Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Emerging Chemotherapeutic Strategies and the Role of Treatment Stratification in Ewing Sarcoma

  • 52 Accesses

  • 14 Citations


The Ewing sarcoma family of tumors (ESFT) is one of the most common groups of malignancies arising in children, adolescents, and young adults up to approximately 25 years of age. It comprises Ewing sarcoma arising from bone and extraosseous Ewing sarcoma arising from soft tissues (which includes peripheral neuroectodermal tumors and Askin tumor arising from the chest wall).

Ewing sarcoma is treated successfully in many cases by a combination of chemotherapy, surgery, and radiotherapy. A number of prognostic factors have been identified that can be used to stratify patients according to the risk of relapse, allowing optimization of treatment. These can be categorized as tumor-related factors (presence of metastases, tumor site, volume, lactic dehydrogenase level, chromosomal translocation type, presence of fusion transcripts in blood and bone marrow), treatment-related factors (local therapy, histologic response to chemotherapy, radiologic response to chemotherapy, chemotherapy regimen), and patient-related factors (gender, age). Newer chemotherapeutic agents are currently being investigated, and there is now increasing interest in the identification of molecular targets in ESFT that could be exploited therapeutically, which include the mammalian target of rapamycin (mTOR) and insulin growth factor-1 (IGF-1) receptor pathways.

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

Table I
Table II


  1. 1.

    Ewing J. Diffuse endothelioma of bone. Proc NY Path Soc 1921; 21: 17–24

  2. 2.

    Weston CL, Douglas C, Craft AW, et al. Establishing long-term survival and cure in young patients with Ewing’s sarcoma. Br J Cancer 2004; 91: 225–32

  3. 3.

    Whelan J, Morland B. Bone tumors. In: Pinkerton CR, Plowman PN, Pieters R, editors. Paediatric Oncology 3rd ed. London: Arnold, 2004: 384

  4. 4.

    Tirode F, Laud-Duval K, Prieur A, et al. Mesenchymal stem cell features of Ewing tumors. Cancer Cell 2007; 11: 421–9

  5. 5.

    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: 3108–14

  6. 6.

    Widhe B, Widhe T. Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. J Bone Joint Surg Am 2000; 82: 667–74

  7. 7.

    Hameed M. Small round cell tumors of bone. Arch Pathol Lab Med 2007; 131: 192–204

  8. 8.

    Turc-Carel C, Aurias A, Mugneret F, et al. Chromosomes in Ewing’s sarcoma: I. An evaluation of 85 cases of remarkable consistency of t(11;22)(q24;q12). Cancer Genet Cytogenet 1988; 32: 229–38

  9. 9.

    Granowetter L, Womer R, Dévidas M, et al. Comparison of dose intensified and standard dose chemotherapy for the treatment of non-metastatic Ewing’s sarcoma (ES) and primitive neuroectodermal tumor (PNET) of bone and soft tissue: a Paediatric Oncology Group Children’s Cancer Group Phase III trial [abstract]. Med Pediatr Oncol 2001; 37: 172

  10. 10.

    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: 694–701

  11. 11.

    Paulussen M, Ahrens S, Braun-Munzinger G, et al. EICESS 92 (European Intergroup Cooperative Ewing’s Sarcoma Study): preliminary results. Klin Padiatr 1999; 211: 276–83

  12. 12.

    Paulussen M, Craft A, Lewis I, et al. Ewing tumor of bone: updated report of the European Intergroup Cooperative Ewing’s Sarcoma Study EICESS 92 [abstract]. Proc Am Soc Clin Oncol 2002; 20: 1568

  13. 13.

    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: 3628–33

  14. 14.

    Craft AW, Cotterill SJ, Bullimore JA, et al. Long-term results from the first UKCCSG Ewing’s Tumor study (ET-1): United Kingdom Children’s Cancer Study Group (UKCCSG) and the Medical Research Council Bone Sarcoma Working Party. Eur J Cancer 1997; 33: 1061–9

  15. 15.

    Elomaa I, Blomqvist CP, Saeter G, et al. Five-year results in Ewing’s sarcoma: the Scandinavian Sarcoma Group experience with the SSG IX protocol. Eur J Cancer 2000; 36: 875–80

  16. 16.

    Nesbit Jr ME, Gehan EA, Burgert Jr EO, 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: 1664–74

  17. 17.

    Burgert Jr EO, 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: 1514–24

  18. 18.

