Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Current Oncology Reports
Published in: Current Oncology Reports 6/2010

01-11-2010

Childhood Rhabdomyosarcoma: New Insight on Biology and Treatment

Authors: Winston W. Huh, Stephen X. Skapek

Published in: Current Oncology Reports | Issue 6/2010

Login to get access

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. The two most common histologic variants are the embryonal and alveolar subtypes. Although successive collaborative group clinical trials have improved survival rates for many RMS patients, the outcome for those patients with metastatic or recurrent disease remains poor. Recent studies have pointed to a possible mesenchymal stem cell as the progenitor for alveolar RMS. Other studies have implicated several cellular mechanisms and pathways being involved in RMS pathogenesis and survival, such as the cyclin-dependent kinase inhibitors, insulin-like growth factor pathway, and the mammalian target of rapamycin pathway, thus providing potential avenues for targeted therapy. Recent clinical trials have tried to improve risk stratification and prediction of clinical outcome based upon clinical or radiographic response to initial therapy and also to determine the role of high-dose chemotherapy with stem cell rescue in high-risk RMS patients.
Literature
1.
Gurney JG, Young JL, Roffers SD, et al.: Soft tissue sarcomas. In Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975–1995. Edited by Ries LAG, Smith MA, Gurney JG, et al. Bethesda, MD: National Cancer Institute SEER Program; 1999:NIH Pub. No. 99–4649.
2.
Ognjanovic S, Linabery AM, Charbonneau B, et al.: Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975–2005. Cancer 2009, 115:4218–4226.PubMedCrossRef
3.
Sorensen PHB, 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 2002, 20:2672–2679.PubMedCrossRef
4.
Malkin D, Li FP, Strong LC, et al.: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990, 240:1233–1238.CrossRef
5.
Sung L, Anderson JR, Arndt C, et al.: Neurofibromatosis in children with rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study IV. J Pediatr 2004, 133:666–668.
6.
Grufferman S, Ruymann F, Ognjanovic S, et al.: Prenatal X-ray exposure and rhabdomyosarcoma: a report from the Children’s Oncology Group. Cancer Epidemiol Biomarkers Prev 2009, 18:1271–1276.PubMedCrossRef
7.
Ognjanovic S, Carozza SE, Chow EJ, et al.: Birth characteristics and the risk of childhood rhabdomyosarcoma based on histological subtype. Br J Cancer 2010, 102:227–231.PubMedCrossRef
8.
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 2001, 23:215–220.PubMedCrossRef
9.
Meza JL, Anderson J, Pappo AS, Meyer WH: 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 2006, 24:3844–3851.PubMedCrossRef
10.
Arndt CAS, 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 2009, 27:5182–5188.PubMedCrossRef
11.
Oberlin O, Rey A, Lyden E, et al.: Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from the United States and European Cooperative Groups. J Clin Oncol 2008, 26:2384–2389.PubMedCrossRef
12.
Bisogno G, Ferrari A, Prete A, et al.: Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma. Eur J Cancer 2009, 45:3035–3041.PubMedCrossRef
13.
• Klingebiel T, Boos J, Beske F, et al.: Treatment of children with metastatic soft tissue sarcoma with oral maintenance compared to high-dose chemotherapy: report of the HD CWS-96 trial. Pediatr Blood Cancer 2008, 50:739–745. This provocative study demonstrates the potential efficacy of low-dose oral therapy versus high-dose therapy with stem cell rescue for high-risk patients. PubMedCrossRef
14.
McDowell HP, Foot ABM, Ellershaw C, et al.: Outcomes in paediatric metastatic rhabdomyosarcoma: results of The International Society of Paediatric Oncology (SIOP) study MMT-98. Eur J Cancer 2010, 46:1588–1595.PubMedCrossRef
15.
Donker AE, Hoogerbrugge PM, Mavinkurve-Groothuis AMC, et al.: Metastatic rhabdomyosarcoma cured after chemotherapy and allogeneic SCT. Bone Marrow Transplant 2009, 43:179–180.PubMedCrossRef
16.
Dantonello TM, Int-Veen C, Harms D, et al.: Cooperative Trial CWS-91 for localized soft tissue sarcoma in children, adolescents, and young adults. J Clin Oncol 2009, 27:1446–1455.PubMedCrossRef
