Skip to main content

Advertisement

Log in

The Adolescent and Young Adult with Cancer: State of the Art - Bone Tumors

  • Pediatric Oncology (S Epelman, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Primary malignant bone tumors in the pediatric to young adult populations are relatively uncommon and account for about 6 % of all cancers in those less than 20 years old [1] and 3 % of all cancers in adolescents and young adults (AYA) within the age range of 15 to 29 years [2]. Osteosarcoma (OS) and Ewing’s sarcoma (ES) comprise the majority of malignant bone tumors. The approach to treatment for both tumors consists of local control measures (surgery or radiation) as well as systemic therapy with high-dose chemotherapy. Despite earlier advances, there have been no substantial improvements in outcomes over the past several decades, particularly for patients with metastatic disease. This review summarizes the major advances in the treatment of OS and ES and the standard therapies available today, current active clinical trials, and areas of investigation into molecularly targeted therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  1. Gurney J, Swensen A, Bulterys M. Malignant bone tumors. In: Ries L, Smith M, Gurney J, et al., editors. Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995, National Cancer Institute, SEER Program. NIH Pub. No. 99–4649. Bethesda, MD; 1999.

  2. Mascarenhas L, Siegel S, Spector L, et al. Malignant Bone Tumors. In: Bleyer A, O’Leary M, Barr R, Ries LAG, editors. Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975–2000. National Cancer Institute, NIH Pub. No. 06–5767. Bethesda, MD 2006.

    Google Scholar 

  3. Wang LL, Levy ML, Lewis RA, Chintagumpala MM, Lev D, Rogers M, et al. Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients. Am J Med Genet. 2001;102(1):11–7. doi:10.1002/1096-8628(20010722)102:1.

    Article  PubMed  CAS  Google Scholar 

  4. Martin JW, Squire JA, Zielenska M. The genetics of osteosarcoma. Sarcoma. 2012:627254. doi:10.1155/2012/627254.

  5. Gorlick R, Khanna C. Osteosarcoma. J Bone Miner Res. 2010;25(4):683–91. doi:10.1002/jbmr.77.

    Article  PubMed  Google Scholar 

  6. Brun J, Dieudonne FX, Marty C, Muller J, Schule R, Patino-Garcia A, et al. FHL2 silencing reduces Wnt signaling and osteosarcoma tumorigenesis in vitro and in vivo. PLoS One. 2013;8(1):e55034. doi:10.1371/journal.pone.0055034.

    Article  PubMed  CAS  Google Scholar 

  7. Rubin EM, Guo Y, Tu K, Xie J, Zi X, Hoang BH. Wnt inhibitory factor 1 decreases tumorigenesis and metastasis in osteosarcoma. Mol Cancer Ther. 2010;9(3):731–41. doi:10.1158/1535-7163.MCT-09-0147.

    Article  PubMed  CAS  Google Scholar 

  8. Engin F, Bertin T, Ma O, Jiang MM, Wang L, Sutton RE, et al. Notch signaling contributes to the pathogenesis of human osteosarcomas. Hum Mol Genet. 2009;18(8):1464–70.

    Article  PubMed  CAS  Google Scholar 

  9. Zhang P, Yang Y, Zweidler-McKay PA, Hughes DP. Critical role of notch signaling in osteosarcoma invasion and metastasis. Clin Cancer Res. 2008;14(10):2962–9.

    Article  PubMed  CAS  Google Scholar 

  10. Ciernik IF, Niemierko A, Harmon DC, Kobayashi W, Chen YL, Yock TI, et al. Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma. Cancer. 2011;117(19):4522–30. doi:10.1002/cncr.26037.

    Article  PubMed  Google Scholar 

  11. Caldarella C, Salsano M, Isgro MA, Treglia G. The role of fluorine-18-fluorodeoxyglucose positron emission tomography in assessing the response to neoadjuvant treatment in patients with osteosarcoma. Int J Mol Imaging. 2012;2012:870301. doi:10.1155/2012/870301.

    PubMed  Google Scholar 

  12. Marina N, Gebhardt M, Teot L, Gorlick R. Biology and therapeutic advances for pediatric osteosarcoma. Oncologist. 2004;9(4):422–41.

    Article  PubMed  Google Scholar 

  13. Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer. 2009;115(7):1531–43. doi:10.1002/cncr.24121.