    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: 23–32

  19. 19.

    Paulussen M, Ahrens S, Dunst J, et al. Localized Ewing tumor of bone: final results of the cooperative Ewing’s Sarcoma Study CESS 86. J Clin Oncol 2001; 19: 1818–29

  20. 20.

    Jurgens H, Ahrens S, Frohlich B, et al. European Intergroup Cooperative Ewing’s Sarcoma Study (EICESS92): first results [abstract]. Proc Am Soc Clin Oncol 2000; 19: 2286

  21. 21.

    Oberlin O, Deley MC, Bui BN, et al. Prognostic factors in localized Ewing’s tumors and peripheral neuroectodermal tumors: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer 2001; 85: 1646–54

  22. 22.

    Bacci G, Picci P, Ferrari S, et al. Neoadjuvant chemotherapy for Ewing’s sarcoma of bone: no benefit observed after adding ifosfamide and etoposide to vincristine, actinomycin, cyclophosphamide, and doxorubicin in the maintenance phase: results of two sequential studies. Cancer 1998; 82: 1174–83

  23. 23.

    Bacci G, Mercuri M, Longhi A, et al. Neoadjuvant chemotherapy for Ewing’s tumor of bone: recent experience at the Rizzoli Orthopaedic Institute. Eur J Cancer 2002; 38: 2243–51

  24. 24.

    EUROpean Ewing tumor Working Initiative of National Groups. EURO-E.W.I.N.G.99 study (EE99) [online]. Available from URL: http://euro-ewing.klinikum.uni-muenster.de/ [Accessed 2007 Dec 16]

  25. 25.

    Juergens C, Weston C, Lewis I, et al. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer 2006; 47: 22–9

  26. 26.

    Kushner BH, Meyers PA. How effective is dose-intensive/myeloablative therapy against Ewing’s sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The Memorial Sloan-Kettering experience and a literature review. J Clin Oncol 2001; 19: 870–80

  27. 27.

    Meyers PA. High-dose therapy with autologous stem cell rescue for pediatric sarcomas. Curr Opin Oncol 2004; 16: 120–5

  28. 28.

    Barker LM, Pendergrass TW, Sanders JE, et al. Survival after recurrence of Ewing’s sarcoma family of tumors. J Clin Oncol 2005; 23: 4354–62

  29. 29.

    Burdach S, Jurgens H, Peters C, et al. Myeloablative radiochemotherapy and hematopoietic stem-cell rescue in poor-prognosis Ewing’s sarcoma. J Clin Oncol 1993; 11: 1482–8

  30. 30.

    Burdach S, Meyer-Bahlburg A, Laws HJ, et al. High-dose therapy for patients with primary multifocal and early relapsed Ewing’s tumors: results of two consecutive regimens assessing the role of total-body irradiation. J Clin Oncol 2003; 21: 3072–8

  31. 31.

    McTiernan A, Driver D, Michelagnoli MP, et al. High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing’s sarcoma family of tumors. Ann Oncol 2006; 17: 1301–5

  32. 32.

    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: 275–81

  33. 33.

    Atra A, Whelan JS, Calvagna V, et al. High-dose busulphan/melphalan with autologous stem cell rescue in Ewing’s sarcoma. Bone Marrow Transplant 1997; 20: 843–6

  34. 34.

    Bertuzzi A, Castagna L, Nozza A, et al. High-dose chemotherapy in poor-prognosis adult small round-cell tumors: clinical and molecular results from a prospective study. J Clin Oncol 2002; 20: 2181–8

  35. 35.

    Horowitz ME, Kinsella TJ, Wexler LH, et al. Total-body irradiation and autologous bone marrow transplant in the treatment of high-risk Ewing’s sarcoma and rhabdomyosarcoma. J Clin Oncol 1993; 11: 1911–8

  36. 36.

    Madero L, Munoz A, Sanchez de Toledo J, et al. Megatherapy in children with high-risk Ewing’s sarcoma in first complete remission. Bone Marrow Transplant 1998; 21: 795–9

  37. 37.

    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: 2812–20

  38. 38.

    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: 3997–4002

  39. 39.

    Meyers PA, Heller G, Healey J, et al. Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience. J Clin Oncol 1992; 10: 5–15

  40. 40.

    Bacci G, Longhi A, Ferrari S, et al. 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 2006; 45: 469–75

  41. 41.

    Hense HW, Ahrens S, Paulussen M, et al. Factors associated with tumor volume and primary metastases in Ewing tumors: results from the (EI)CESS studies. Ann Oncol 1999; 10: 1073–7

  42. 42.

    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: 2873–6

  43. 43.

    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: 3044–52

  44. 44.

    Arvand A, Denny CT. Biology of EWS/ETS fusions in Ewing’s family tumors. Oncogene 2001; 20: 5747–54

  45. 45.

    Delattre O, Zucman J, Plougastel B, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumors. Nature 1992; 359: 162–5

  46. 46.

    Delattre O, Zucman J, Melot T, et al. The Ewing family of tumors: a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 1994; 331: 294–9

  47. 47.

    Sorensen PH, Lessnick SL, Lopez-Terrada D, et al. A second Ewing’s sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nat Genet 1994; 6: 146–51

  48. 48.

    Zucman J, Melot T, Desmaze C, et al. Combinatorial generation of variable fusion proteins in the Ewing family of tumors. EMBO J 1993; 12: 4481–7

  49. 49.

    Zoubek A, Dockhorn-Dworniczak B, Delattre O, et al. Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients? J Clin Oncol 1996; 14: 1245–51

  50. 50.

    de Alva E, Kawai A, Healey JH, et al. EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing’s sarcoma. J Clin Oncol 1998; 16: 1248–55

  51. 51.

    Ginsberg JP, de Alva E, Ladanyi M, et al. EWS-FLI1 and EWS-ERG gene fusions are associated with similar clinical phenotypes in Ewing’s sarcoma. J Clin Oncol 1999; 17: 1809–14

  52. 52.

    Peter M, Magdelenat H, Michon J, et al. Sensitive detection of occult Ewing’s cells by the reverse transcriptase-polymerase chain reaction. Br J Cancer 1995; 72: 96–100

  53. 53.

    Pfleiderer C, Zoubek A, Gruber B, et al. Detection of tumor cells in peripheral blood and bone marrow from Ewing tumor patients by RT-PCR. Int J Cancer 1995; 64: 135–9

  54. 54.

    Toretsky JA, Neckers L, Wexler LH. Detection of (11;22)(q24;ql2) translocation-bearing cells in peripheral blood progenitor cells of patients with Ewing’s sarcoma family of tumors. J Natl Cancer Inst 1995; 87: 385–6

  55. 55.

    West DC, Grier HE, Swallow MM, et al. Detection of circulating tumor cells in patients with Ewing’s sarcoma and peripheral primitive neuroectodermal tumor. J Clin Oncol 1997; 15: 583–8

  56. 56.

    Fagnou C, Michon J, Peter M, et al. Presence of tumor cells in bone marrow but not in blood is associated with adverse prognosis in patients with Ewing’s tumor: Societe; Francaise d’Oncologie Pediatrique. J Clin Oncol 1998; 16: 1707–11

  57. 57.

    Schleiermacher G, Peter M, Oberlin O, et al. Increased risk of systemic relapses associated with bone marrow micrometastasis and circulating tumor cells in localized Ewing tumor. J Clin Oncol 2003; 21: 85–91

  58. 58.

    Avigad S, Cohen IJ, Zilberstein J, et al. The predictive potential of molecular detection in the nonmetastatic Ewing family of tumors. Cancer 2004; 100: 1053–8

  59. 59.

    Zoubek A, Ladenstein R, Windhager R, et al. Predictive potential of testing for bone marrow involvement in Ewing tumor patients by RT-PCR: a preliminary evaluation. Int J Cancer 1998; 79: 56–60

  60. 60.

    de Alva E, Lozano MD, Patino A, et al. Ewing family tumors: potential prognostic value of reverse-transcriptase polymerase chain reaction detection of minimal residual disease in peripheral blood samples. Diagn Mol Pathol 1998; 7: 152–7

  61. 61.

    Bacci G, Picci P, Ruggieri P, et al. Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities: the Istituto Rizzoli Experience in 127 patients treated preoperatively with intravenous methotrexate (high versus moderate doses) and intraarterial cisplatin. Cancer 1990; 65: 2539–53

  62. 62.

    Bacci G, Picci P, Ferrari S, et al. Primary chemotherapy and delayed surgery for nonmetastatic osteosarcoma of the extremities: results in 164 patients preoperatively treated with high doses of methotrexate followed by cisplatin and doxorubicin. Cancer 1993; 72: 3227–38

  63. 63.

    Bramwell VH, Burgers M, Sneath R, et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol 1992; 10: 1579–91

  64. 64.

    Provisor AJ, Ettinger LJ, Nachman JB, 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: 76–84

  65. 65.

    Rosen G, Caparros B, Huvos AG, et al. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 1982; 49: 1221–30

  66. 66.

    Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet 1997; 350: 911–7

  67. 67.

    Winkler K, Beron G, Delling G, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol 1988; 6: 329–37

  68. 68.

    Bacci G, Picci P, Mercuri M, et al. Predictive factors of histological response to primary chemotherapy in Ewing’s sarcoma. Acta Oncol 1998; 37: 671–6

  69. 69.

    Picci P, Rougraff BT, Bacci G, et al. Prognostic significance of histopathologic response to chemotherapy in nonmetastatic Ewing’s sarcoma of the extremities. J Clin Oncol 1993; 11: 1763–9

  70. 70.

    Picci P, Bohling T, Bacci G, et al. Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing’s sarcoma of the extremities. J Clin Oncol 1997; 15: 1553–9

  71. 71.

    Salzer-Kuntschik M, Delling G, Beron G, et al. Morphological grades of regression in osteosarcoma after polychemotherapy: study COSS 80. J Cancer Res Clin Oncol 1983; 106 Suppl.: 21–4

  72. 72.

    Scurr M, Judson I. How to treat the Ewing’s family of sarcomas in adult patients. Oncologist 2006; 11: 65–72

  73. 73.

    Bacci G, Ferrari S, Comandone A, et al. Neoadjuvant chemotherapy for Ewing’s sarcoma of bone in patients older than thirty-nine years. Acta Oncol 2000; 39: 111–6

  74. 74.

    Verrill MW, Judson IR, Wiltshaw E, et al. The use of paediatric chemotherapy protocols at full dose is both a rational and feasible treatment strategy in adults with Ewing’s family tumors. Ann Oncol 1997; 8: 1099–105

  75. 75.

    Paulussen M, Ahrens S, Juergens H. Cure rates in Ewing tumor patients aged over 15 years are better in pediatric oncology units: results of GPOH CESS/EICESS studies [abstract]. Proc Am Soc Clin Oncol 2003; 22: 3279

  76. 76.

    Whelan J. Where should teenagers with cancer be treated? Eur J Cancer 2003; 39: 2573–8

  77. 77.

    Whelan J, Dolbear C, Mak V, et al. Where do teenagers and young adults receive treatment for cancer? J Public Health (Oxf) 2007; 29: 178–82. Epub 2007 Feb 27

  78. 78.

    Wagner LM, Crews KR, Iacono LC, et al. Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Clin Cancer Res 2004; 10: 840–8

  79. 79.

    Wagner LM, McAllister N, Goldsby RE, et al. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer 2007; 48: 132–9

  80. 80.

    Hunold A, Liebscher C, Paulussen M, et al. Topotecan and cyclophosphamide for refractory or relapsed Ewing tumors [abstract]. Sarcoma Meeting Stuttgart (SMS); 2005 Jun 15–17; Stuttgart

  81. 81.

    Kushner BH, Kramer K, Meyers PA, et al. Pilot study of topotecan and high-dose cyclophosphamide for resistant pediatric solid tumors. Med Pediatr Oncol 2000; 35: 468–74

  82. 82.

    Saylors III RL, 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: 3463–9

  83. 83.

    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: 152–9

  84. 84.

    National Cancer Institute, U.S. National Institutes of Health. Phase III randomized study of doxorubicin hydrochloride, cyclophosphamide, vincristine, etoposide, and ifosfamide with versus without topotecan hydrochloride in patients with newly diagnosed localized Ewing’s sarcoma [online]. Available from URL: http://www.cancer.gov/clinicaltrials/COG-AEWS0531 [Accessed 2007 Dec 16]

  85. 85.

    Wu S, Dahut WL, Gulley JL. The use of bisphosphonates in cancer patients. Acta Oncol 2007; 46: 581–91

  86. 86.

    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: 1138–44

  87. 87.

    Sonnemann J, Eckervogt V, Truckenbrod B, et al. The bisphosphonate pamidronate is a potent inhibitor of Ewing’s sarcoma cell growth in vitro. Anticancer Drugs 2003; 14: 767–71

  88. 88.