17.
Qualman S, Lynch J, Bridge J, et al.: Prevalence and clinical impact of anaplasia in childhood rhabdomyosarcoma. Cancer 2008, 113:3242–3247.PubMedCrossRef
18.
•• Williamson D, Missiaglia E, de Reynies A, et al.: Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol 2010, 28:2151–2158. This European study demonstrates that fusion gene–negative ARMS has a clinical presentation and genetic expression profile similar to ERMS, which raises the potential question of decreased intensity of therapy for this subset of patients. PubMedCrossRef
19.
Davicioni E, Anderson JR, Buckley JD, et al.: Gene expression profiling for survival prediction in pediatric rhabdomyosarcomas: a report from the Children’s Oncology Group. J Clin Oncol 2010, 28:1240–1246.PubMedCrossRef
20.
Sumegi J, Streblow R, Frayer RW, et al.: Recurrent t(2;2) and t(2;8) translocations in rhabdomyosarcoma without the canonical PAX-FOXO1 fuse PAX3 to members of the nuclear receptor transcriptional coactivator family. Genes Chromosomes Cancer 2010, 49:224–236.PubMed
21.
Burke M, Anderson JT, Kao SC, et al.: Assessment of response to induction therapy and its influence on 5-year failure-free survival in Group III rhabdomyosarcoma: the Intergroup Rhabdomyosarcoma Study IV experience—a report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. J Clin Oncol 2007, 25:4909–4913.PubMedCrossRef
22.
•• 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 2009, 27:3705–3711. This relevant clinical study demonstrates no relationship between radiographic response and clinical outcome in patients with group III disease. PubMedCrossRef
23.
Ferrari A, Miceli R, Meazza C, et al.: Comparison of the prognostic value of assessing tumor diameter versus tumor volume at diagnosis or in response to initial chemotherapy in rhabdomyosarcoma. J Clin Oncol 2010, 28:1322–1328.PubMedCrossRef
24.
Volker 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 2007, 25:5435–5441.PubMedCrossRef
25.
Tateishi U, Hosono A, Makimoto A, et al.: Accuracy of 18F fluorodeoxyglucose positron emission tomography/computed tomography in staging of pediatric sarcomas. J Pediatr Hematol Oncol 2007, 29:608–612.PubMedCrossRef
26.
Das B, Tsuchida R, Malkin D, et al.: Hypoxia enhances tumor stemness by increasing the invasive and tumorigenic side population fraction. Stem Cells 2008, 26:1818–1830.PubMedCrossRef
27.
• Charytonowicz E, Cordon-Cardo C, Matushansky I, Ziman M: Alveolar rhabdomyosarcoma: is the cell of origin a mesenchymal stem cell? Cancer Lett 2009, 279:126–136. This is an excellent review of available data on differentiating the stem cell of origin for alveolar rhabdomyosarcomas.PubMedCrossRef
28.
Ren YX, Finckenstein FG, Abdueva DA, et al.: Mouse mesenchymal stem cells expressing PAX-FKHR form alveolar rhabdomyosarcomas by cooperating with secondary mutation. Cancer Res 2008, 68:6587–6597.PubMedCrossRef
29.
Wagers AJ, Conboy IM: Cellular and molecular signatures of muscle regeneration: current concepts and controversies in adult myogenesis. Cell 2005, 122:659–667.PubMedCrossRef
30.
Tiffin N, Williams RD, Shipley J, et al.: PAX7 expression in embryonal rhabdomyosarcoma suggests an origin in muscle satellite cells. Br J Cancer 2003, 89:327–332.PubMedCrossRef
31.
Linardic CM, Downie DL, Qualman S, et al.: Genetic modeling of human rhabdomyosarcoma. Cancer Res 2005, 65:4490–4495.PubMedCrossRef
32.
Odelberg SJ, Kollhoff A, Keating MT: Dedifferentiation of mammalian myotubes induced by msx1. Cell 2000, 103:1099–1109.PubMedCrossRef
33.
Keller C, Arenkiel BR, Coffin CM, et al.: Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function. Genes Develop 2004, 18:2614–2626.PubMedCrossRef
34.
Kassar-Duchossoy L, Gayraud-Morel B, Gomes D, et al.: Mrf4 determines skeletal muscle identity in Myf5:Myod double-mutant mice. Nature 2004, 431:466–471.PubMedCrossRef
35.
Chen Y, Takita J, Mizuguchi M, et al.: Mutation and expression analyses of the MET and CDKN2A genes in rhabdomyosarcoma with emphasis on MET overexpression. Genes Chromosomes Cancer 2007, 46:348–358.PubMedCrossRef
36.