    Article  PubMed  Google Scholar 

  14. Fuchs N, Bielack SS, Epler D, Bieling P, Delling G, Korholz D, et al. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group's protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol. 1998;9(8):893–9.

    Article  PubMed  CAS  Google Scholar 

  15. Meyers PA, Heller G, Healey J, Huvos A, Lane J, Marcove R, et al. Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience. J Clin Oncol. 1992;10(1):5–15.

    PubMed  CAS  Google Scholar 

  16. Provisor AJ, Ettinger LJ, Nachman JB, Krailo MD, Makley JT, Yunis EJ, et al. Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: a report from the Children's Cancer Group. J Clin Oncol. 1997;15(1):76–84.

    PubMed  CAS  Google Scholar 

  17. Anninga JK, Gelderblom H, Fiocco M, Kroep JR, Taminiau AH, Hogendoorn PC, et al. Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? Eur J Cancer. 2011;47(16):2431–45. doi:10.1016/j.ejca.2011.05.030.

    Article  PubMed  CAS  Google Scholar 

  18. • Goorin AM, Schwartzentruber DJ, Devidas M, Gebhardt MC, Ayala AG, Harris MB, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol. 2003;21(8):1574–80. doi:10.1200/JCO.2003.08.165. This is a prospective randomized study that demonstrated no advantage in EFS for patients given presurgical chemotherapy compared with immediate surgery.

    Article  PubMed  CAS  Google Scholar 

  19. Huvos AG, Rosen G, Marcove RC. Primary osteogenic sarcoma: pathologic aspects in 20 patients after treatment with chemotherapy en bloc resection, and prosthetic bone replacement. Arch Pathol Lab Med. 1977;101(1):14–8.

    PubMed  CAS  Google Scholar 

  20. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002;20(3):776–90.

    Article  PubMed  Google Scholar 

  21. Meyers PA, Schwartz CL, Krailo M, Kleinerman ES, Betcher D, Bernstein ML, et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol. 2005;23(9):2004–11. doi:10.1200/JCO.2005.06.031.

    Article  PubMed  CAS  Google Scholar 

  22. Ferrari S, Ruggieri P, Cefalo G, Tamburini A, Capanna R, Fagioli F, et al. Neoadjuvant chemotherapy with methotrexate, cisplatin, and doxorubicin with or without ifosfamide in nonmetastatic osteosarcoma of the extremity: an Italian sarcoma group trial ISG/OS-1. J Clin Oncol. 2012;30(17):2112–8. doi:JCO.2011.38.4420.

    Google Scholar 

  23. Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, et al. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007;99(2):112–28. doi:10.1093/jnci/djk015.

    Article  PubMed  CAS  Google Scholar 

  24. Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol. 2000;18(24):4016–27.

    PubMed  CAS  Google Scholar 

  25. Smeland S, Bruland OS, Hjorth L, Brosjo O, Bjerkehagen B, Osterlundh G, et al. Results of the Scandinavian Sarcoma Group XIV protocol for classical osteosarcoma: 63 patients with a minimum follow-up of 4 years. Acta Orthop. 2011;82(2):211–6. doi:10.3109/17453674.2011.566141.

    Article  PubMed  Google Scholar 

  26. •• Marina N, Bielack S, Whelan J, Smeland S, Krailo M, Sydes MR, et al. International collaboration is feasible in trials for rare conditions: the EURAMOS experience. Cancer Treat Res. 2009;152:339–53. doi:10.1007/978-1-4419-0284-9_18. This paper describes the international efforts to conduct a randomized study to improve treatments for good and poor responders in osteosarcoma.

    Article  PubMed  CAS  Google Scholar 

  27. Goorin AM, Harris MB, Bernstein M, Ferguson W, Devidas M, Siegal GP, et al. Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J Clin Oncol. 2002;20(2):426–33.

    Article  PubMed  CAS  Google Scholar 

  28. Gosiengfiao Y, Reichek J, Woodman J, Ben-Ami T, Walterhouse D. Gemcitabine with or without docetaxel and resection for recurrent osteosarcoma: the experience at Children's Memorial Hospital. J Pediatr Hematol Oncol. 2012;34(2):e63–5. doi:10.1097/MPH.0b013e3182331ee8.

    Article  PubMed  CAS  Google Scholar 

  29. Navid F, Willert JR, McCarville MB, Furman W, Watkins A, Roberts W, et al. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008;113(2):419–25.

    Article  PubMed  CAS  Google Scholar 

  30. Fox E, Patel S, Wathen JK, Schuetze S, Chawla S, Harmon D, et al. Phase II study of sequential gemcitabine followed by docetaxel for recurrent Ewing sarcoma, osteosarcoma, or unresectable or locally recurrent chondrosarcoma: results of sarcoma alliance for research through collaboration study 003. Oncologist. 2012;17(3):321–e9.

    Article  PubMed  Google Scholar 

  31. Meyers PA, Healey JH, Chou AJ, Wexler LH, Merola PR, Morris CD, et al. Addition of pamidronate to chemotherapy for the treatment of osteosarcoma. Cancer. 2011;117(8):1736–44. doi:10.1002/cncr.25744.

    Article  PubMed  CAS  Google Scholar 

  32. Casey DA, Wexler LH, Merchant MS, Chou AJ, Merola PR, Price AP, et al. Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer. 2009;53(6):1029–34.

    Article  PubMed  Google Scholar 

  33. Bulut G, Hong SH, Chen K, Beauchamp EM, Rahim S, Kosturko GW, et al. Small molecule inhibitors of ezrin inhibit the invasive phenotype of osteosarcoma cells. Oncogene. 2012;31(3):269–81.

    Article  PubMed  CAS  Google Scholar 

  34. Khanna C, Wan X, Bose S, Cassaday R, Olomu O, Mendoza A, et al. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med. 2004;10(2):182–6. doi:10.1038/nm982 nm982.

    Article  PubMed  CAS  Google Scholar 

  35. Ebb D, Meyers P, Grier H, Bernstein M, Gorlick R, Lipshultz SE, et al. Phase II trial of trastuzumab in combination with cytotoxic chemotherapy for treatment of metastatic osteosarcoma with human epidermal growth factor receptor 2 overexpression: a report from the children's oncology group. J Clin Oncol. 2012;30(20):2545–51. doi:10.1200/JCO.2011.37.4546.

    Article  PubMed  CAS  Google Scholar 

  36. • Ahmed N, Salsman VS, Yvon E, Louis CU, Perlaky L, Wels WS, et al. Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression. Mol Ther. 2009;17(10):1779–87. doi:10.1038/mt.2009.133. This preclinical study showed that immunotherapy may be an effective approach to treat metastatic disease in osteosarcoma. The same group also demonstrated that immunotherapy effectively eliminates osteosarcoma cancer stem cells.

    Article  PubMed  CAS  Google Scholar 

  37. Rosen JM, Jordan CT. The increasing complexity of the cancer stem cell paradigm. Science. 2009;324(5935):1670–3. doi:10.1126/science.1171837.

    Article  PubMed  CAS  Google Scholar 

  38. • Basu-Roy U, Basilico C, Mansukhani A. Perspectives on cancer stem cells in osteosarcoma. Cancer Lett. 2012. doi:10.1016/j.canlet.2012.05.028. This is a review paper that describes the current knowledge regarding osteosarcoma cancer stem cells and the implications for designing future therapies.

    PubMed  Google Scholar 

  39. Rainusso N, Brawley VS, Ghazi A, Hicks MJ, Gottschalk S, Rosen JM, et al. Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma. Cancer Gene Ther. 2012;19(3):212–7. doi:10.1038/cgt.2011.83.

    Article  PubMed  CAS  Google Scholar 

  40. Lazar A, Abruzzo LV, Pollock RE, Lee S, Czerniak B. Molecular diagnosis of sarcomas: chromosomal translocations in sarcomas. Arch Pathol Lab Med. 2006;130(8):1199–207.

    PubMed  CAS  Google Scholar 

  41. Riggi N, Stamenkovic I. The biology of Ewing sarcoma. Cancer Lett. 2007;254(1):1–10.

    Article  PubMed  CAS  Google Scholar 

  42. Cavazzana AO, Miser JS, Jefferson J, Triche TJ. Experimental evidence for a neural origin of Ewing's sarcoma of bone. Am J Pathol. 1987;127(3):507–18.

    PubMed  CAS  Google Scholar 

  43. Potikyan G, France KA, Carlson MR, Dong J, Nelson SF, Denny CT. Genetically defined EWS/FLI1 model system suggests mesenchymal origin of Ewing's family tumors. Lab Invest J Tech Methods Pathol. 2008;88(12):1291–302.

    Article  CAS  Google Scholar 

  44. Meltzer PS. Is Ewing's sarcoma a stem cell tumor? Cell Stem Cell. 2007;1(1):13–5.

    Article  PubMed  CAS  Google Scholar 

  45. Riggi N, Suva ML, Suva D, Cironi L, Provero P, Tercier S, et al. EWS-FLI-1 expression triggers a Ewing's sarcoma initiation program in primary human mesenchymal stem cells. Cancer Res. 2008;68(7):2176–85.

    Article  PubMed  CAS  Google Scholar 

  46. • Lin PP, Pandey MK, Jin F, Xiong S, Deavers M, Parant JM, et al. EWS-FLI1 induces developmental abnormalities and accelerates sarcoma formation in a transgenic mouse model. Cancer Res. 2008;68(21):8968–75. This report demonstrates that the mesenchymal-specific activation of EWS-Fli1alone was not sufficient to drive sarcomagenesis, but required additional genetic mutations (p53 alterations) to produce undifferentiated sarcomas.

    Article  PubMed  CAS  Google Scholar 

  47. Leacock SW, Basse AN, Chandler GL, Kirk AM, Rakheja D, Amatruda JF. A zebrafish transgenic model of Ewing's sarcoma reveals conserved mediators of EWS-FLI1 tumorigenesis. Dis Model Mech. 2012;5(1):95–106.

    Article  PubMed  CAS  Google Scholar 

  48. France KA, Anderson JL, Park A, Denny CT. Oncogenic fusion protein EWS/FLI1 down-regulates gene expression by both transcriptional and posttranscriptional mechanisms. J Biol Chem. 2011;286(26):22750–7.

    Article  PubMed  CAS  Google Scholar 

  49. • McKinsey EL, Parrish JK, Irwin AE, Niemeyer BF, Kern HB, Birks DK, et al. A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs. Oncogene. 2011;30(49):4910–20. This report provides evidence for the importance of miRNAs in ES biology by determining a novel post-transcriptional mechanism of derepression of IGF signaling by the EWS/Fli1 suppression of miRNAs.

    Article  PubMed  CAS  Google Scholar 

  50. Ban J, Jug G, Mestdagh P, Schwentner R, Kauer M, Aryee DN, et al. Hsa-mir-145 is the top EWS-FLI1-repressed microRNA involved in a positive feedback loop in Ewing's sarcoma. Oncogene. 2011;30(18):2173–80.

    Article  PubMed  CAS  Google Scholar 

  51. De Vito C, Riggi N, Cornaz S, Suva ML, Baumer K, Provero P, et al. A TARBP2-dependent miRNA expression profile underlies cancer stem cell properties and provides candidate therapeutic reagents in Ewing sarcoma. Cancer Cell. 2012;21(6):807–21.

    Article  PubMed  Google Scholar 

  52. Nakatani F, Ferracin M, Manara MC, Ventura S, Del Monaco V, Ferrari S, et al. miR-34a predicts survival of Ewing's sarcoma patients and directly influences cell chemo-sensitivity and malignancy. J Pathol. 2012;226(5):796–805.

    Article  PubMed  CAS  Google Scholar 

  53. Treglia G, Salsano M, Stefanelli A, Mattoli MV, Giordano A, Bonomo L. Diagnostic accuracy of (1)(8)F-FDG-PET and PET/CT in patients with Ewing sarcoma family tumours: a systematic review and a meta-analysis. Skeletal Radiol. 2012;41(3):249–56.

    Article  PubMed  Google Scholar 

  54. Applebaum MA, Goldsby R, Neuhaus J, DuBois SG. Clinical features and outcomes in patients with Ewing sarcoma and regional lymph node involvement. Pediatr Blood Cancer. 2012;59(4):617–20.

    Article  PubMed  Google Scholar 

  55. Ash S, Luria D, Cohen IJ, Goshen Y, Toledano H, Issakov J, et al. Excellent prognosis in a subset of patients with Ewing sarcoma identified at diagnosis by CD56 using flow cytometry. Clin Cancer Res. 2011;17(9):2900–7.

    Article  PubMed  CAS  Google Scholar 

  56. Rodriguez-Galindo C, Spunt SL, Pappo AS. Treatment of Ewing sarcoma family of tumors: current status and outlook for the future. Med Pediatr Oncol. 2003;40(5):276–87.

    Article  PubMed  Google Scholar 

  57. Navid F, Billups C, Liu T, Krasin MJ, Rodriguez-Galindo C. Second cancers in patients with the Ewing sarcoma family of tumours. Eur J Cancer. 2008;44(7):983–91.

    Article  PubMed  Google Scholar 

  58. Rodriguez-Galindo C, Liu T, Krasin MJ, Wu J, Billups CA, Daw NC, et al. Analysis of prognostic factors in ewing sarcoma family of tumors: review of St. Jude Children's Research Hospital studies. Cancer. 2007;110(2):375–84.

    Article  PubMed  Google Scholar 

  59. Bacci G, Ferrari S, Bertoni F, Rimondini S, Longhi A, Bacchini P, et al. Prognostic factors in nonmetastatic Ewing's sarcoma of bone treated with adjuvant chemotherapy: analysis of 359 patients at the Istituto Ortopedico Rizzoli. J Clin Oncol. 2000;18(1):4–11.

    PubMed  CAS  Google Scholar 

  60. Bacci G, Longhi A, Ferrari S, Mercuri M, Versari M, Bertoni F. Prognostic factors in non-metastatic Ewing's sarcoma tumor of bone: an analysis of 579 patients treated at a single institution with adjuvant or neoadjuvant chemotherapy between 1972 and 1998. Acta Oncol Stockholm Sweden. 2006;45(4):469–75.

    Article  Google Scholar 

  61. Kikuta K, Tochigi N, Shimoda T, Yabe H, Morioka H, Toyama Y, et al. Nucleophosmin as a candidate prognostic biomarker of Ewing's sarcoma revealed by proteomics. Clin Cancer Res. 2009;15(8):2885–94.

    Article  PubMed  CAS  Google Scholar 

  62. Nesbit Jr ME, Perez CA, Tefft M, Burgert Jr EO, Vietti TJ, Kissane J, et al. Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: an Intergroup Study. Natl Cancer Inst Monogr. 1981;56:255–62.

    PubMed  Google Scholar 

  63. Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348(8):694–701.

    Article  PubMed  CAS  Google Scholar 

  64. •• Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HE, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the children's oncology group. J Clin Oncol. 2012;30(33):4148–54. This study determined that interval compression of chemotherapy from every 21 days to every 14 days provided significant prognostic benefit to nonmetastatic ES patients without an increase in toxicities. This has now become the standard of care for nonmetastatic patients in North America.

    Article  PubMed  CAS  Google Scholar 

  65. Dunst J, Schuck A. Role of radiotherapy in Ewing tumors. Pediatr Blood Cancer. 2004;42(5):465–70.

    Article  PubMed  Google Scholar 

  66. Bolling T, Schuck A, Paulussen M, Dirksen U, Ranft A, Konemann S, et al. Whole lung irradiation in patients with exclusively pulmonary metastases of Ewing tumors. Toxicity analysis and treatment results of the EICESS-92 trial. Strahlenther Onkol. 2008;184(4):193–7.

    Article  PubMed  Google Scholar 

  67. Subbiah V, Anderson P, Lazar AJ, Burdett E, Raymond K, Ludwig JA. Ewing's sarcoma: standard and experimental treatment options. Curr Treat Options Oncol. 2009;10(1–2):126–40.

    Article  PubMed  Google Scholar 

  68. Rodriguez-Galindo C, Billups CA, Kun LE, Rao BN, Pratt CB, Merchant TE, et al. Survival after recurrence of Ewing tumors: the St Jude Children's Research Hospital experience, 1979–1999. Cancer. 2002;94(2):561–9.

    Article  PubMed  Google Scholar 

  69. Huang M, Lucas K. Current therapeutic approaches in metastatic and recurrent ewing sarcoma. Sarcoma. 2011;863210.

  70. Paulussen M, Ahrens S, Craft AW, Dunst J, Frohlich B, Jabar S, et al. Ewing's tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing's Sarcoma Studies patients. J Clin Oncol. 1998;16(9):3044–52.

    PubMed  CAS  Google Scholar 

  71. Farhat R, Raad R, Khoury NJ, Feghaly J, Eid T, Muwakkit S, et al. Cyclophosphamide and topotecan as first-line salvage therapy in patients with relapsed Ewing sarcoma at a single institution. J Pediatr Hematol Oncol. 2012.

  72. Owens C, Laurence V, Benboubker L, Defachelles AS, Cupissol D, Rubie H, et al. Phase II study of cisplatin and oral VP16 in patients with refractory or relapsed Ewing sarcoma. Cancer Chemother Pharmacol. 2013;71(2):339–404. doi:10.1007/S00280-012-2015-7.

    Google Scholar 

  73. Meyers PA, Krailo MD, Ladanyi M, Chan KW, Sailer SL, Dickman PS, et al. High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis. J Clin Oncol. 2001;19(11):2812–20.

    PubMed  CAS  Google Scholar 

  74. Drabko K, Raciborska A, Bilska K, Styczynski J, Ussowicz M, Choma M, et al. Consolidation of first-line therapy with busulphan and melphalan, and autologous stem cell rescue in children with Ewing's sarcoma. Bone Marrow Transplantation. 2012;47(12):1530–4.

    Article  PubMed  CAS  Google Scholar 

  75. Pappo AS, Patel SR, Crowley J, Reinke DK, Kuenkele KP, 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(34):4541–7.

    Article  PubMed  CAS  Google Scholar 

  76. Juergens H, Daw NC, Geoerger B, Ferrari S, Villarroel M, Aerts I, et al. Preliminary efficacy of the anti-insulin-like growth factor type 1 receptor antibody figitumumab in patients with refractory Ewing sarcoma. J Clin Oncol. 2011;29(34):4534–40.

    Google Scholar 

  77. 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(3):256–62.

    Article  PubMed  CAS  Google Scholar 

  78. Beltran PJ, Chung YA, Moody G, Mitchell P, Cajulis E, Vonderfecht S, et al. Efficacy of ganitumab (AMG 479), alone and in combination with rapamycin, in Ewing's and osteogenic sarcoma models. J Pharmacol Exp Ther. 2011;337(3):644–54.

    Article  PubMed  CAS  Google Scholar 

  79. Garofalo C, Mancarella C, Grilli A, Manara MC, Astolfi A, Marino MT, et al. Identification of common and distinctive mechanisms of resistance to different anti-IGF-IR agents in Ewing's sarcoma. Mol Endocrinol. 2012;26(9):1603–16.

    Article  PubMed  CAS  Google Scholar 

  80. • Garofalo C, Manara MC, Nicoletti G, Marino MT, Lollini PL, Astolfi A, et al. Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling. Oncogene. 2011;30(24):2730–40. This report elucidates the role of insulin signaling as a possible mechanism towards IGF-1R antibody therapy, thus suggesting that targeting the insulin receptor pathway, or its downstream signaling cascade, could be an avenue of therapeutic potential.

    Article  PubMed  CAS  Google Scholar 

  81. • Erkizan HV, Kong Y, Merchant M, Schlottmann S, Barber-Rotenberg JS, Yuan L, et al. A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma. Nat Med. 2009;15(7):750–6. This report describes the identification of one of the first small molecules specifically designed to target the transcriptional activity of the oncogenic EWS-Fli1 protein. They demonstrate that inhibition of the EWS-Fli1 and RHA interaction leads to altered cell proliferation and xenograft tumor progression.

    Article  PubMed  CAS  Google Scholar 

  82. Boro A, Pretre K, Rechfeld F, Thalhammer V, Oesch S, Wachtel M, et al. Small-molecule screen identifies modulators of EWS/FLI1 target gene expression and cell survival in Ewing's sarcoma. Int J Cancer. 2012;131(9):2153–64.

    Article  PubMed  CAS  Google Scholar 

  83. Grohar PJ, Griffin LB, Yeung C, Chen QR, Pommier Y, Khanna C, et al. Ecteinascidin 743 interferes with the activity of EWS-FLI1 in Ewing sarcoma cells. Neoplasia. 2011;13(2):145–53.

    PubMed  CAS  Google Scholar 

  84. 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(4):579–85.

    Article  PubMed  CAS  Google Scholar 

  85. Carol H, Reynolds CP, Kang MH, Keir ST, Maris JM, Gorlick R, et al. Initial testing of the MDM2 inhibitor RG7112 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2013;60(4):633–41. doi:10.1002/pbc.24235.

    Article  PubMed  Google Scholar 

  86. Neilsen PM, Pishas KI, Callen DF, Thomas DM. Targeting the p53 Pathway in Ewing Sarcoma. Sarcoma. 2011;746939.

  87. • Pishas KI, Al-Ejeh F, Zinonos I, Kumar R, Evdokiou A, Brown MP, et al. Nutlin-3a is a potential therapeutic for ewing sarcoma. Clin Cancer Res. 2011;17(3):494–504. This study demonstrates that activating the endogenous, unmutated p53 pathway, through the inhibition of MDM2 via Nutlin-3a, can lead to significant antitumor activity and synergism with standard chemotherapy. This is a potentially exciting new therapeutic target for ES.

    Article  PubMed  CAS  Google Scholar 

  88. Kailayangiri S, Altvater B, Meltzer J, Pscherer S, Luecke A, Dierkes C, et al. The ganglioside antigen G(D2) is surface-expressed in Ewing sarcoma and allows for MHC-independent immune targeting. Br J Cancer. 2012;106(6):1123–33.

    Article  PubMed  CAS  Google Scholar 

  89. Lehner M, Gotz G, Proff J, Schaft N, Dorrie J, Full F, et al. Redirecting T cells to Ewing's sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection. PLoS One. 2012;7(2):e31210.

    Article  PubMed  CAS  Google Scholar 

  90. Hingorani P, Zhang W, Lin J, Liu L, Guha C, Kolb EA. Systemic administration of reovirus (Reolysin) inhibits growth of human sarcoma xenografts. Cancer. 2011;117(8):1764–74.

    Article  PubMed  CAS  Google Scholar 

  91. Manara MC, Nicoletti G, Zambelli D, Ventura S, Guerzoni C, Landuzzi L, et al. NVP-BEZ235 as a new therapeutic option for sarcomas. Clin Cancer Res. 2010;16(2):530–40.

    Article  PubMed  CAS  Google Scholar 

  92. Sonnemann J, Palani CD, Wittig S, Becker S, Eichhorn F, Voigt A, et al. Anticancer effects of the p53 activator nutlin-3 in Ewing's sarcoma cells. Eur J Cancer. 2011;47(9):1432–41.

    Article  PubMed  CAS  Google Scholar 

  93. Odri GA, Dumoucel S, Picarda G, Battaglia S, Lamoureux F, Corradini N, et al. Zoledronic acid as a new adjuvant therapeutic strategy for Ewing's sarcoma patients. Cancer Res. 2010;70(19):7610–9.

    Article  PubMed  CAS  Google Scholar 

  94. Picarda G, Lamoureux F, Geffroy L, Delepine P, Montier T, Laud K, et al. Preclinical evidence that use of TRAIL in Ewing's sarcoma and osteosarcoma therapy inhibits tumor growth, prevents osteolysis, and increases animal survival. Clin Cancer Res. 2010;16(8):2363–74.

    Article  PubMed  CAS  Google Scholar 

  95. Lock RB, Carol H, Morton CL, Keir ST, Reynolds CP, Kang MH, et al. Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012;58(6):916–23.

    Article  PubMed  Google Scholar 

  96. • Brenner JC, Feng FY, Han S, Patel S, Goyal SV, Bou-Maroun LM, et al. PARP-1 inhibition as a targeted strategy to treat Ewing's sarcoma. Cancer Res. 2012;72(7):1608–13. This study demonstrated that targeting the interaction between EWS-Fli1 and the DNA damaging response protein, PARP-1, led to significant decrease in tumor growth and metastasis. Addition of Temozolomide resulted in complete responses in xenograft models.

    Article  PubMed  CAS  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Nino Rainusso declares that he has no conflict of interest.

Lisa L. Wang has received royalties for Up-To-Date chapter on osteosarcoma.

Jason T. Yustein declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jason T. Yustein.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rainusso, N., Wang, L.L. & Yustein, J.T. The Adolescent and Young Adult with Cancer: State of the Art - Bone Tumors. Curr Oncol Rep 15, 296–307 (2013). https://doi.org/10.1007/s11912-013-0321-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-013-0321-9

Keywords

Navigation