UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Radiation therapy for Ewing sarcoma family of tumors

Author
Thomas F DeLaney, MD
Section Editors
Robert Maki, MD, PhD
Alberto S Pappo, MD
Deputy Editor
Diane MF Savarese, MD

INTRODUCTION

Ewing sarcoma (ES) is a rare malignancy that most often presents as an undifferentiated primary bone tumor; less commonly, it arises in soft tissue (extraosseous Ewing sarcoma, EES). Both are part of a spectrum of neoplastic diseases known as the Ewing sarcoma family of tumors (EFT), which also includes the more differentiated peripheral primitive neuroectodermal tumor (PNET, previously called peripheral neuroepithelioma, adult neuroblastoma, and Askin's tumor of the chest wall) [1]. PNET can also present either in bone or soft tissue. Because these tumors share similar histological and immunohistochemical characteristics and unique nonrandom chromosomal translocations, they are considered to have a common origin. (See "Epidemiology, pathology, and molecular genetics of the Ewing sarcoma family of tumors".)

EFT also share important clinical features, including a peak incidence between the age of 10 and 20, a tendency towards rapid spread to lungs, bone, and bone marrow, and responsiveness to the same chemotherapeutic regimens and radiotherapy (RT). Because relapse rates are high in patients undergoing local therapy alone (80 to 90 percent), it is surmised that the majority have subclinical metastatic disease at the time of diagnosis, even in the absence of overt metastases. The routine administration of intensive multiagent chemotherapy, which can eradicate these deposits, has had a dramatic impact on outcomes. Five-year survival rates for patients with Ewing sarcoma in the United States rose from 36 to 56 percent during the periods 1975 to 1984 and 1985 to 1994 [2]. (See "Treatment of the Ewing sarcoma family of tumors".)

Local control at the primary tumor site can be accomplished by surgery, RT, or both. The choice of modality usually represents a tradeoff between functional result and treatment-related morbidity, particularly the risk of a secondary radiation-induced malignancy. Although modern treatment protocols emphasize surgery for optimal local control, patients who lack a function-preserving surgical option because of tumor location or extent, and those who have clearly unresectable primary tumors following induction chemotherapy are appropriate candidates for RT.

Since more than 90 percent of patients with EFT have either detectable or subclinical metastases at diagnosis, local therapy, if delivered correctly, is probably not the critical event in determining survival. However, if local therapy is delivered poorly or given in such a way that it compromises the delivery of adequate chemotherapy, survival can be greatly compromised. Moreover, local failure is associated with a very poor survival outcome [3].

Here we will discuss the role of radiation therapy in the local management of the EFT. Epidemiology, pathology, molecular genetics, clinical presentation, and diagnosis of these tumors, as well as surgical principles and the use of chemotherapy are presented elsewhere. Central (supratentorial) PNET tumors are also discussed elsewhere. (See "Epidemiology, pathology, and molecular genetics of the Ewing sarcoma family of tumors" and "Clinical presentation, staging, and prognostic factors of the Ewing sarcoma family of tumors" and "Treatment of the Ewing sarcoma family of tumors" and "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management" and "Uncommon brain tumors", section on 'Supratentorial primitive neuroectodermal tumors'.)

                           