Davicioni E, Anderson MJ, Finckenstein FG, et al.: Molecular classification of rhabdomyosarcoma—genotypic and phenotypic determinants of diagnosis: a report from the Children’s Oncology Group. Am J Pathol 2009, 174:550–564.PubMedCrossRef
37.
• De Giovanni C, Landuzzi L, Nicoletti G, et al.: Molecular and cellular biology of rhabdomyosarcoma. Future Oncol 2009, 5:1449–1475. This is a good review of recent data on molecular pathways and animal models for rhabdomyosarcoma. PubMedCrossRef
38.
Makawita S, Ho M, Durbin AD, et al.: Expression of insulin-like growth factor pathway proteins in rhabdomyosarcoma: IGF-2 expression is associated with translocation-negative tumors. Pediatr Develop Path 2009, 12:127–135.CrossRef
39.
Missiaglia E, Selfe J, Hamdi M, et al.: Genomic imbalances in rhabdomyosarcoma cell lines affect expression of genes frequently altered in primary tumors: an approach to identify candidate genes involved in tumor development. Genes Chromosomes Cancer 2009, 48:455–467.PubMedCrossRef
40.
Martinelli S, McDowell HP, Delle Vigne S, et al.: RAS signaling dysregulation in human embryonal rhabdomyosarcoma. Genes Chromosomes Cancer 2009, 48:975–982.PubMedCrossRef
41.
Barr FG, Duan F, Smith LM, et al.: Genomic and clinical analyses of 2p24 and 12q13-q14 amplification in alveolar rhabdomyosarcoma: a report from the Children’s Oncology Group. Genes Chromosomes Cancer 2009, 48:661–672.PubMedCrossRef
42.
Davicioni E, Finckenstein FG, Shahbazian V, et al.: Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas. Cancer Res 2006, 66:6936–6946.PubMedCrossRef
43.
Taylor JG, Cheuk AT, Tsang PS, et al.: Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. J Clin Invest 2009, 119:3395–3407.PubMed
44.
Huang F, Greer A, Hurlburt W, et al.: The mechanisms of differential sensitivity to an insulin-like growth factor-1 receptor inhibitor (BMS-536924) and rationale for combining EGFR/HER2 inhibitors. Cancer Res 2009, 69:161–170.PubMedCrossRef
45.
Kurmasheva RT, Dudkin L, Billups C, et al.: The insulin-like growth factor-1 receptor-targeting antibody, CP-751, 871, suppresses tumor-derived VEGF and synergizes with rapamycin in models of childhood sarcoma. Cancer Res 2009, 69:7662–7671.PubMedCrossRef
46.
Petricoin III EF, Espina V, Araujo RP, et al.: Phosphoprotein pathway mapping: Akt/mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival. Cancer Res 2007, 67:3431–3440.PubMedCrossRef
47.
Houghton PJ, Morton CL, Kolb EA, et al.: Initial testing (stage 1) of the mTOR inhibitor rapamycin by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 2008, 50:799–805.PubMedCrossRef
48.
Sharp R, Recio JA, Jhappan C, et al.: Synergism between Ink4a/Arf inactivation and aberrant HGF/SF signaling in rhabdomyosarcoma genesis. Nat Med 2002, 8:1276–1280.PubMedCrossRef
49.
Galindo RL, Allport JA, Olson EN: A Drosophila model of rhabdomyosarcoma initiator PAX7-FKHR. Proc Natl Acad Sci U S A 2006, 103:13439–13444.PubMedCrossRef
50.
Langenau DM, Keefe MD, Storer NY, et al.: Effects of RAS on the genesis of embryonal rhabdomyosarcoma. Genes Dev 2007, 21:1382–1395.PubMedCrossRef
Metadata
Title
Childhood Rhabdomyosarcoma: New Insight on Biology and Treatment
Authors
Winston W. Huh
Stephen X. Skapek
Publication date
01-11-2010
Publisher
Current Science Inc.
Published in
Current Oncology Reports / Issue 6/2010
Print ISSN: 1523-3790
Electronic ISSN: 1534-6269
DOI
https://doi.org/10.1007/s11912-010-0130-3

Other articles of this Issue 6/2010

Current Oncology Reports 6/2010 Go to the issue

ReviewPaper

State-of-the-art Issues in Hodgkin’s Lymphoma Survivorship

ReviewPaper

Should Eligible Patients with T-Cell Lymphoma Receive High-Dose Therapy and Autologous Stem Cell Transplant in the Upfront Setting?

Clinical Trial Report

Is Maintenance Rituximab Now Ready for PRIMA-Time?

ReviewPaper

Maintenance and Consolidation Strategies in Non-Hodgkin’s Lymphoma: A Review of the Data

ReviewPaper

Maintenance Chemotherapy: An Evolving and Increasingly Acceptable Strategy in Cancer Management

Clinical Trial Report

The Addition of Rituximab to Fludarabine and Cyclophosphamide Improves Progression-free Survival in Patients with Previously Treated Chronic Lymphocytic Leukemia
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits