Optimal management of Ewing sarcoma family of tumors: Recent developments in systemic therapy

Pediatric Drugs

Volumn 15, Issue 6, 2013, Pages 473-492

  Owens, Cormac ^a   Abbott, Lesleigh S ^a   Gupta, Abha A ^a  

^a HOSPITAL FOR SICK CHILDREN   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ALKYLATING AGENT; CAMPTOTHECIN; CEDIRANIB; CIXUTUMUMAB; CYCLOPHOSPHAMIDE; DACTINOMYCIN; DOCETAXEL; DOXORUBICIN; ETOPOSIDE; FENRETINIDE; GANITUMAB; GEMCITABINE; IFOSFAMIDE; IMATINIB; IRINOTECAN; NAVELBINE; NIRAPARIB; OLAPARIB; SORAFENIB; SUNITINIB; TEMOZOLOMIDE; TEMSIROLIMUS; TOPOTECAN; TRABECTEDIN; TREOSULFAN; UNINDEXED DRUG; VALPROIC ACID; VINCRISTINE; VORINOSTAT; ZOLEDRONIC ACID;

BONE METASTASIS; CANCER COMBINATION CHEMOTHERAPY; DISEASE COURSE; DRUG SCREENING; DRUG TARGETING; ENZYME INHIBITION; EWING SARCOMA; HUMAN; METASTASIS; NONHUMAN; PRIORITY JOURNAL; RELAPSE; REVIEW; SYSTEMIC THERAPY; UNSPECIFIED SIDE EFFECT;

ANIMALS; BONE NEOPLASMS; CHEMOTHERAPY, ADJUVANT; HUMANS; INSULIN-LIKE GROWTH FACTOR I; METABOLIC NETWORKS AND PATHWAYS; NEOPLASM RECURRENCE, LOCAL; POLY(ADP-RIBOSE) POLYMERASES; PROTEIN KINASE INHIBITORS; PROTEIN-TYROSINE KINASES; SARCOMA, EWING; TOR SERINE-THREONINE KINASES; TRANSLOCATION, GENETIC;

EID: 84890517952     PISSN: 11745878     EISSN: 11792019     Source Type: Journal    
DOI: 10.1007/s40272-013-0037-1     Document Type: Review

References (228)

1. Dehner LP. Primitive neuroectodermal tumor and Ewing's sarcoma. Am J Surg Pathol. 1993;17(1):1-13.
2. Ewing J. The Classic: diffuse endothelioma of bone. Proceedings of the New York Pathological Society. 1921;12:17. Clin Orthop Relat Res. 2006;450:25-7.
3. Balamuth NJ, Womer RB. Ewing's sarcoma. Lancet Oncol. 2010;11(2):184-92.
4. Delattre O, Zucman J, Plougastel B, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992;359(6391):162-5.
5. Bernstein M, Kovar H, Paulussen M, et al. Ewing's sarcoma family of tumors: current management. Oncologist. 2006;11(5):503-19.
6. Gurney JG, Swensen AR, Bulterys M. Malignant bone tumors. In: Ries LAG, Smith MA, Gurney, et al., editors. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. NIH Pub. No. 99-4649. Bethesda: National Institutes of Health; 1999. p. 99-110.
7. Dahlin DC, Coventry MB, Scanlon PW. Ewing's sarcoma: a critical analysis of 165 cases. J Bone Joint Surg Am. 1961;43-A:185-92.
8. Womer RB, West DC, Krailo MD, 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.
9. Cotterill SJ, Ahrens S, Paulussen M, et al. Prognostic factors in Ewing's tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group. J Clin Oncol. 2000;18(17):3108-14.
10. Miser JS, Krailo MD, Tarbell NJ, et al. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide: a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004;22(14):2873-6.
11. Ladenstein R, Potschger U, Le Deley MC, et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol. 2010;28(20):3284-91.
12. Haeusler J, Ranft A, Boelling T, et al. The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES). Cancer. 2010;116(2):443-50.
13. Paulussen M, Ahrens S, Burdach S, et al. Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol. 1998;9(3):275-81.
14. Grier HE, Krailo MD, Tarbell NJ, 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.
15. Granowetter L, Womer R, Devidas M, et al. Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children's Oncology Group Study. J Clin Oncol. 2009;27(15):2536-41.
16. Oberlin O, Deley MC, Bui BN, et al. Prognostic factors in localized Ewing's tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer. 2001;85(11):1646-54.
17. Rodriguez-Galindo C, Liu T, Krasin MJ, 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.
18. Gupta AA, Pappo A, Saunders N, et al. Clinical outcome of children and adults with localized Ewing sarcoma: impact of chemotherapy dose and timing of local therapy. Cancer. 2010;116(13):3189-94.
19. Lee J, Hoang BH, Ziogas A, Zell JA. Analysis of prognostic factors in Ewing sarcoma using a population-based cancer registry. Cancer. 2010;116(8):1964-73.
20. Strauss SJ, McTiernan A, Driver D, et al. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003;21(15):2974-81.
21. Oberlin O, Le Deley M, Dirksen U, Lewis IJ, Ranft A, Michon JM, et al. Randomized comparison of VAC versus VAI chemotherapy (CT) as consolidation for standard risk (SR) Ewing sarcoma tumor (ES): results of the Euro-EWING.99-R1 trial [American Society of Clinical Oncology meeting abstract]. J Clin Oncol. 2011;15S:9517.