    Zhou Z, Guan H, Duan X, et al. Zoledronic acid inhibits primary bone tumor growth in Ewing sarcoma. Cancer 2005; 104: 1713–20

  89. 89.

    Kontny U. Regulation of apoptosis and proliferation in Ewing’s sarcoma: opportunities for targeted therapy. Hematol Oncol 2006; 24: 14–21

  90. 90.

    Dohjima T, Lee NS, Li H, et al. Small interfering RNAs expressed from a Pol III promoter suppress the EWS/Fli-1 transcript in an Ewing sarcoma cell line. Mol Ther 2003; 7: 811–6

  91. 91.

    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: 429–37

  92. 92.

    Kovar H, Ban J, Pospisilova S. Potentials for RNAi in sarcoma research and therapy: Ewing’s sarcoma as a model. Semin Cancer Biol 2003; 13: 275–81

  93. 93.

    Ouchida M, Ohno T, Fujimura Y, et al. Loss of tumorigenicity of Ewing’s sarcoma cells expressing antisense RNA to EWS-fusion transcripts. Oncogene 1995; 11: 1049–54

  94. 94.

    Tanaka K, Iwakuma T, Harimaya K, et al. EWS-Flil antisense oligodeoxynucleotide inhibits proliferation of human Ewing’s sarcoma and primitive neuroectodermal tumor cells. J Clin Invest 1997; 99: 239–47

  95. 95.

    Toretsky JA, Connell Y, Neckers L, et al. Inhibition of EWS-FLI-1 fusion protein with antisense oligodeoxynucleotides. J Neurooncol 1997; 31: 9–16

  96. 96.

    Ambros IM, Ambros PF, Strehl S, et al. MIC2 is a specific marker for Ewing’s sarcoma and peripheral primitive neuroectodermal tumors: evidence for a common histogenesis of Ewing’s sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression and specific chromosome aberration. Cancer 1991; 67: 1886–93

  97. 97.

    Kovar H, Dworzak M, Strehl S, et al. Overexpression of the pseudoautosomal gene MIC2 in Ewing’s sarcoma and peripheral primitive neuroectodermal tumor. Oncogene 1990; 5: 1067–70

  98. 98.

    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: 5664–74

  99. 99.

    Scotlandi K, Baldini N, Cerisano V, et al. CD99 engagement: an effective therapeutic strategy for Ewing tumors. Cancer Res 2000; 60: 5134–42

  100. 100.

    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: 91–6

  101. 101.

    Buletic Z, Soprano KJ, Soprano DR. Retinoid targets for the treatment of cancer. Crit Rev Eukaryot Gene Expr 2006; 16: 193–210

  102. 102.

    Burchill SA, Berry PA, Bradbury FM, et al. Contrasting levels of p21ras activation and expression of neurofibromin in peripheral primitive neuroectodermal tumor and neuroblastoma cells, and their response to retinoic acid. J Neurol Sci 1998; 157: 129–37

  103. 103.

    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: 5415–24

  104. 104.

    Myatt SS, Redfern CP, Burchill SA. p38MAPK-dependent sensitivity of Ewing’s sarcoma family of tumors to fenretinide-induced cell death. Clin Cancer Res 2005; 11: 3136–48

  105. 105.

    Rowinsky EK. Targeted induction of apoptosis in cancer management: the emerging role of tumor necrosis factor-related apoptosis-inducing ligand receptor activating agents. J Clin Oncol 2005; 23: 9394–407

  106. 106.

    Kontny HU, Hammerle K, Klein R, et al. Sensitivity of Ewing’s sarcoma to TRAIL-induced apoptosis. Cell Death Differ 2001; 8: 506–14

  107. 107.

    Kumar A, Jasmin A, Eby MT, et al. Cytotoxicity of tumor necrosis factor related apoptosis-inducing ligand towards Ewing’ 6+s sarcoma cell lines. Qncogene 2001; 20: 1010–4

  108. 108.

    Mitsiades N, Poulaki V, Mitsiades C, et al. Ewing’s sarcoma family tumors are sensitive to tumor necrosis factor-related apoptosis-inducing ligand and express death receptor 4 and death receptor 5. Cancer Res 2001; 61: 2704–12

  109. 109.

    Van VF, Fulda S, Truckenbrod B, et al. Apoptotic responsiveness of the Ewing’s sarcoma family of tumors to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Int J Cancer 2000; 88: 252–9

  110. 110.

