Advertisement

Current Oncology Reports

, Volume 14, Issue 4, pp 311–319 | Cite as

Current State-of-the-Art Systemic Therapy for Pediatric Soft Tissue Sarcomas

  • Anish Ray
  • Winston W. Huh
Sarcomas (SR Patel, Section Editor)

Abstract

Pediatric soft tissue sarcomas (STS) are a heterogeneous group of tumors. Rhabdomyosarcomas (RMS) are the most common histologic subtype, while synovial sarcomas and undifferentiated sarcomas are among the more common non-rhabdomyosarcomatous soft tissue sarcomas (NRSTS) encountered. While the survival outcome for certain groups of RMS patients is quite good, the prognosis for those with alveolar histology or those with metastatic or relapsed disease remains dismal. Also, the response rate for some NRSTS to conventional chemotherapy is suboptimal. Thus increased understanding of involved molecular pathways, such as the insulin growth factor and mammalian target of rapamycin pathways, may indicate potential targets for therapy. In addition, immunotherapy-based approaches that include both non-specific activation with interleukins as well as targeted tumor antigen specific T lymphocytes are emerging avenues in the treatment of children with soft tissue sarcomas.

Keywords

Soft tissue sarcoma Rhabdomyosarcoma Chemotherapy Targeted therapy Childhood cancer 