22. Combination chemotherapy with or without peripheral stem cell transplantation, radiation therapy, and/or surgery in treating patients with Ewing's sarcoma (Euro-EWING 99) [NCT00020566]. http://www.clinicaltrials.gov/ ct2/show/NCT00020566 (Accessed 10 Jul 2012).
23. Miser JS, Goldsby RE, Chen Z, et al. Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2007;49(7):894-900.
24. Paulussen M, Ahrens S, Craft AW, 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.
25. Nesbit ME Jr, Gehan EA, Burgert EO Jr, et al. Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the First Intergroup study. J Clin Oncol. 1990;8(10):1664-74.
26. Paulussen M, Braun-Munzinger G, Burdach S, et al. Results of treatment of primary exclusively pulmonary metastatic Ewing sarcoma. A retrospective analysis of 41 patients (in German). Klin Padiatr. 1993;205(4):210-6.
27. Pinkerton CR, Bataillard A, Guillo S, Oberlin O, Fervers B, Philip T. Treatment strategies for metastatic Ewing's sarcoma. Eur J Cancer. 2001;37(11):1338-44.
28. Bolling T, Schuck A, Paulussen M, 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.
29. Spunt SL, McCarville MB, Kun LE, et al. Selective use of whole-lung irradiation for patients with Ewing sarcoma family tumors and pulmonary metastases at the time of diagnosis. J Pediatr Hematol Oncol. 2001;23(2):93-8.
30. Oberlin O, Rey A, Desfachelles AS, et al. Impact of high-dose busulfan plus melphalan as consolidation in metastatic Ewing tumors: a study by the Societe Francaise des Cancers de l'Enfant. J Clin Oncol. 2006;24(24):3997-4002.
31. Ladenstein R, Lasset C, Pinkerton R, et al. Impact of megatherapy in children with high-risk Ewing's tumours in complete remission: a report from the EBMT Solid Tumour Registry. Bone Marrow Transplant. 1995;15(5):697-705.
32. Meyers PA, Krailo MD, Ladanyi M, 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.
33. Burdach S, Thiel U, Schoniger M, et al. Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases. Bone Marrow Transplant. 2010;45(3):483-9.
34. Owens C, Le Deley MC, Michon J, Marzouk I, Thebault E, Marec-Berard P, Oberlin O. The management of pulmonary nodules at diagnosis in patients with Ewing sarcoma (ES) [American Society of Clinical Oncology meeting abstract]. J Clin Oncol. 2011;15S:9527.
35. Letourneau PA, Shackett B, Xiao L, et al. Resection of pulmonary metastases in pediatric patients with Ewing sarcoma improves survival. J Pediatr Surg. 2011;46(2):332-5.
36. Shankar AG, Ashley S, Craft AW, Pinkerton CR. Outcome after relapse in an unselected cohort of children and adolescents with Ewing sarcoma. Med Pediatr Oncol. 2003;40(3):141-7.
37. Rodriguez-Galindo C, Billups CA, Kun LE, et al. Survival after recurrence of Ewing tumors: the St Jude Children's Research Hospital experience, 1979-1999. Cancer. 2002;94(2):561-9.
38. Leavey PJ, Mascarenhas L, Marina N, et al. Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multi-modality therapy: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2008;51(3):334-8.
39. Bacci G, Ferrari S, Longhi A, et al. Therapy and survival after recurrence of Ewing's tumors: the Rizzoli experience in 195 patients treated with adjuvant and neoadjuvant chemotherapy from 1979 to 1997. Ann Oncol. 2003;14(11):1654-9.
40. Cersosimo RJ. Topotecan: a new topoisomerase I inhibiting antineoplastic agent. Ann Pharmacother. 1998;32(12):1334-43.
41. Saylors RL 3rd, Stewart CF, Zamboni WC, et al. Phase I study of topotecan in combination with cyclophosphamide in pediatric patients with malignant solid tumors: a Pediatric Oncology Group Study. J Clin Oncol. 1998;16(3):945-52.
42. Saylors RL 3rd, Stine KC, Sullivan J, et al. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001;19(15):3463-9.
43. Hunold A, Weddeling N, Paulussen M, Ranft A, Liebscher C, Jurgens H. Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer. 2006;47(6):795-800.
44. Bernstein ML, Devidas M, Lafreniere D, et al. Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group phase II study 9457 - a report from the Children's Oncology Group. J Clin Oncol. 2006;24(1):152-9.
45. Blanchette P, Hogg D, Ferguson P, et al. Topotecan and cyclophosphamide in adults with relapsed sarcoma. Sarcoma. 2012;2012:749067.
46. Combination chemotherapy in treating patients with non-metastatic extracranial Ewing sarcoma (COG AEWS1031 NCT01231906). http://www. clinicaltrials.gov/ct2/show/NCT01231906 (Accessed 10 Jul 2012).
47. Wagner L. Camptothecin-based regimens for treatment of Ewing sarcoma: past studies and future directions. Sarcoma. 2011;2011:957957.
48. Jones SF, Gian VG, Greco FA, et al. Phase I. Trial of irinotecan and temozolomide in patients with solid tumors. Oncology (Williston Park). 2003;17(5 Suppl 5):41-5.
49. Reardon DA, Quinn JA, Rich JN, et al. Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma. Cancer. 2005;104(7):1478-86.
50. Kushner BH, Kramer K, Modak S, Cheung NK. Irinotecan plus temozolomide for relapsed or refractory neuroblastoma. J Clin Oncol. 2006;24(33):5271-6.
51. Newlands ES, Stevens MF, Wedge SR, Wheelhouse RT, Brock C. Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev. 1997;23(1):35-61.
52. Wagner LM, McAllister N, Goldsby RE, et al. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer. 2007;48(2):132-9.
53. Casey DA, Wexler LH, Merchant MS, et al. Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer. 2009;53(6):1029-34.
54. Wagner LM. Oral irinotecan for treatment of pediatric solid tumors: ready for prime time? Pediatr Blood Cancer. 2010;54(5):661-2.
55. Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol. 2002;20(12):2824-31.
56. Mini E, Nobili S, Caciagli B, Landini I, Mazzei T. Cellular pharmacology of gemcitabine. Ann Oncol. 2006;17(Suppl 5):v7-12.
57. Maki RG. Gemcitabine and docetaxel in metastatic sarcoma: past, present, and future. Oncologist. 2007;12(8):999-1006.
58. Lyseng-Williamson KA, Fenton C. Docetaxel: a review of its use in metastatic breast cancer. Drugs. 2005;65(17):2513-31.
59. Mora J, Cruz CO, Parareda A, de Torres C. Treatment of relapsed/refractory pediatric sarcomas with gemcitabine and docetaxel. J Pediatr Hematol Oncol. 2009;31(10):723-9.
60. Fox E, Patel S, Wathen JK, 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):e321-9.
61. Turc-Carel C, Philip I, Berger MP, Philip T, Lenoir G. Chromosomal translocation (11; 22) in cell lines of Ewing's sarcoma [in French]. C R Seances Acad Sci III. 1983;296(23):1101-3.
62. Aurias A, Rimbaut C, Buffe D, Dubousset J, Mazabraud A. Translocation of chromosome 22 in Ewing's sarcoma (in French). C R Seances Acad Sci III. 1983;296(23):1105-7.
63. Lessnick SL, Ladanyi M. Molecular pathogenesis of Ewing sarcoma: new therapeutic and transcriptional targets. Ann Rev Pathol. 2012;7:145-59.
64. Toomey EC, Schiffman JD, Lessnick SL. Recent advances in the molecular pathogenesis of Ewing's sarcoma. Oncogene. 2010;29(32):4504-16.
65. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74.
66. Potratz J, Jurgens H, Craft A, Dirksen U. Ewing sarcoma: biology-based therapeutic perspectives. Pediatr Hematol Oncol. 2012;29(1):12-27.
67. Pinto A, Dickman P, Parham D. Pathobiologic markers of the Ewing sarcoma family of tumors: state of the art and prediction of behaviour. Sarcoma. 2011;2011:856190.
68. Janknecht R. EWS-ETS oncoproteins: the linchpins of Ewing tumors. Gene. 2005;363:1-14.
69. Mackintosh C, Madoz-Gurpide J, Ordonez JL, Osuna D, Herrero-Martin D. The molecular pathogenesis of Ewing's sarcoma. Cancer Biol Ther. 2010;9(9):655-67.
70. Smith R, Owen LA, Trem DJ, et al. Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing's sarcoma. Cancer Cell. 2006;9(5):405-16.
71. Owen LA, Kowalewski AA, Lessnick SL. EWS/FLI mediates transcriptional repression via NKX2.2 during oncogenic transformation in Ewing's sarcoma. PLoS One. 2008;3(4):e1965.
72. Keshelava N, Houghton PJ, Morton CL, et al. Initial testing (stage 1) of vorinostat (SAHA) by the pediatric preclinical testing program. Pediatr Blood Cancer. 2009;53(3):505-8.
73. Sakimura R, Tanaka K, Nakatani F, et al. Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors. Int J Cancer. 2005;116(5):784-92.
74. Sonnemann J, Dreyer L, Hartwig M, et al. Histone deacetylase inhibitors induce cell death and enhance the apoptosis-inducing activity of TRAIL in Ewing's sarcoma cells. J Cancer Res Clin Oncol. 2007;133(11):847-58.
75. Valproic acid in treating young patients with recurrent or refractory solid tumors or CNS tumors (NCI ADVL04190 [NCT00107458]). http://www. clinicaltrials.gov/ct2/show/NCT00107458 (Accessed 10 Jul 2012).
76. Vorinostat in children [NCT01422499]. http://www.clinicaltrials.gov/cts/ show/NCT01422499 (Accessed 10 Jul 2012).
77. Shahi MH, Schiapparelli P, Afzal M, Sinha S, Rey JA, Castresana JS. Expression and epigenetic modulation of sonic hedgehog-GLI1 pathway genes in neuroblastoma cell lines and tumors. Tumour Biol. 2011;32(1):113-27.
78. Beauchamp EM, Ringer L, Bulut G, et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest. 2011;121(1):148-60.
79. Smith MA, Kang MH, Reynolds CP, et al. Evaluation of arsenic trioxide by the pediatric preclinical testing program with a focus on Ewing sarcoma. Pediatr Blood Cancer. 2012;59(4):753-5.
