcoma will be treated on a non-rhabdomyosarcomatous soft tissue sarcoma protocol using agents active in adult soft tissue sarcoma. In therapeutic trials for adults with soft tissue sarcoma, patients with undifferentiated sarcoma are included with all other histologies and treated in a similar manner. Contemporary treatment for adult soft tissue sarcoma utilizes ifosfamide and doxorubicin, sometimes with the addition of other chemotherapeutic agents, surgery, and radiation therapy. There are no data to compare these two approaches.

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

References:

  1. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.
  2. Gurney JG, Severson RK, Davis S, et al.: Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer 75 (8): 2186-95, 1995.
  3. Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review, 1973-1996. Bethesda, Md: National Cancer Institute, 1999. Also available online. Last accessed April 19, 2007.
  4. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995.
  5. Maurer HM, Gehan EA, Beltangady M, et al.: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71 (5): 1904-22, 1993.
  6. 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.
  7. Sung L, Anderson JR, Donaldson SS, et al.: Late events occurring five years or more after successful therapy for childhood rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Eur J Cancer 40 (12): 1878-85, 2004.
  8. Gurney JG, Young JL Jr, Roffers SD, et al.: Soft tissue sarcomas. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp 111-123. Also available online. Last accessed July 20, 2006.
  9. Li FP, Fraumeni JF Jr: Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst 43 (6): 1365-73, 1969.
  10. Diller L, Sexsmith E, Gottlieb A, et al.: Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. J Clin Invest 95 (4): 1606-11, 1995.
  11. Trahair T, Andrews L, Cohn RJ: Recognition of Li Fraumeni syndrome at diagnosis of a locally advanced extremity rhabdomyosarcoma. Pediatr Blood Cancer 48 (3): 345-8, 2007.
  12. Ferrari A, Bisogno G, Macaluso A, et al.: Soft-tissue sarcomas in children and adolescents with neurofibromatosis type 1. Cancer 109 (7): 1406-12, 2007.
  13. Gripp KW, Lin AE, Stabley DL, et al.: HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A 140 (1): 1-7, 2006.
  14. Aoki Y, Niihori T, Kawame H, et al.: Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 37 (10): 1038-40, 2005.
  15. Gripp KW: Tumor predisposition in Costello syndrome. Am J Med Genet C Semin Med Genet 137 (1): 72-7, 2005.
  16. Samuel DP, Tsokos M, DeBaun MR: Hemihypertrophy and a poorly differentiated embryonal rhabdomyosarcoma of the pelvis. Med Pediatr Oncol 32 (1): 38-43, 1999.
  17. DeBaun MR, Tucker MA: Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr 132 (3 Pt 1): 398-400, 1998.
  18. Smith LM, Anderson JR, Qualman SJ, et al.: Which patients with microscopic disease and rhabdomyosarcoma experience relapse after therapy? A report from the soft tissue sarcoma committee of the children's oncology group. J Clin Oncol 19 (20): 4058-64, 2001.
  19. Joshi D, Anderson JR, Paidas C, et al.: Age is an independent prognostic factor in rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Pediatr Blood Cancer 42 (1): 64-73, 2004.
  20. 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.
  21. La Quaglia MP, Heller G, Ghavimi F, et al.: The effect of age at diagnosis on outcome in rhabdomyosarcoma. Cancer 73 (1): 109-17, 1994.
  22. Punyko JA, Mertens AC, Baker KS, et al.: Long-term survival probabilities for childhood rhabdomyosarcoma. A population-based evaluation. Cancer 103 (7): 1475-83, 2005.
  23. Lawrence W Jr, Hays DM, Heyn R, et al.: Lymphatic metastases with childhood rhabdomyosarcoma. A report from the Intergroup Rhabdomyosarcoma Study. Cancer 60 (4): 910-5, 1987.
  24. Mandell L, Ghavimi F, LaQuaglia M, et al.: Prognostic significance of regional lymph node involvement in childhood extremity rhabdomyosarcoma. Med Pediatr Oncol 18 (6): 466-71, 1990.
  25. Ferrari A, Casanova M, Bisogno G, et al.: Rhabdomyosarcoma in infants younger than one year old: a report from the Italian Cooperative Group. Cancer 97 (10): 2597-604, 2003.
  26. Koscielniak E, Jürgens H, Winkler K, et al.: Treatment of soft tissue sarcoma in childhood and adolescence. A report of the German Cooperative Soft Tissue Sarcoma Study. Cancer 70 (10): 2557-67, 1992.
  27. 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.
  28. Spunt SL, Lobe TE, Pappo AS, et al.: Aggressive surgery is unwarranted for biliary tract rhabdomyosarcoma. J Pediatr Surg 35 (2): 309-16, 2000.
  29. Lawrence W Jr, Anderson JR, Gehan EA, et al.: Pretreatment TNM staging of childhood rhabdomyosarcoma: a report of the Intergroup Rhabdomyosarcoma Study Group. Children's Cancer Study Group. Pediatric Oncology Group. Cancer 80 (6): 1165-70, 1997.
  30. Koscielniak E, Rodary C, Flamant F, et al.: Metastatic rhabdomyosarcoma and histologically similar tumors in childhood: a retrospective European multi-center analysis. Med Pediatr Oncol 20 (3): 209-14, 1992.
  31. Lawrence W Jr, Gehan EA, Hays DM, et al.: Prognostic significance of staging factors of the UICC staging system in childhood rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study (IRS-II). J Clin Oncol 5 (1): 46-54, 1987.
  32. Meza JL, Anderson J, Pappo AS, et al.: Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: the Children's Oncology Group. J Clin Oncol 24 (24): 3844-51, 2006.

