The Adolescent and Young Adult with Cancer: State of the Art - Bone Tumors
- 816 Downloads
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  and 3 % of all cancers in adolescents and young adults (AYA) within the age range of 15 to 29 years . 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.
KeywordsOsteosarcoma Ewing sarcoma Bone tumor Molecular biology Targeted therapies
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.
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.Google Scholar
- 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
- 4.Martin JW, Squire JA, Zielenska M. The genetics of osteosarcoma. Sarcoma. 2012:627254. doi: 10.1155/2012/627254.
- 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle Scholar
- 69.Huang M, Lucas K. Current therapeutic approaches in metastatic and recurrent ewing sarcoma. Sarcoma. 2011;863210.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.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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle Scholar
- 86.Neilsen PM, Pishas KI, Callen DF, Thomas DM. Targeting the p53 Pathway in Ewing Sarcoma. Sarcoma. 2011;746939.Google Scholar
- 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle Scholar