80. Kinsey M, Smith R, Lessnick SL. NR0B1 is required for the oncogenic phenotype mediated by EWS/FLI in Ewing's sarcoma. Mol Cancer Res. 2006;4(11):851-9.
81. Garcia-Aragoncillo E, Carrillo J, Lalli E, et al. DAX1, a direct target of EWS/FLI1 oncoprotein, is a principal regulator of cell-cycle progression in Ewing's tumor cells. Oncogene. 2008;27(46):6034-43.
82. D'Incalci M, Galmarini CM. A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther. 2010;9(8):2157-63.
83. Grohar PJ, Griffin LB, Yeung C, et al. Ecteinascidin 743 interferes with the activity of EWS-FLI1 in Ewing sarcoma cells. Neoplasia. 2011;13(2):145-53.
84. Lau L, Supko JG, Blaney S, et al. A phase I and pharmacokinetic study of ecteinascidin-743 (Yondelis) in children with refractory solid tumors: a Children's Oncology Group study. Clin Cancer Res. 2005;11(2 Pt 1):672-7.
85. Baruchel S, Pappo A, Krailo M, 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.
86. Kovar H. Ewing tumor biology: perspectives for innovative treatment approaches. Adv Exp Med Biol. 2003;532:27-37.
87. Kelleher FC, Thomas DM. Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours. Clin Sarcoma Res. 2012;2(1):6.
88. Kovar H, Aryee DN, Jug G, et al. EWS/FLI-1 antagonists induce growth inhibition of Ewing tumor cells in vitro. Cell Growth Differ. 1996;7(4):429-37.
89. Tanaka K, Iwakuma T, Harimaya K, Sato H, Iwamoto Y. EWS-Fli1 antisense oligodeoxynucleotide inhibits proliferation of human Ewing's sarcoma and primitive neuroectodermal tumor cells. J Clin Invest. 1997;99(2):239-47.
90. Chansky HA, Barahmand-Pour F, Mei Q, et al. Targeting of EWS/FLI-1 by RNA interference attenuates the tumor phenotype of Ewing's sarcoma cells in vitro. J Orthop Res. 2004;22(4):910-7.
91. Mateo-Lozano S, Gokhale PC, Soldatenkov VA, Dritschilo A, Tirado OM, Notario V. Combined transcriptional and translational targeting of EWS/FLI-1 in Ewing's sarcoma. Clin Cancer Res. 2006;12(22):6781-90.
92. Erkizan HV, Scher LJ, Gamble SE, et al. Novel peptide binds EWS-FLI1 and reduces the oncogenic potential in Ewing tumors. Cell Cycle. 2011;10(19):3397-408.
93. Garnett MJ, Edelman EJ, Heidorn SJ, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483(7391):570-5.
94. Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;72(21):5588-99.
95. Carey LA, Sharpless NE. PARP and cancer: if it's broke, don't fix it. N Engl J Med. 2011;364(3):277-9.
96. Brenner JC, Feng FY, Han S, et al. PARP-1 inhibition as a targeted strategy to treat Ewing's sarcoma. Cancer Res. 2012;72(7):1608-13.
97. O'Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364(3):205-14.
98. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117-34.
99. Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353(2):172-87.
100. Doolittle RF, Hunkapiller MW, Hood LE, et al. Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science. 1983;221(4607):275-7.
101. Waterfield MD, Scrace GT, Whittle N, et al. Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus. Nature. 1983;304(5921):35-9.
102. DuBois SG, Marina N, Glade-Bender J. Angiogenesis and vascular targeting in Ewing sarcoma: a review of preclinical and clinical data. Cancer. 2010;116(3):749-57.
103. Dalal S, Berry AM, Cullinane CJ, et al. Vascular endothelial growth factor: a therapeutic target for tumors of the Ewing's sarcoma family. Clin Cancer Res. 2005;11(6):2364-78.
104. Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039-49.
105. de Castro Junior G, Puglisi F, de Azambuja E, El Saghir NS, Awada A. Angiogenesis and cancer: a cross-talk between basic science and clinical trials (the "do ut des" paradigm). Crit Rev Oncol Hematol. 2006;59(1):40-50.
106. Bid HK, Houghton PJ. Targeting angiogenesis in childhood sarcomas. Sarcoma. 2011;2011:601514.
107. Fuchs B, Inwards CY, Janknecht R. Vascular endothelial growth factor expression is up-regulated by EWS-ETS oncoproteins and Sp1 and may represent an independent predictor of survival in Ewing's sarcoma. Clin Cancer Res. 2004;10(4):1344-53.
108. Strammiello R, Benini S, Manara MC, Perdichizzi S, Serra M, Spisni E, et al. Impact of IGF-I/IGF-IR circuit on the angiogenetic properties of Ewing's sarcoma cells. Horm Metab Res. 2003;35(11-12):675-84.
109. Simpson A, Grimer R, Mangham C, Cullinane C, Lewis I, Burchill S. MVD predicts disease-free and overall survival in tumours of the Ewing sarcoma family (ESFT) (abstract). Br J Cancer. 2002;86(Suppl 1):S95.