Cellular Classification

Rhabdomyosarcoma can be divided into several histologic subsets: embryonal rhabdomyosarcoma, which has embryonal, botryoid, and spindle cell subtypes; alveolar rhabdomyosarcoma; and pleomorphic rhabdomyosarcoma.[1,2]

Embryonal Rhabdomyosarcoma

The embryonal subtype is the most frequently observed subtype in children, accounting for approximately 60% to 70% of rhabdomyosarcomas of childhood.[1] Tumors with embryonal histology typically arise in the head and neck region or in the genitourinary tract, although they may occur at any primary site.

Botryoid and spindle cell subtypes

Botryoid tumors represent about 10% of all rhabdomyosarcoma cases and are embryonal tumors that arise under the mucosal surface of body orifices such as the vagina, bladder, nasopharynx, and biliary tract. The spindle cell variant of embryonal rhabdomyosarcoma is most frequently observed at the paratesticular site.[3] Both the botryoid and the spindle cell subtypes are associated with very favorable outcomes.[2]

Alveolar Rhabdomyosarcoma

Approximately 20% of children with rhabdomyosarcoma have the alveolar subtype. An increased frequency of this subtype is noted in adolescents and in patients with primary sites involving the extremities, trunk, and perineum/perianal region.[1]

Pleomorphic (Anaplastic) Rhabdomyosarcoma

Pleomorphic rhabdomyosarcoma occurs predominantly in patients aged 30 to 50 years and is rarely seen in children. In children, the term "pleomorphic" has been replaced by the term "anaplastic."[4]