Notes

Disclosure

No potential conflicts of interest relevant to this article were reported.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Pappo AS, Pratt CB. Soft tissue sarcomas in children. Cancer Treat Res. 1997;91:205–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Okcu MF, Hicks J, et al. The nonrhabdomyosarcoma soft tissue sarcomas. In: Pizzo PA, editor. Principles and Practice of Pediatric Oncology. 6th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2010. p. 954–86.Google Scholar
  3. 3.
    Ferrari A, Sultan I, Huang TT, Rodriguez-Galindo C, Shehadeh A, Meazza C, et al. Soft tissue sarcoma across the age spectrum: a population-based study from the Surveillance Epidemiology and End Results database. Pediatr Blood Cancer. 2011;57:943–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Marcus KC, Grien HE, Shamberger RC, Gebhardt MC, PerezAtayde A, Silver B, et al. Childhood soft tissue sarcoma: A 20-year experience. J Pediatr. 1997;131:603–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Ognjanovic S, Linabery AM, Charbonneau B, Ross JA. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975–2005. Cancer. 2009;115:4218–26.PubMedCrossRefGoogle Scholar
  6. 6.
    Li FP, Fraumeni J. F. Rhabdomyosarcoma in children—epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst. 1969;43:1365–73.PubMedGoogle Scholar
  7. 7.
    Samuel DP, Tsokos M, DeBaun MR. Hemihypertrophy and a poorly differentiated embryonal rhabdomyosarcoma of the pelvis. Med Pediatr Oncol. 1999;32:38–43.PubMedCrossRefGoogle Scholar
  8. 8.
    Jones AE, Albano EA, Lovell MA, Hunger SP. Metastatic alveolar rhabdomyosarcoma in multiple endocrine neoplasia type 2A. Pediatr Blood Cancer. 2010;55:1213–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Crist W, Gehan EA, Ragab AH, Dickman PS, Donaldson SS, Fryer C, et al. The third intergroup rhabdomyosarcoma study. J Clin Oncol. 1995;13:610–30.PubMedGoogle Scholar
  10. 10.
    •• Sorensen PHB, Lynch JC, Qualman SJ, Tirabosco R, Lim JF, Maurer HM, 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;20:2672–9. This report from a COG study addresses the genetic basis underlying the poor outcome seen in alveolar rhabdomyosarcoma. PubMedCrossRefGoogle Scholar
  11. 11.
    Williamson D, Missiaglia E, de Reynies A, Pierron G, Thuille B, Palenzuela G, et al. Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol. 2010;28:2151–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Neerav Shukla NA, Yilmaz I, Nafa K, Lau C-Y, Marchetti A, Borsu L, Barr FG, Ladanyi M. Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways. Clin Cancer Res. 2012;18:748–57.PubMedCrossRefGoogle Scholar
  13. 13.
    Chen Y, Takita J, Mizuguchi M, Tanaka K, Ida K, Koh K, et al. Mutation and expression analyses of the MET and CDKN2A genes in rhabdomyosarcoma with emphasis on MET overexpression. Genes Chromosomes Cancer. 2007;46:348–58.PubMedCrossRefGoogle Scholar
  14. 14.
    Mercado GE, Xia SJ, Zhang C, Ahn EH, Gustafson DM, Lae M, et al. Identification of PAX3-FKHR-regulated genes differentially expressed between alveolar and embryonal rhabdomyosarcoma: Focus on MYCN as a biologically relevant target. Genes Chromosomes Cancer. 2008;47:510–20.PubMedCrossRefGoogle Scholar
  15. 15.
    Oberlin O, Rey A, Lyden E, Bisogno G, Stevens MCG, Meyer WH, et al. Prognostic factors in metastatic rhabdomyosarcomas: Results of a pooled analysis from United States and European cooperative groups. J Clin Oncol. 2008;26:2384–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Sultan I, Casanova M, Al-Jumaily U, Meazza C, Rodriguez-Galindo C, Ferrari A. Soft tissue sarcomas in the first year of life. Eur J Canc. 2010;46:2449–56.Google Scholar
  17. 17.
    Breneman JC, Lyden E, Pappo AS, Link MP, Anderson JR, Parham DM, 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. 2003;21:78–84.PubMedCrossRefGoogle Scholar
  18. 18.
    Arndt CAS, Stoner JA, Hawkins DS, Rodeberg DA, Hayes-Jordan AA, Paidas CN, 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;27:5182–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Crist WM, Anderson JR, Meza JL, Fryer C, Raney RB, Ruymann FB, et al. Intergroup rhabdomyosarcoma study-IV: Results for patients with nonmetastatic disease. J Clin Oncol. 2001;19:3091–102.PubMedGoogle Scholar