110. Shawver LK, Slamon D, Ullrich A. Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell. 2002;1(2):117-23.
111. Reichert JM, Valge-Archer VE. Development trends for monoclonal antibody cancer therapeutics. Nat Rev Drug Discov. 2007;6(5):349-56.
112. Merchant MS, Woo CW, Mackall CL, Thiele CJ. Potential use of imatinib in Ewing's sarcoma: evidence for in vitro and in vivo activity. J Natl Cancer Inst. 2002;94(22):1673-9.
113. Maris JM, Courtright J, Houghton PJ, et al. Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008;51(1):42-8.
114. Keir ST, Maris JM, Lock R, et al. Initial testing (stage 1) of the multi-targeted kinase inhibitor sorafenib by the pediatric preclinical testing program. Pediatr Blood Cancer. 2010;55(6):1126-33.
115. Bond M, Bernstein ML, Pappo A, et al. A phase II study of imatinib mesylate in children with refractory or relapsed solid tumors: a Children's Oncology Group study. Pediatr Blood Cancer. 2008;50(2):254-8.
116. Ugurel S, Hildenbrand R, Zimpfer A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer. 2005;92(8):1398-405.
117. Krug LM, Crapanzano JP, Azzoli CG, et al. Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: a phase II clinical trial. Cancer. 2005;103(10):2128-31.
118. Modi S, Seidman AD, Dickler M, et al. A phase II trial of imatinib mesylate monotherapy in patients with metastatic breast cancer. Breast Cancer Res Treat. 2005;90(2):157-63.
119. Kang MH, Smith MA, Morton CL, Keshelava N, Houghton PJ, Reynolds CP. National Cancer Institute pediatric preclinical testing program: model description for in vitro cytotoxicity testing. Pediatr Blood Cancer. 2011;56(2):239-49.
120. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7(10):3129-40.
121. Papaetis GS, Syrigos KN. Sunitinib: a multitargeted receptor tyrosine kinase inhibitor in the era of molecular cancer therapies. BioDrugs. 2009;23(6):377-89.
122. Dubois SG, Shusterman S, Ingle AM, et al. Phase I and pharmacokinetic study of sunitinib in pediatric patients with refractory solid tumors: a children's oncology group study. Clin Cancer Res. 2011;17(15):5113-22.
123. Benesch M, Windelberg M, Sauseng W, et al. Compassionate use of bevacizumab (Avastin) in children and young adults with refractory or recurrent solid tumors. Ann Oncol. 2008;19(4):807-13.
124. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3(5):391-400.
125. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA. 2002;99(17):11393-8.
126. Glade Bender JL, Adamson PC, Reid JM, 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(3):399-405.
127. Leavey PJ, Mascarenhas L, Granowetter L, et al. Feasibility of bevacizumab (NSC 704865, BB-IND no. 7921) combined with vincristine, topotecan, and cyclophosphamide in patients with first recurrent Ewing sarcoma (EWS): a Children's Oncology Group (COG) study [American Society of Clinical Oncology meeting abstract]. J Clin Oncol. 2010;28(15 Suppl):9552.
128. Park JR, Hawkins DS, Ingle M, Borinstein SC, Glade Bender JL, Yamashiro D, et al. A pediatric phase I trial and pharmacokinetic study of aflibercept (VEGF Trap): a COG phase I consortium study [American Society of Clinical Oncology meeting abstract]. J Clin Oncol. 2010;28(15):9530.
129. Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 2005;65(10):4389-400.
130. Gardner K, Judson I, Leahy M, et al. Activity of cediranib, a highly potent and selective VEGF signalling inhibitor, in alveolar soft part sarcoma [American Society of Clinical Oncology meeting abstract]. J Clin Oncol. 2009;27(15Suppl):10523A.
131. Morton CL, Maris JM, Keir ST, et al. Combination testing of cediranib (AZD2171) against childhood cancer models by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012;58(4):566-71.
132. Fox E, Aplenc R, Bagatell R, 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(35):5174-81.
133. Engelman JA, Settleman J. Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr Opin Genet Dev. 2008;18(1):73-9.
134. Rosenzweig SA. Acquired resistance to drugs targeting receptor tyrosine kinases. Biochem Pharmacol. 2012;83(8):1041-8.
135. Rexer BN, Engelman JA, Arteaga CL. Overcoming resistance to tyrosine kinase inhibitors: lessons learned from cancer cells treated with EGFR antagonists. Cell Cycle. 2009;8(1):18-22.
136. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-93.
137. Mateo-Lozano S, Tirado OM, Notario V. Rapamycin induces the fusion-type independent downregulation of the EWS/FLI-1 proteins and inhibits Ewing's sarcoma cell proliferation. Oncogene. 2003;22(58):9282-7.
138. Spunt SL, Grupp SA, Vik TA, et al. Phase I study of temsirolimus in pediatric patients with recurrent/refractory solid tumors. J Clin Oncol. 2011;29(21):2933-40.
139. Mita MM, Mita AC, Chu QS, et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol. 2008;26(3):361-7.
140. Chawla SP, Staddon AP, Baker LH, et al. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J Clin Oncol. 2012;30(1):78-84.
141. Temsirolimus, irinotecan hydrochoride, and temozolomide in treating young patients with relapsed or refractory solid tumors (ADVL0918) [NCT01141244]. http://www.clinicaltrials/gov/ct2/show/NCT01141244 (Accessed 10 Jul 2012).
142. Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther. 2007;6(1):1-12.
143. Scotlandi K, Picci P. Targeting insulin-like growth factor 1 receptor in sarcomas. Curr Opin Oncol. 2008;20(4):419-27.
144. Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12(3):159-69.
145. Sheppard K, Kinross KM, Solomon B, Pearson RB, Phillips WA. Targeting PI3 kinase/AKT/mTOR signaling in cancer. Crit Rev Oncog. 2012;17(1):69-95.
146. Kim SY, Toretsky JA, Scher D, Helman LJ. The role of IGF-1R in pediatric malignancies. Oncologist. 2009;14(1):83-91.
147. Olmos D, Tan DS, Jones RL, Judson IR. Biological rationale and current clinical experience with anti-insulin-like growth factor 1 receptor monoclonal antibodies in treating sarcoma: twenty years from the bench to the bedside. Cancer J. 2010;16(3):183-94.
148. Olmos D, Martins AS, Jones RL, Alam S, Scurr M, Judson IR. Targeting the insulin-like growth factor 1 receptor in Ewing's sarcoma: reality and expectations. Sarcoma. 2011;2011:402508.
149. Erkizan HV, Uversky VN, Toretsky JA. Oncogenic partnerships: EWS-FLI1 protein interactions initiate key pathways of Ewing's sarcoma. Clin Cancer Res. 2010;16(16):4077-83.
150. Prieur A, Tirode F, Cohen P, Delattre O. EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Mol Cell Biol. 2004;24(16):7275-83.
151. Benini S, Zuntini M, Manara MC, et al. Insulin-like growth factor binding protein 3 as an anticancer molecule in Ewing's sarcoma. Int J Cancer. 2006;119(5):1039-46.
152. Valenciano A, Henriquez-Hernandez LA, Moreno M, Lloret M, Lara PC. Role of IGF-1 receptor in radiation response. Transl Oncol. 2012;5(1):1-9.
153. Tognon CE, Sorensen PH. Targeting the insulin-like growth factor 1 receptor (IGF1R) signaling pathway for cancer therapy. Expert Opin Ther Targets. 2012;16(1):33-48.
154. Borinstein SC, Barkauskas DA, Krailo M, et al. Investigation of the insulin-like growth factor-1 signaling pathway in localized Ewing sarcoma: a report from the Children's Oncology Group. Cancer. 2011;117(21):4966-76.
155. Gombos A, Metzger-Filho O, Dal Lago L, Awada-Hussein A. Clinical development of insulin-like growth factor receptor-1 (IGF-1R) inhibitors: at the crossroad? Invest New Drugs. 2012;30:2433-42.
156. Kolb EA, Gorlick R, Maris JM, et al. Combination testing (stage 2) of the anti-IGF-1 receptor antibody IMC-A12 with rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012;58(5):729-35.
157. Maki RG. Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer. J Clin Oncol. 2010;28(33):4985-95.
158. Kolb EA, Gorlick R, Houghton PJ, et al. Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008;50(6):1190-7.
159. Houghton PJ, Morton CL, Gorlick R, et al. Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2010;54(7):921-6.
160. Tolcher AW, Sarantopoulos J, Patnaik A, et al. Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1. J Clin Oncol. 2009;27(34):5800-7.
161. Juergens H, Daw NC, Geoerger B, et al. Preliminary efficacy of the
162. Pappo AS, Patel SR, Crowley J, 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.
163. Tap WD, Demetri G, Barnette P, et al. Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. J Clin Oncol. 2012;30(15):1849-56.
164. Gualberto A, Pollak M. Clinical development of inhibitors of the insulin-like growth factor receptor in oncology. Curr Drug Targets. 2009;10(10):923-36.
165. Garofalo C, Manara MC, Nicoletti G, 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.
166. Huang F, Hurlburt W, Greer A, et al. Differential mechanisms of acquired resistance to insulin-like growth factor-i receptor antibody therapy or to a small-molecule inhibitor, BMS-754807, in a human rhabdomyosarcoma model. Cancer Res. 2010;70(18):7221-31.
167. Ho AL, Schwartz GK. Targeting of insulin-like growth factor type 1 receptor in Ewing sarcoma: unfulfilled promise or a promising beginning? J Clin Oncol. 2011;29(34):4581-3.
168. Asmane I, Watkin E, Alberti L, et al. Insulin-like growth factor type 1 receptor (IGF-1R) exclusive nuclear staining: a predictive biomarker for IGF-1R monoclonal antibody (Ab) therapy in sarcomas. Eur J Cancer. 2012;48(16):3027-35.
169. Gong Y, Yao E, Shen R, et al. High expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-IGF-1R antibody (R1507). PLoS One. 2009;4(10):e7273.
170. Zha J, Lackner MR. Targeting the insulin-like growth factor receptor-1R pathway for cancer therapy. Clin Cancer Res. 2010;16(9):2512-7.
171. Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by co-targeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18(6):683-95.
172. Chandarlapaty S, Sawai A, Scaltriti M, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 2011;19(1):58-71.
173. Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene. 2007;26(13):1932-40.
174. Naing A, LoRusso P, Fu S, et al. Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing's sarcoma family tumors. Clin Cancer Res. 2012;18(9):2625-31.