Chromosomal and Molecular Characteristics

The embryonal and alveolar histologies have distinctive molecular characteristics that have been used for diagnostic confirmation and which may be useful in the future for monitoring minimal residual disease during treatment.[5,6,7,8] Unique translocations between the FKHR gene on chromosome 13 and either the PAX3 gene on chromosome 2 or the PAX7 gene on chromosome 1 are characteristic of alveolar rhabdomyosarcoma.[5,9] Translocations involving the PAX3 gene occur in approximately 55% of alveolar rhabdomyosarcoma cases, while the PAX7 gene appears to be involved in about 20% of cases.[5] Among patients with alveolar histology and metastatic disease, those with PAX7 gene involvement appear to fare better.[10] In alveolar cases associated with the PAX3 gene, patients are older and have a higher incidence of invasive tumor (T2). Alveolar cases associated with the PAX7 gene appear to occur in patients at a younger age, and they may have longer event-free survival rates than those associated with PAX3 gene rearrangements.[10,11,12] Embryonal tumors, on the other hand, often show loss of specific genomic material from the short arm of chromosome 11.[9,13,14] The consistent loss of genomic material from the chromosome 11p15 region in embryonal tumors suggests the presence of a tumor suppressor gene, though no such gene has yet been identified. Breakpoints involving the 1p11-1q11 region are relatively common (36%) in embryonal rhabdomyosarcoma.[15]

References:

  1. Parham DM: Pathologic classification of rhabdomyosarcomas and correlations with molecular studies. Mod Pathol 14 (5): 506-14, 2001.
  2. Newton WA Jr, Gehan EA, Webber BL, et al.: Classification of rhabdomyosarcomas and related sarcomas. Pathologic aspects and proposal for a new classification--an Intergroup Rhabdomyosarcoma Study. Cancer 76 (6): 1073-85, 1995.
  3. Leuschner I: Spindle cell rhabdomyosarcoma: histologic variant of embryonal rhabdomyosarcoma with association to favorable prognosis. Curr Top Pathol 89: 261-72, 1995.
  4. Kodet R, Newton WA Jr, Hamoudi AB, et al.: Childhood rhabdomyosarcoma with anaplastic (pleomorphic) features. A report of the Intergroup Rhabdomyosarcoma Study. Am J Surg Pathol 17 (5): 443-53, 1993.
  5. Barr FG: Molecular genetics and pathogenesis of rhabdomyosarcoma. J Pediatr Hematol Oncol 19 (6): 483-91, 1997 Nov-Dec.
  6. Kelly KM, Womer RB, Barr FG: Minimal disease detection in patients with alveolar rhabdomyosarcoma using a reverse transcriptase-polymerase chain reaction method. Cancer 78 (6): 1320-7, 1996.
  7. Edwards RH, Chatten J, Xiong QB, et al.: Detection of gene fusions in rhabdomyosarcoma by reverse transcriptase-polymerase chain reaction assay of archival samples. Diagn Mol Pathol 6 (2): 91-7, 1997.
  8. Sartori F, Alaggio R, Zanazzo G, et al.: Results of a prospective minimal disseminated disease study in human rhabdomyosarcoma using three different molecular markers. Cancer 106 (8): 1766-75, 2006.
  9. Merlino G, Helman LJ: Rhabdomyosarcoma--working out the pathways. Oncogene 18 (38): 5340-8, 1999.
  10. Sorensen PH, Lynch JC, Qualman SJ, et al.: PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 20 (11): 2672-9, 2002.
  11. Kelly KM, Womer RB, Sorensen PH, et al.: Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J Clin Oncol 15 (5): 1831-6, 1997.
  12. Barr FG, Qualman SJ, Macris MH, et al.: Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Cancer Res 62 (16): 4704-10, 2002.
  13. Koufos A, Hansen MF, Copeland NG, et al.: Loss of heterozygosity in three embryonal tumours suggests a common pathogenetic mechanism. Nature 316 (6026): 330-4, 1985 Jul 25-31.
  14. Scrable H, Witte D, Shimada H, et al.: Molecular differential pathology of rhabdomyosarcoma. Genes Chromosomes Cancer 1 (1): 23-35, 1989.
  15. Gordon T, McManus A, Anderson J, et al.: Cytogenetic abnormalities in 42 rhabdomyosarcoma: a United Kingdom Cancer Cytogenetics Group Study. Med Pediatr Oncol 36 (2): 259-67, 2001.