  20. 20.
    Dantonello TM, Int-Veen C, Harms D, Leuschner I, Schmidt BF, Herbst M, et al. Cooperative trial CWS-91 for localized soft tissue sarcoma in children, adolescents, and young adults. J Clin Oncol. 2009;27:1446–55.PubMedCrossRefGoogle Scholar
  21. 21.
    McDowell HP, Foot ABM, Ellershaw C, Machin D, Giraud C, Bergeron C. Outcomes in paediatric metastatic rhabdomyosarcoma: results of The International Society of Paediatric Oncology (SIOP) study MMT-98. Eur J Cancer. 2010;46(9):1588–95.PubMedCrossRefGoogle Scholar
  22. 22.
    Dantonello TM, Winkler P, Boelling T, Friedel G, Schmid I, Mattke AC, et al. Embryonal rhabdomyosarcoma with metastases confined to the lungs: report from the CWS Study Group. Pediatr Blood Cancer. 2011;56(5):725–32.PubMedCrossRefGoogle Scholar
  23. 23.
    Klingebiel T, Boos J, Beske F, Hallmen E, int-Veen C, Dantonello T, 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;50:739–45.PubMedCrossRefGoogle Scholar
  24. 24.
    Admiraal R, van der Paardt M, Kobes J, Kremer LCM, Bisogno G, Merks JHM. High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma. Cochrane Database Syst Rev. 2010;12:CD006669.Google Scholar
  25. 25.
    Chisholm J, Marandet J, Rey A, Oberlin O. Prognostic factors after relapse in non-metastatic rhabdomyosarcoma: who can be salvaged? Pediatr Blood Cancer. 2010;55:836.Google Scholar
  26. 26.
    Pappo AS, Anderson JR, Crist WM, Wharam MD, Breitfeld PP, Hawkins D, et al. Survival after relapse in children and adolescents with rhabdomyosarcoma: A report from the intergroup rhabdomyosarcoma study group. J Clin Oncol. 1999;17:3487–93.PubMedGoogle Scholar
  27. 27.
    McNall-Knapp RY, Williams CN, Reeves EN, Heideman RL, Meyer WH. Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory solid tumors. Pediatr Blood Cancer. 2010;54:909–15.PubMedCrossRefGoogle Scholar
  28. 28.
    Wagner LM, Perentesis JP, Reid JM, Ames MM, Safgren SL, Nelson Jr MD, et al. Phase I trial of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors: a Children’s Oncology Group phase I consortium study. Pediatr Blood Cancer. 2010;54:538–45.PubMedGoogle Scholar
  29. 29.
    Casanova M, Ferrari A, Bisogno G, Merks JHM, De Salvo GL, Meazza C, et al. Vinorelbine and low-dose cyclophosphamide in the treatment of pediatric sarcomas—Pilot study for the upcoming European rhabdomyosarcoma protocol. Cancer. 2004;101:1664–71.PubMedCrossRefGoogle Scholar
  30. 30.
    Rapkin L QM, Brill P, Martin M, Clark D, George BA et al. Gemcitabine and docetaxel (GEMDOX) for the treatment of relapsed and refractory pediatric sarcomas. Pediatr Blood Cancer. 2012.Google Scholar
  31. 31.
    Chang FJ, Syrjanen S, Syrjanen K. Implications of the p53 tumor-suppressor gene in clinical oncology. J Clin Oncol. 1995;13:1009–22.PubMedGoogle Scholar
  32. 32.
    Khoury JD, Coffin CM, Spunt SL, Anderson JR, Meyer WH, Parham DM. Grading of nonrhabdomyosarcoma soft tissue sarcoma in children and adolescents: a comparison of parameters used for the Fédération Nationale des Centers de Lutte Contre le Cancer and Pediatric Oncology Group Systems. Cancer. 2010;116:2266–74.PubMedGoogle Scholar
  33. 33.
    Hawkins DS, Schuetze SM, Butrynski JE, Rajendran JG, Vernon CB, Conrad EU, et al. [F-18] fluorodeoxyglucose positron emission tomography predicts outcome for Ewing sarcoma family of tumors. J Clin Oncol. 2005;23:8828–34.PubMedCrossRefGoogle Scholar
  34. 34.
    Brems H, Beert E, de Ravel T, Legius E. Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1. Lancet Oncol. 2009;10:508–15.PubMedCrossRefGoogle Scholar
  35. 35.
    Evans DGR, Baser ME, Friedman JM, McGaughran J, Timms B, Moran A. Malignant peripheral nerve sheath tumors in neurofibromatosis 1. Am J Hum Genet. 2001;69:311–4.CrossRefGoogle Scholar
  36. 36.
    Carli M, Ferrari A, Mattke A, Zanetti I, Casanova M, Bisogno G, et al. Pediatric malignant peripheral nerve sheath tumor: The Italian and German soft tissue sarcoma cooperative group. J Clin Oncol. 2005;23:8422–30.PubMedCrossRefGoogle Scholar
  37. 37.