175. Schwartz G, Tap WD, Qin LX, Livingston MB, Undevia SD, Chmielowski B, et al. A phase II multicenter study of the IGF-1 receptor antibody cixutumumab (A12) and the mTOR inhibitor temsirolimus (TEM) in patients (pts) with refractory IGF-1R positive (+) and negative (-) bone and soft tissue sarcomas (STS) [American Society of Clinical Oncology meeting abstract]. J Clin Oncol. 2012;29(10 Suppl):10003.
176. Dong J, Demarest SJ, Sereno A, et al. Combination of two insulin-like growth factor-I receptor inhibitory antibodies targeting distinct epitopes leads to an enhanced antitumor response. Mol Cancer Ther. 2010;9(9):2593-604.
177. Mulvihill MJ, Cooke A, Rosenfeld-Franklin M, et al. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med Chem. 2009;1(6):1153-71.
178. Buck E, Gokhale PC, Koujak S, et al. Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer. Mol Cancer Ther. 2010;9(10):2652-64.
179. Blackburn EH. Structure and function of telomeres. Nature. 1991;350(6319):569-73.
180. Tabori U, Dome JS. Telomere biology of pediatric cancer. Cancer Invest. 2007;25(3):197-208.
181. Proctor A, Brownhill SC, Burchill SA. The promise of telomere length, telomerase activity and its regulation in the translocation-dependent cancer ESFT; clinical challenges and utility. Biochim Biophys Acta. 2009;1792(4):260-74.
182. Avigad S, Naumov I, Ohali A, et al. Short telomeres: a novel potential predictor of relapse in Ewing sarcoma. Clin Cancer Res. 2007;13(19):5777-83.
183. Boro A, Pretre K, Rechfeld F, 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.
184. Hofbauer S, Hamilton G, Theyer G, Wollmann K, Gabor F. Insulin-like growth factor-I-dependent growth and in vitro chemosensitivity of Ewing's sarcoma and peripheral primitive neuroectodermal tumour cell lines. Eur J Cancer. 1993;29A(2):241-5.
185. Stegmaier K, Wong JS, Ross KN, et al. Signature-based small molecule screening identifies cytosine arabinoside as an EWS/FLI modulator in Ewing sarcoma. PLoS Med. 2007;4(4):e122.
186. DuBois SG, Krailo MD, Lessnick SL, et al. Phase II study of intermediate-dose cytarabine in patients with relapsed or refractory Ewing sarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2009;52(3):324-7.
187. Grohar PJ, Woldemichael GM, Griffin LB, et al. Identification of an inhibitor of the EWS-FLI1 oncogenic transcription factor by high-throughput screening. J Natl Cancer Inst. 2011;103(12):962-78.
188. Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324-34.
189. Scotlandi K, Baldini N, Cerisano V, et al. CD99 engagement: an effective therapeutic strategy for Ewing tumors. Cancer Res. 2000;60(18):5134-42.
190. Rocchi A, Manara MC, Sciandra M, et al. CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis. J Clin Invest. 2010;120(3):668-80.
191. Franzetti GA, Laud-Duval K, Bellanger D, Stern MH, Sastre-Garau X, Delattre O. MiR-30a-5p connects EWS-FLI1 and CD99, two major therapeutic targets in Ewing tumor. Oncogene. 2012;. doi: 10.1038/onc.2012.403.
192. Cerisano V, Aalto Y, Perdichizzi S, et al. Molecular mechanisms of CD99-induced caspase-independent cell death and cell-cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators. Oncogene. 2004;23(33):5664-74.
193. Scotlandi K, Perdichizzi S, Bernard G, et al. Targeting CD99 in association with doxorubicin: an effective combined treatment for Ewing's sarcoma. Eur J Cancer. 2006;42(1):91-6.
194. Gellini M, Ascione A, Flego M, et al. Generation of human single-chain antibody to the CD99 cell surface determinant specifically recognizing Ewing's sarcoma tumor cells. Curr Pharm Biotechnol. 2012 (Epub ahead of print).
195. Green JR. Bisphosphonates: preclinical review. Oncologist. 2004;9(Suppl 4):3-13.
196. Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev. 2012;(2):CD003474.
197. Sonnemann J, Eckervogt V, Truckenbrod B, Boos J, Winkelmann W, van Valen F. The bisphosphonate pamidronate is a potent inhibitor of Ewing's sarcoma cell growth in vitro. Anticancer Drugs. 2003;14(9):767-71.
198. Kubo T, Shimose S, Matsuo T, et al. Inhibitory effects of a new bisphosphonate, minodronate, on proliferation and invasion of a variety of malignant bone tumor cells. J Orthop Res. 2006;24(6):1138-44.
199. Study in localized and disseminated Ewing sarcoma (EWING 2008) [NCT 00987636]. http://www.clinicaltrials.gov/ct2/show/NCT00987636 (Accessed 10 Jul 2012).
200. Burchill SA, Berry PA, Bradbury FM, Lewis IJ. Contrasting levels of p21ras activation and expression of neurofibromin in peripheral primitive neuroectodermal tumour and neuroblastoma cells, and their response to retinoic acid. J Neurol Sci. 1998;157(2):129-37.
201. Batra S, Reynolds CP, Maurer BJ. Fenretinide cytotoxicity for Ewing's sarcoma and primitive neuroectodermal tumor cell lines is decreased by hypoxia and synergistically enhanced by ceramide modulators. Cancer Res. 2004;64(15):5415-24.
202. Myatt SS, Burchill SA. The sensitivity of the Ewing's sarcoma family of tumours to fenretinide-induced cell death is increased by EWS-Fli1-dependent modulation of p38(MAPK) activity. Oncogene. 2008;27(7):985-96.
203. Villablanca JG, Krailo MD, Ames MM, Reid JM, Reaman GH, Reynolds CP. Phase I trial of oral fenretinide in children with high-risk solid tumors: a report from the Children's Oncology Group (CCG 09709). J Clin Oncol. 2006;24(21):3423-30.
204. Suva ML, Riggi N, Stehle JC, et al. Identification of cancer stem cells in Ewing's sarcoma. Cancer Res. 2009;69(5):1776-81.
205. 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.
206. Honoki K. Do stem-like cells play a role in drug resistance of sarcomas? Expert Rev Anticancer Ther. 2010;10(2):261-70.
207. Trucco M, Loeb D. Sarcoma stem cells: do we know what we are looking for? Sarcoma. 2012;2012:291705.
208. Jiang X, Gwye Y, Russell D, et al. CD133 expression in chemo-resistant Ewing sarcoma cells. BMC Cancer. 2010;10:116.
209. Hirschmann-Jax C, Foster AE, Wulf GG, et al. A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA. 2004;101(39):14228-33.
210. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275-84.
211. Mimeault M, Hauke R, Batra SK. Recent advances on the molecular mechanisms involved in the drug resistance of cancer cells and novel targeting therapies. Clin Pharmacol Ther. 2008;83(5):673-91.
212. Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene. 2003;22(47):7369-75.
213. Besancon R, Valsesia-Wittmann S, Puisieux A, Caron de Fromentel C, Maguer-Satta V. Cancer stem cells: the emerging challenge of drug targeting. Curr Med Chem. 2009;16(4):394-416.
214. Scotlandi K, Remondini D, Castellani G, et al. Overcoming resistance to conventional drugs in Ewing sarcoma and identification of molecular predictors of outcome. J Clin Oncol. 2009;27(13):2209-16.
215. Kovar H, Alonso J, Aman P, et al. The first European interdisciplinary Ewing sarcoma research summit. Front Oncol. 2012;2:54.
216. Burgert EO Jr, Nesbit ME, Garnsey LA, et al. Multimodal therapy for the management of nonpelvic, localized Ewing's sarcoma of bone: Intergroup study IESS-II. J Clin Oncol. 1990;8(9):1514-24.
217. Paulussen M, Craft AW, Lewis I, et al. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment - cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008;26(27):4385-93.
218. Rosen G, Caparros B, Mosende C, McCormick B, Huvos AG, Marcove RC. Curability of Ewing's sarcoma and considerations for future therapeutic trials. Cancer. 1978;41(3):888-99.
219. Hayes FA, Thompson EI, Meyer WH, et al. Therapy for localized Ewing's sarcoma of bone. J Clin Oncol. 1989;7(2):208-13.
220. Jurgens H, Exner U, Gadner H, et al. Multidisciplinary treatment of primary Ewing's sarcoma of bone: a 6-year experience of a European Cooperative Trial. Cancer. 1988;61(1):23-32.
221. Craft A, Cotterill S, Malcolm A, et al. Ifosfamide-containing chemotherapy in Ewing's sarcoma: the Second United Kingdom Children's Cancer Study Group and the Medical Research Council Ewing's Tumor Study. J Clin Oncol. 1998;16(11):3628-33.
222. Bacci G, Mercuri M, Longhi A, et al. Neoadjuvant chemotherapy for Ewing's tumour of bone: recent experience at the Rizzoli Orthopaedic Institute. Eur J Cancer. 2002;38(17):2243-51.
223. Kolb EA, Kushner BH, Gorlick R, et al. Long-term event-free survival after intensive chemotherapy for Ewing's family of tumors in children and young adults. J Clin Oncol. 2003;21(18):3423-30.
224. Minard-Colin V, Ichante JL, Nguyen L, et al. Phase II study of vinorelbine and continuous low doses cyclophosphamide in children and young adults with a relapsed or refractory malignant solid tumour: good tolerance profile and efficacy in rhabdomyosarcoma - a report from the Societe Francaise des Cancers et leucemies de l'Enfant et de l'adolescent (SFCE). Eur J Cancer. 2012;45(15):2409-16.
225. Widemann BC, Kim A, Fox E, et al. A phase I trial and pharmacokinetic study of sorafenib in children with refractory solid tumors or leukemias: a Children's Oncology Group Phase I Consortium Report. Clin Cancer Res. 2012;18(21):6021-2.
226. Malempati S, Weigel B, Ingle AM, 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.
227. Imetelstat sodium in treating young patients with refractory or recurrent solid tumors or lymphoma. (COG ADVL1112 [NCT01273090]). http://www. clinicaltrials.gov/ct2/show/NCT0273090 (Accessed 30 Nov 2012).
228. Mithramycin for children and adults with solid tumors or Ewing sarcoma. [NCT01610570]. http://www.clinicaltrials.gov/ct2/show/NCT01610570 (Accessed 30 Nov 2012).