Stage Information

Terms used in this summary section are defined below in Table 1.:

Table 1: Definition of Terms

TermDefinition
Favorable siteOrbit; non-parameningeal head and neck; genitourinary excluding kidney, bladder, and prostate; biliary tract.
Unfavorable siteAny site not considered favorable.
T1Confined to anatomic site of origin.
T2Extension and/or fixative to surrounding tissue.
aTumor =5 cm in maximum diameter.
bTumor >5 cm in maximum diameter.
N0No clinical regional lymph node involvement.
N1Clinical regional lymph node involvement.
NXRegional lymph nodes not examined; no information.
M0No metastatic disease.
M1Metastatic disease.

Staging of rhabdomyosarcoma is relatively complex. The process includes:

  1. Assigning a local tumor Group (status postsurgical resection/biopsy).
  2. Assigning stage (consider site, size, Group, presence/absence of metastases).
  3. Assigning a risk group (consider stage, Group, and histology).

As noted previously, prognosis for children with rhabdomyosarcoma is dependent on the primary site, size, Group, and histologic subtype. Favorable prognostic Groups have been identified by previous Intergroup Rhabdomyosarcoma Studies (IRS), and treatment plans have been designed based on assignment of patients to different Groups based on prognosis. The IRS-I, IRS-II, and IRS-III studies prescribed treatment plans based on a surgicopathologic grouping system. In this system, Groups are defined by the extent of disease and by the extent of initial surgical resection after pathologic review of the tumor specimen(s). The definitions of these Groups in the IRS-I, IRS-II, and IRS-III studies are given in Table 2 below.[1,2]

Table 2: IRS Group Surgicopathologic Grouping System

GroupDefinition
I Approximately 13% of all patients are in this Group.A localized tumor that is completely removed with pathologically clear margins and no regional lymph node involvement.
II Approximately 20% of all patients are in this Group.A localized tumor that is grossly removed with: (A) microscopic disease at the margin, (B) involved, grossly removed regional lymph nodes, OR (C) both A and B.
III Approximately 48% of all patients are in this Group.A localized tumor with gross residual disease after incomplete removal or biopsy only.
IV Approximately 18% of all patients are in this Group.Distant metastases are present at diagnosis.

The Intergroup Rhabdomyosarcoma Study Group (IRSG) has merged with the National Wilm Tumor Study Group and with the two large cooperative pediatric cancer treatment groups to form the Children’s Oncology Group (COG). New protocols for children with soft tissue sarcoma are developed by the Soft Tissue Sarcoma Committee of the COG (STS-COG).

Current STS-COG protocols for rhabdomyosarcoma utilize a TNM-based pretreatment staging system which incorporates the surgicopathologic Group, primary tumor site, regional lymph node status, and the presence or absence of metastases. This staging system is described in Table 3 below.[3,4]

Table 3: STS-COG Pretreatment Staging System


StageSites of Primary TumorTumor SizeRegional Lymph NodesDistant Metastases
1 Favorable sitesAny sizeN0 , or N1, or NXM0
2 Unfavorable sites T1a or T2a N0 or NXM0
3 Unfavorable sitesT1a, T2a, ORN1 ORM0
T1b, T2b N0 or N1 or NX
4Any siteAny sizeN0 or N1M1

Following stage assignment, a risk group is assigned. This takes into account stage, Group, and histology. Patients are classified for protocol purposes as low risk, intermediate risk, or high risk.[5,6] Treatment assignment is based on risk group. Table 4 shows the current risk group classification.

Table 4: IRSG Rhabdomyosarcoma Risk Group Classification


Risk GroupHistologyStageGroup
Low RiskEmbryonal1I, II, III
Embryonal2, 3I, II
Intermediate RiskEmbryonal2, 3III
Alveolar1, 2, 3I, II, III
High RiskEmbryonal or Alveolar4IV

Since 2006, patients with undifferentiated sarcoma are treated on the COG-STS protocol for non-rhabdomyosarcomatous soft tissue sarcoma.

References:

  1. 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.
  2. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995.
  3. Lawrence W Jr, Gehan EA, Hays DM, et al.: Prognostic significance of staging factors of the UICC staging system in childhood rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study (IRS-II). J Clin Oncol 5 (1): 46-54, 1987.
  4. Lawrence W Jr, Anderson JR, Gehan EA, et al.: Pretreatment TNM staging of childhood rhabdomyosarcoma: a report of the Intergroup Rhabdomyosarcoma Study Group. Children's Cancer Study Group. Pediatric Oncology Group. Cancer 80 (6): 1165-70, 1997.
  5. 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.
  6. Breneman JC, Lyden E, Pappo AS, et al.: Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma--a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21 (1): 78-84, 2003.

Treatment Option Overview

All children with rhabdomyosarcoma require multimodality therapy with systemic chemotherapy, in conjunction with either surgery, radiation therapy, or both modalities for local tumor control.[1,2,3] This entails surgical resection, if feasible without major functional/cosmetic impairment, followed by chemotherapy. Some patients with initially unresected tumors may undergo second-look surgery to remove residual tumor. Since rhabdomyosarcoma is sensitive to chemotherapy and radiation therapy, surgery is delayed if it will result in disfigurement or will interfere with organ function. Chemotherapy and possibly radiation therapy are administered in advance with the hope that subsequent surgical resection will be successful without undesirable side effects. Radiation therapy is indicated for patients with microscopic residual (Group II) disease and gross residual (Group III) disease. It is also recommended for Group I patients with alveolar histology. The discussion of treatment options for children with rhabdomyosarcoma is therefore divided into separate sections describing surgery, chemotherapy, and radiation therapy.

Before biopsy of a suspected tumor mass, imaging studies of the mass and baseline laboratory studies should be obtained. After the diagnosis of rhabdomyosarcoma has been made, an extensive evaluation to determine the extent of the disease should be done prior to instituting therapy. This evaluation should include a chest x-ray, computed tomography (CT) scan of the chest, bilateral bone marrow aspirates and biopsies, bone scan, magnetic resonance imaging of the base of the skull and brain (for parameningeal primary tumors only), and CT scan of the abdomen and pelvis (for lower extremity or genitourinary primary tumors).

The treatment of rhabdomyosarcoma by the Children's Oncology Group and in Europe, as exemplified by the Intergroup Rhabdomyosarcoma Study Group (IRSG) trials and the International Society of Pediatric Oncology Malignant Mesenchymal Tumor (MMT) studies, respectively, differ in their management and overall treatment philosophies.[2] In the MMT trials, a primary objective is to reduce the use of local therapy, relying on initial frontline chemotherapy followed by alternate chemotherapy in the event of a poor response to initial therapy. Local therapy focused on surgical resection is then administered, reserving radiation therapy for use only after incomplete resection, documented regional lymph node involvement, or a poor clinical response to combination chemotherapy. This approach is designed to avoid major surgery and especially radiation therapy, and their attendant morbidities. Overall survival (OS) is the primary end point, accepting the possibility of an inferior event-free survival (EFS) that might accompany nonaggressive local therapy when compared with more routine and earlier use of surgery and radiation therapy. The necessity of salvage therapy for those who relapse is accepted in these trials. Conversely, the primary IRSG objective has been to employ local therapy soon after induction chemotherapy, using radiation therapy for patients with residual disease after initial surgery or biopsy only, and for all patients with alveolar histology. EFS is the target end point, attempting to avoid relapse and salvage therapy. Results of these two approaches confirm that the IRSG trials result in superior EFS and better OS than the most recently published MMT (MMT 89) therapy. In some subsets of patients defined by primary site, the survival differences are greater (extremities, nonparameningeal head and neck); in others, the results are largely similar (genitourinary). Nevertheless, the overall impression is that survival for most patient subsets is superior with the use of early local therapy, including irradiation. However, in the MMT trials, some patients are spared aggressive local therapy, which may reduce the potential for morbidities associated with such therapy.[1,2,3]

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

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.