    Merchant MS, Yang X, Melchionda F, et al. Interferon gamma enhances the effectiveness of tumor necrosis factor-related apoptosis-inducing ligand receptor agonists in a xenograft model of Ewing’s sarcoma. Cancer Res 2004; 64: 8349–56

  111. 111.

    Hotte SJ, Hirte HW, Chen EX, et al. HGS-ETRl, a fully human monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand death receptor 1 (TRAIL-R1) in patients with advanced solid cancer: results of a phase 1 trial [abstract]. Proc Am Soc Clin Oncol 2005; 23: 3052

  112. 112.

    Tolcher AW, Mita M, Patnaik A, et al. A phase I and pharmacokinetic study of HGS-ETRl(TRM-l), a human monoclonal agonist-antibody to TRAIL Rl, in patients with advanced solid tumors [abstract]. ASCO Meeting Abstracts 2004; 22: 3060

  113. 113.

    Rubio-Viqueira B, Hidalgo M. Targeting mTOR for cancer treatment. Curr Opin Investig Drugs 2006; 7: 501–12

  114. 114.

    Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 2000; 19: 6680–6

  115. 115.

    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: 9282–7

  116. 116.

    Chawla SP, Tolcher AW, Staddon AP, et al. Survival results with AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas: update of phase II trial [abstract]. Proc Am Soc Clin Oncol 2007; 25: 10076

  117. 117.

    Deforolimus (AP23573) in treatment of sarcoma: SUCCEED (Sarcoma Multi-Center Clinical Evaluation of the Efficacy of Deforolimus) study [NCT00538239]. Clinical Trials.gov [online]. Available from URL: http://www.clinicaltrials.gov/ct2/show/NCT005382397spons=%22Ariad+pharmaceuticals%22&spons_ex=y&rank=10 [Accessed 2007 Dec 16]

  118. 118.

    Deforolimus: on the fast track in cancer [online]. Cambridge (MA): Ariad. Available from URL: http://www.ariad.com/we/page/ap23573 [Accessed 2007 Dec 16]

  119. 119.

    Jerome L, Shiry L, Leyland-Jones B. Deregulation of the IGF axis in cancer: epidemiological evidence and potential therapeutic interventions. Endocr Relat Cancer 2003; 10: 561–78

  120. 120.

    Riedemann J, Macaulay VM. IGF1R signalling and its inhibition. Endocr Relat Cancer 2006; 13Suppl. 1: S33–43

  121. 121.

    Scotlandi K, Benini S, Sarti M, et al. Insulin-like growth factor I receptor-mediated circuit in Ewing’s sarcoma/peripheral neuroectodermal tumor: a possible therapeutic target. Cancer Res 1996; 56: 4570–4

  122. 122.

    Prieur A, Tirode F, Cohen P, et al. 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: 7275–83

  123. 123.

    Scotlandi K, Benini S, Nanni P, et al. Blockage of insulin-like growth factor-I receptor inhibits the growth of Ewing’s sarcoma in athymic mice. Cancer Res 1998; 58: 4127–31

  124. 124.

    Manara MC, Landuzzi L, Nanni P, et al. Preclinical in vivo study of new insulin-like growth factor-I receptor: specific inhibitor in Ewing’s sarcoma. Clin Cancer Res 2007; 13: 1322–30

  125. 125.

    Scotlandi K, Manara MC, Nicoletti G, et al. Antitumor activity of the insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 in musculoskeletal tumors. Cancer Res 2005; 65: 3868–76

  126. 126.

    Tolcher AW, Rothenberg ML, Rodon J, et al. A phase I pharmacokinetic and pharmacodynamic study of AMG 479, a fully human monoclonal antibody against insulin-like growth factor type 1 receptor (IGF-1R), in advanced solid tumors [abstract]. Proc Am Soc Clin Oncol 2007; 25: 3002

Download references


No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Correspondence to Dr Beatrice M. Seddon.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Seddon, B.M., Whelan, J.S. Emerging Chemotherapeutic Strategies and the Role of Treatment Stratification in Ewing Sarcoma. Pediatr-Drugs 10, 93–105 (2008). https://doi.org/10.2165/00148581-200810020-00004

Download citation


  • Ifosfamide
  • Ewing Sarcoma
  • Bone Marrow Sample
  • Histologic Response
  • Fenretinide