    •• Ferner RE, Gutmann DH. International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis 1. Cancer Res. 2002;62:1573–7. An excellent review by a panel of experts who have formulated a standardized approach in diagnosing and treating neurofibromatosis type 1 patients who develop malignant peripheral nerve sheath tumors. PubMedGoogle Scholar
  38. 38.
    Yang J, Ylipaa A, Sun Y, Zheng H, Chen K, Nykter M, et al. Genomic and molecular characterization of malignant peripheral nerve sheath tumor identifies the IGF1R pathway as a primary target for treatment. Clin Cancer Res. 2011;17:7563–73.PubMedCrossRefGoogle Scholar
  39. 39.
    Torres KE, Zhu Q-S, Bill K, Lopez G, Ghadimi MP, Xie X, et al. Activated MET is a molecular prognosticator and potential therapeutic target for malignant peripheral nerve sheath tumors. Clin Cancer Res. 2011;17:3943–55.PubMedCrossRefGoogle Scholar
  40. 40.
    Palmerini E, Staals EL, Alberghini M, Zanella L, Ferrari C, Benassi MS, et al. Synovial sarcoma. Cancer. 2009;115:2988–98.PubMedCrossRefGoogle Scholar
  41. 41.
    Okcu MF, Munsell M, Treuner J, Mattke A, Pappo A, Cain A, et al. Synovial sarcoma of childhood and adolescence: A multicenter, multivariate analysis of outcome. J Clin Oncol. 2003;21:1602–11.PubMedCrossRefGoogle Scholar
  42. 42.
    Brennan B, Stevens M, Kelsey A, Stiller CA. Synovial sarcoma in childhood and adolescence: a retrospective series of 77 patients registered by the Children’s Cancer and Leukaemia Group between 1991 and 2006. Pediatr Blood Cancer. 2010;55:85–90.PubMedGoogle Scholar
  43. 43.
    Pappo AS, Devidas M, Jenkins J, Rao B, Marcus R, Thomas P, et al. Phase II trial of neoadjuvant vincristine, ifosfamide, and doxorubicin with granulocyte colony-stimulating factor support in children and adolescents with advanced-stage nonrhabdomyosarcomatous soft tissue sarcomas: A pediatric oncology group study. J Clin Oncol. 2005;23:4031–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Sultan I, Rodriguez-Galindo C, Saab R, Yasir S, Casanova M, Ferrari A. Comparing children and adults with synovial sarcoma in the Surveillance, Epidemiology, and End Results program, 1983 to 2005: an analysis of 1268 patients. Cancer. 2009;115:3537–47.PubMedCrossRefGoogle Scholar
  45. 45.
    Teng H, Wang H, Chen W, Chao T, Hsieh Y, Hsih C, Tzeng C, Chen P, Yen C. Prevalence and prognostic influence of genomic changes of EGFR pathway markers in synovial sarcoma. J Surg Oncol. 2011;103:773–81.PubMedCrossRefGoogle Scholar
  46. 46.
    Friedrichs N, Trautmann M, Endl E, Sievers E, Kindler D, Wurst P, et al. Phosphatidylinositol-3 ′-kinase/AKT signaling is essential in synovial sarcoma. Int J Cancer. 2011;129:1564–75.PubMedCrossRefGoogle Scholar
  47. 47.
    Nakayama R, Mitani S, Nakagawa T, Hasegawa T, Kawai A, Morioka H, et al. Gene expression profiling of synovial sarcoma: distinct signature of poorly differentiated type. Am J Surg Pathol. 2010;34:1599–607.PubMedGoogle Scholar
  48. 48.
    Alaggio R, Bisogno G, Rosato A, Ninfo V, Coffin CM. Undifferentiated sarcoma: does it exist? A clinicopathologic study of 7 pediatric cases and review of literature. Hum Pathol. 2009;40:1600–10.PubMedCrossRefGoogle Scholar
  49. 49.
    Geoerger B, Kieran MW, Grupp S, Perek D, Clancy J, Krygowski M, et al. Phase II trial of temsirolimus in children with high-grade glioma, neuroblastoma and rhabdomyosarcoma. Eur J Cancer. 2012;48:253–62.PubMedCrossRefGoogle Scholar
  50. 50.
    • Ganjoo K, Jacobs C. Antiangiogenesis agents in the treatment of soft tissue sarcomas. Cancer. 2010;116:1177–83. A good synopsis of the molecules upregulated in the angiogenesis pathways in soft tissue sarcomas. PubMedCrossRefGoogle Scholar
  51. 51.
    Gerber HP, Kowalski J, Sherman D, Eberhard DA, Ferrara N. Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res. 2000;60:6253–8.PubMedGoogle Scholar
  52. 52.
    Bender JLG, Adamson PC, Reid JM, Xu L, Baruchel S, Shaked Y, et al. Phase I trial and pharmacokinetic study of bevacizumab in pediatric patients with refractory solid tumors: A children’s oncology group study. J Clin Oncol. 2008;26:399–405.CrossRefGoogle Scholar
  53. 53.
    Petrillo M, Scambia G, Ferrandina G. Novel targets for VEGF-independent anti-angiogenic drugs. Expert Opin Investig Drugs. 2012;21(4):451–72.Google Scholar
  54. 54.
    Hilbert M, Mary P, Larroquet M, Serinet M-O, Helfre S, Brisse H, et al. Alveolar soft part sarcoma in childhood: Is Sunitinib-Sutent (R) treatment an effective approach? Pediatr Blood Cancer. 2011;58:475–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Grupo Espanol de Investigacion en Sarcoma, Grupo GEIS. Phase I-II trial of sorafenib in combination with ifosfamide in soft tissue sarcoma. ClinicalTrials.gov. 2008. Available from: http://clinicaltrials.gov/show/NCT00541840. Accessed 17 April 2012.
  56. 56.
    Children’s Oncology Group, National Cancer Institute (NCI). Sorafenib in treating young patients with relapsed or refractory solid tumors or leukemia. ClinicalTrials.gov. 2011. Available from: http://clinicaltrials.gov/ct2/show/NCT00343694
  57. 57.
    Fox E, Aplenc R, Bagatell R, Chuk MK, Dombi E, Goodspeed W, et al. A phase 1 trial and pharmacokinetic study of cediranib, an orally bioavailable pan-vascular endothelial growth factor receptor inhibitor, in children and adolescents with refractory solid tumors. J Clin Oncol. 2010;28:5174–81.PubMedCrossRefGoogle Scholar
  58. 58.
    • Leroith D, Werner H, Beitnerjohnson D, Roberts CT. Molecular and cellular aspects of the insulin-like growth-factor-I receptor. Endocr Rev. 1995;16:143–63. This a good example that illustrate the role played by the IGF1 pathway in patients with sarcomas, and provide a basis for targeted therapy for treating such patients. PubMedGoogle Scholar
  59. 59.
    • Pappo AS, Patel SR, Crowley J, Reinke DK, Kuenkele K-P, Chawla SP, et al. R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through Collaboration study. J Clin Oncol. 2011;29:4541–7. This another good example that illustrate the role played by the IGF1 pathway in patients with sarcomas, and provide a basis for targeted therapy for treating such patients. PubMedCrossRefGoogle Scholar
  60. 60.
    Malempati S, Weigel B, Ingle AM, Ahern CH, Carroll JM, Roberts CT, et al. Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30:256–62.PubMedCrossRefGoogle Scholar
  61. 61.
    Meadors JL, Cui Y, Chen Q-R, Song YK, Khan J, Merlino G, et al. Murine rhabdomyosarcoma is immunogenic and responsive to T-cell-based immunotherapy. Pediatr Blood Cancer. 2011;57:921–9.PubMedCrossRefGoogle Scholar
  62. 62.
    •• Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2010;29:917–24. This immunotherapy based clinical trial demonstrates objective response using adoptive transfer of T cells among patients with synovial sarcoma and melanoma. The response duration is meaningful (>1 year) and will likely lead to other similar trials. CrossRefGoogle Scholar
  63. 63.
    Mackall CL, Rhee EH, Read EJ, Khuu HM, Leitman SF, Bernstein D, et al. A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas. Clin Cancer Res. 2008;14:4850–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Robertson MJ, Ritz J. Biology and clinical relevance of human natural-killer-cells. Blood. 1990;76:2421–38.PubMedGoogle Scholar
  65. 65.
    Cho D, Shook DR, Shimasaki N, Chang Y-H, Fujisaki H, Campana D. Cytotoxicity of activated natural killer cells against pediatric solid tumors. Clin Cancer Res. 2010;16:3901–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Denman CJ, Senyukov VV, Somanchi SS, Phatarpekar PV, Kopp LM, Johnson JL, et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PloS One. 2012;7(1):e30264.Google Scholar
  67. 67.
    Meazza C, Casanova M, Zaffignani E, Luksch R, Podda M, Favini F, et al. Efficacy of topotecan plus vincristine and doxorubicin in children with recurrent/refractory rhabdomyosarcoma. Med Oncol. 2009;26:67–72.PubMedCrossRefGoogle Scholar
  68. 68.
    Baruchel S, Pappo A, Krailo M, Baker KS, Wu B, Villaluna D, et al. A phase 2 trial of trabectedin in children with recurrent rhabdomyosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: A report from the Children’s Oncology Group. Eur J Cancer. 2012;48:579–85.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of PediatricsThe University of Texas MD Anderson Cancer CenterHoustonUSA

Personalised recommendations