Previously Untreated Childhood Rhabdomyosarcoma

Surgical Management Treatment Options

The basic principle for the initial surgical treatment of children with rhabdomyosarcoma is complete resection of the primary tumor with a surrounding margin of normal tissue and lymph node sampling of the draining nodal basin provided that major functional/cosmetic impairment is not necessary. Important exceptions to the rule of normal margin exist (e.g., tumors of the orbit and of the genitourinary region).[1,2] The principle of wide and complete resection of the primary tumor is less applicable to patients known to have metastatic disease at the initial operation, but is a reasonable concept if easily accomplished. Patients with microscopic residual tumor following their initial excisional procedure appear to have improved prognoses if a second operative procedure consisting of re-excision of the primary tumor bed, prior to initiation of chemotherapy, can achieve complete removal of tumor.[3] Because rhabdomyosarcoma can arise from multiple sites, surgical care must be tailored to the unique aspects of each site. Surgical management of the more common primary sites is given below.

Head and neck

If the tumors are parameningeal (in the nasopharynx/nasal cavity, middle ear/mastoid, paranasal sinus, or parapharyngeal/infratemporal fossa region), 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 through the dura. If skull erosion and/or transdural extension is equivocal, a computed tomography (CT) scan of the same regions with contrast is indicated. If there is any suspicion of extension down the spinal cord, an MRI scan with contrast of the entire cord should be obtained. The cerebrospinal fluid (CSF) should be examined for malignant cells in all patients with parameningeal tumors. For head and neck tumors that are superficial and nonorbital, wide excision of the primary tumor (when feasible) and ipsilateral neck lymph node sampling of clinically involved nodes are appropriate. Narrower resection margins (<1 mm) are acceptable because of anatomic restrictions. Cosmetic and functional factors should always be considered, but with modern techniques, complete resection in patients with superficial tumors need not be inconsistent with good cosmetic and functional results. Specialized, multidisciplinary surgical teams have performed resections of anterior skull-based tumors in areas previously considered inaccessible to definitive surgical management, including the nasal areas, paranasal sinuses, and temporal fossa. These procedures should only be considered, however, in children with recurrent locoregional disease or residual disease following chemotherapy and radiation therapy. For patients with head and neck primary tumors that are considered unresectable, chemotherapy and radiation therapy are the mainstay of primary management.[4,5,6,7,8] Rhabdomyosarcomas of the orbit do not require orbital exenteration at diagnosis; only a biopsy is needed to establish diagnosis.[9,10] Biopsy is followed by chemotherapy and radiation therapy, with orbital exenteration reserved for the small number of patients with locally persistent or recurrent disease.[6,11] Despite its parameningeal site, middle ear rhabdomyosarcoma has a favorable prognosis.[7]

Extremity sites

The definitive surgical procedure involves wide local excision with en bloc removal of a cuff of normal tissue.[1] Primary re-excision may be appropriate in patients whose initial surgical procedure leaves microscopic residual disease that is resectable by a second procedure.[3] Because of the significant incidence of nodal spread for extremity primary tumors (often without clinical evidence of involvement), and because of the prognostic and therapeutic implications of nodal involvement, extensive pretreatment assessment for regional nodal involvement is warranted.[12,13,14,15] The Soft Tissue Sarcoma Committee of the Children’s Oncology Group (STS-COG) recommends systematic aggressive axillary node sampling for patients with upper-extremity primary tumors and clinically and radiographically negative nodes. The STS-COG also recommends inguinal and femoral triangle node sampling for patients with lower-extremity primary tumors. If clinically positive nodes are present, biopsy of more proximal nodes is recommended prior to sampling the involved nodal region. Sentinel lymph node (SLN) mapping is employed at some centers to identify the regional nodes that are the most likely to be involved. The contribution of SLN mapping is not yet clearly defined in pediatric patients.[15,16,17]

Truncal sites

The surgical management of patients with lesions of the chest wall or abdominal wall should follow the same guidelines as those used for lesions of the extremities (i.e., wide local excision and an attempt to achieve negative microscopic margins). These resections may require use of prosthetic materials. Very large truncal masses should be biopsied prior to the administration of chemotherapy and/or radiation and should be followed by delayed primary resection to achieve negative margins and reconstruction. Most patients that present with large tumors in these sites have localized disease that is amenable to complete resection with negative margins after preoperative therapy and is therefore associated with excellent long-term survival.[18,19,20]

Intrathoracic or intra-abdominal disease may not be resectable because of the massive size of the tumor at the time of the diagnosis and extension into vital organs.[21] In two retrospective studies of children with LOCALIZED RETROPERITONEAL TUMORS, the outcome was somewhat better for patients who received debulking surgery initially or after chemotherapy and radiation therapy compared with those whose surgical therapy consisted only of initial biopsy.[21,22] Patients with rhabdomyosarcoma arising from tissues around the PERINEUM or ANUS usually have advanced disease. These patients have a high likelihood of regional lymph node involvement, and many of the tumors have alveolar histology. The current recommendation is to sample the lymph nodes. When feasible, without unacceptable morbidity, removing all gross tumor prior to beginning chemotherapy improves the likelihood of cure. The overall survival (OS) after aggressive therapy for tumors in this location was 49%.[23] An exception is a rhabdomyosarcoma arising within the BILIARY TREE, but even at that location, total resection is rarely feasible. Outcome is good despite residual disease after surgery. External biliary drains significantly increase the risk of postoperative infectious complications. Thus, external biliary drainage and aggressive resection for biliary tract rhabdomyosarcoma are not warranted.[24] For patients with initially unresectable abdominal disease, complete surgical resection following chemotherapy offers a significant survival advantage (73% vs. 34% to 44% without resection).[21]

Genitourinary system

Primary sites for childhood rhabdomyosarcoma within the genitourinary system include the PARATESTICULAR area, bladder, prostate, vagina, uterus, and vulva. Specific considerations for the surgical management of tumors arising at each of these sites are discussed in the paragraphs below.

Lesions occurring adjacent to the testis or spermatic cord and up to the internal inguinal ring should be removed by orchiectomy with resection of the entire spermatic cord, utilizing an inguinal incision with proximal vascular control (i.e., radical orchiectomy).[25] Resection of hemiscrotal skin is required when there is tumor fixation or invasion, or when a previous trans-scrotal biopsy has been performed. Paratesticular tumors have been found to have a relatively high incidence of lymphatic spread (26% in Intergroup Rhabdomyosarcoma Study [IRS]-I and IRS-II studies),[12] and all patients with paratesticular primary tumors should have thin-cut abdominal and pelvic CT scans with contrast to evaluate nodal involvement. For patients who are younger than 10 years with Group I disease, and whose 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.[26,27] For patients with suggestive or positive CT scans, retroperitoneal lymph node sampling (but not formal node dissection) is recommended, and treatment is based on the findings of this procedure.[2,28,29] In contrast, a staging ipsilateral retroperitoneal lymph node dissection is currently required for all children older than 10 years with paratesticular rhabdomyosarcoma on Intergroup Rhabdomyosarcoma Study Group (IRSG) and STS-COG studies. Node dissection is not routine in Europe for adolescents with resected paratesticular rhabdomyosarcoma. European investigators tend to rely on radiographic rather than surgical assessment of retroperitoneal lymph node involvement.[25,26] It appears, however, that the ability of the CT scan to predict the presence of lymph node involvement needs further study.[30]

Bladder salvage is an important goal of therapy for patients with tumors arising in the PROSTATE AND BLADDER. In rare cases, the tumor is confined to the dome of the bladder and can be completely resected. Otherwise, to preserve a functional bladder in patients with gross residual disease, chemotherapy and radiation therapy have been used to reduce tumor bulk,[