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Thu Jul 23 00:00:00 GMT 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Grier HE. The Ewing family of tumors. Ewing's sarcoma and primitive neuroectodermal tumors. Pediatr Clin North Am 1997; 44:991.
  2. Smith MA, Gurney JG, Ries LA. Cancer in adolescents 15 to 19 years old. In: Cancer incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995, Ries, LA, Smith, MAS, Gurney, JG, et al (Eds). SEER program, National Cancer Institute, Bethesda MD, 1999. (Pub #99-4649).
  3. 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; 14:1654.
  4. Ewing J. Diffuse endothelioma of bone. Proc NY Pathol Soc 1921; 21:17.
  5. WANG CC, SCHULZ MD. Ewing's sarcoma; a study of fifty cases treated at the Massachusetts General Hospital, 1930-1952 inclusive. N Engl J Med 1953; 248:571.
  6. Dunst J, Jürgens H, Sauer R, et al. Radiation therapy in Ewing's sarcoma: an update of the CESS 86 trial. Int J Radiat Oncol Biol Phys 1995; 32:919.
  7. Perez CA, Tefft M, Nesbit M, et al. The role of radiation therapy in the management of non-metastatic Ewing's sarcoma of bone. Report of the Intergroup Ewing's Sarcoma Study. Int J Radiat Oncol Biol Phys 1981; 7:141.
  8. 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; 8:1664.
  9. Schuck A, Ahrens S, Paulussen M, et al. Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. Int J Radiat Oncol Biol Phys 2003; 55:168.
  10. Rosito P, Mancini AF, Rondelli R, et al. Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer 1999; 86:421.
  11. Evans R, Nesbit M, Askin F, et al. Local recurrence, rate and sites of metastases, and time to relapse as a function of treatment regimen, size of primary and surgical history in 62 patients presenting with non-metastatic Ewing's sarcoma of the pelvic bones. Int J Radiat Oncol Biol Phys 1985; 11:129.
  12. Jenkin RD. Ewing's sarcoma: radiation treatment at the primary site--regarding Dunst et al., IJROBP 32:919-930; 1995. Int J Radiat Oncol Biol Phys 1995; 32:1253.
  13. Schuck A, Ahrens S, von Schorlemer I, et al. Radiotherapy in Ewing tumors of the vertebrae: treatment results and local relapse analysis of the CESS 81/86 and EICESS 92 trials. Int J Radiat Oncol Biol Phys 2005; 63:1562.
  14. Donati D, Yin J, Di Bella C, et al. Local and distant control in non-metastatic pelvic Ewing's sarcoma patients. J Surg Oncol 2007; 96:19.
  15. Hoffmann C, Ahrens S, Dunst J, et al. Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. Cancer 1999; 85:869.
  16. Carrie C, Mascard E, Gomez F, et al. Nonmetastatic pelvic Ewing sarcoma: report of the French society of pediatric oncology. Med Pediatr Oncol 1999; 33:444.
  17. Sucato DJ, Rougraff B, McGrath BE, et al. Ewing's sarcoma of the pelvis. Long-term survival and functional outcome. Clin Orthop Relat Res 2000; :193.
  18. Indelicato DJ, Keole SR, Shahlaee AH, et al. Impact of local management on long-term outcomes in Ewing tumors of the pelvis and sacral bones: the University of Florida experience. Int J Radiat Oncol Biol Phys 2008; 72:41.
  19. Indelicato DJ, Keole SR, Shahlaee AH, et al. Definitive radiotherapy for ewing tumors of extremities and pelvis: long-term disease control, limb function, and treatment toxicity. Int J Radiat Oncol Biol Phys 2008; 72:871.
  20. 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.
  21. Donaldson SS, Torrey M, Link MP, et al. A multidisciplinary study investigating radiotherapy in Ewing's sarcoma: end results of POG #8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys 1998; 42:125.
  22. Dunst J, Sauer R, Burgers JM, et al. Radiation therapy as local treatment in Ewing's sarcoma. Results of the Cooperative Ewing's Sarcoma Studies CESS 81 and CESS 86. Cancer 1991; 67:2818.
  23. Ahmad R, Mayol BR, Davis M, Rougraff BT. Extraskeletal Ewing's sarcoma. Cancer 1999; 85:725.
  24. Wilkins RM, Pritchard DJ, Burgert EO Jr, Unni KK. Ewing's sarcoma of bone. Experience with 140 patients. Cancer 1986; 58:2551.
  25. Givens SS, Woo SY, Huang LY, et al. Non-metastatic Ewing's sarcoma: twenty years of experience suggests that surgery is a prime factor for successful multimodality therapy. Int J Oncol 1999; 14:1039.
  26. Indelicato DJ, Keole SR, Shahlaee AH, et al. Long-term clinical and functional outcomes after treatment for localized Ewing's tumor of the lower extremity. Int J Radiat Oncol Biol Phys 2008; 70:501.
  27. Ozaki T, Hillmann A, Hoffmann C, et al. Significance of surgical margin on the prognosis of patients with Ewing's sarcoma. A report from the Cooperative Ewing's Sarcoma Study. Cancer 1996; 78:892.
  28. Marcove RC, Rosen G. Radical en bloc excision of Ewing's sarcoma. Clin Orthop Relat Res 1980; :86.
  29. Sailer SL, Harmon DC, Mankin HJ, et al. Ewing's sarcoma: surgical resection as a prognostic factor. Int J Radiat Oncol Biol Phys 1988; 15:43.
  30. Aparicio J, Munárriz B, Pastor M, et al. Long-term follow-up and prognostic factors in Ewing's sarcoma. A multivariate analysis of 116 patients from a single institution. Oncology 1998; 55:20.
  31. Bacci G, Ferrari S, Mercuri M, et al. Multimodal therapy for the treatment of nonmetastatic Ewing sarcoma of pelvis. J Pediatr Hematol Oncol 2003; 25:118.
  32. DuBois SG, Krailo MD, Gebhardt MC, et al. Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children's Oncology Group. Cancer 2015; 121:467.
  33. Sailer SL. The Role of Radiation Therapy in Localized Ewing' Sarcoma. Semin Radiat Oncol 1997; 7:225.
  34. La TH, Meyers PA, Wexler LH, et al. Radiation therapy for Ewing's sarcoma: results from Memorial Sloan-Kettering in the modern era. Int J Radiat Oncol Biol Phys 2006; 64:544.
  35. Casey DL, Meyers PA, Alektiar KM, et al. Ewing sarcoma in adults treated with modern radiotherapy techniques. Radiother Oncol 2014; 113:248.
  36. Krasin MJ, Rodriguez-Galindo C, Billups CA, et al. Definitive irradiation in multidisciplinary management of localized Ewing sarcoma family of tumors in pediatric patients: outcome and prognostic factors. Int J Radiat Oncol Biol Phys 2004; 60:830.
  37. Yock TI, Krailo M, Fryer CJ, et al. Local control in pelvic Ewing sarcoma: analysis from INT-0091--a report from the Children's Oncology Group. J Clin Oncol 2006; 24:3838.
  38. Marcus RB Jr, Cantor A, Heare TC, et al. Local control and function after twice-a-day radiotherapy for Ewing's sarcoma of bone. Int J Radiat Oncol Biol Phys 1991; 21:1509.
  39. 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.
  40. Barbieri E, Emiliani E, Zini G, et al. Combined therapy of localized Ewing's sarcoma of bone: analysis of results in 100 patients. Int J Radiat Oncol Biol Phys 1990; 19:1165.
  41. Jürgens 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.
  42. Venkateswaran L, Rodriguez-Galindo C, Merchant TE, et al. Primary Ewing tumor of the vertebrae: clinical characteristics, prognostic factors, and outcome. Med Pediatr Oncol 2001; 37:30.
  43. Ahrens S, Hoffmann C, Jabar S, et al. Evaluation of prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study. Med Pediatr Oncol 1999; 32:186.
  44. Dunst J, Schuck A. Role of radiotherapy in Ewing tumors. Pediatr Blood Cancer 2004; 42:465.
  45. Rödl RW, Hoffmann C, Gosheger G, et al. Ewing's sarcoma of the pelvis: combined surgery and radiotherapy treatment. J Surg Oncol 2003; 83:154.
  46. Wunder JS, Paulian G, Huvos AG, et al. The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint Surg Am 1998; 80:1020.
  47. 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; 85:1646.
  48. Bacci G, Forni C, Longhi A, et al. Long-term outcome for patients with non-metastatic Ewing's sarcoma treated with adjuvant and neoadjuvant chemotherapies. 402 patients treated at Rizzoli between 1972 and 1992. Eur J Cancer 2004; 40:73.
  49. 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.
  50. Whelan JS, Burcombe RJ, Janinis J, et al. A systematic review of the role of pulmonary irradiation in the management of primary bone tumours. Ann Oncol 2002; 13:23.
  51. Schuck A, Ahrens S, Konarzewska A, et al. Hemithorax irradiation for Ewing tumors of the chest wall. Int J Radiat Oncol Biol Phys 2002; 54:830.
  52. Shamberger RC, LaQuaglia MP, Gebhardt MC, et al. Ewing sarcoma/primitive neuroectodermal tumor of the chest wall: impact of initial versus delayed resection on tumor margins, survival, and use of radiation therapy. Ann Surg 2003; 238:563.
  53. Sluga M, Windhager R, Lang S, et al. The role of surgery and resection margins in the treatment of Ewing's sarcoma. Clin Orthop Relat Res 2001; :394.
  54. Krasin MJ, Rodriguez-Galindo C, Davidoff AM, et al. Efficacy of combined surgery and irradiation for localized Ewings sarcoma family of tumors. Pediatr Blood Cancer 2004; 43:229.
  55. Bacci G, Longhi A, Briccoli A, et al. The role of surgical margins in treatment of Ewing's sarcoma family tumors: experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys 2006; 65:766.
  56. Koontz BF, Clough RW, Halperin EC. Palliative radiation therapy for metastatic Ewing sarcoma. Cancer 2006; 106:1790.
  57. Pinkerton CR, Bataillard A, Guillo S, et al. Treatment strategies for metastatic Ewing's sarcoma. Eur J Cancer 2001; 37:1338.
  58. Arai Y, Kun LE, Brooks MT, et al. Ewing's sarcoma: local tumor control and patterns of failure following limited-volume radiation therapy. Int J Radiat Oncol Biol Phys 1991; 21:1501.
  59. 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.
  60. Bacci G, Briccoli A, Picci P, Ferrari S. Metachronous pulmonary metastases resection in patients with Ewing's sarcoma initially treated with adjuvant or neoadjuvant chemotherapy. Eur J Cancer 1995; 31A:999.
  61. Dunst J, Paulussen M, Jürgens H. Lung irradiation for Ewing's sarcoma with pulmonary metastases at diagnosis: results of the CESS-studies. Strahlenther Onkol 1993; 169:621.
  62. 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.
  63. Pilepich MV, Vietti TJ, Nesbit ME, et al. Radiotherapy and combination chemotherapy in advanced Ewing's Sarcoma-Intergroup study. Cancer 1981; 47:1930.
  64. 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; 23:93.
  65. Cangir A, Vietti TJ, Gehan EA, et al. Ewing's sarcoma metastatic at diagnosis. Results and comparisons of two intergroup Ewing's sarcoma studies. Cancer 1990; 66:887.
  66. Casey DL, Alektiar KM, Gerber NK, Wolden SL. Whole lung irradiation for adults with pulmonary metastases from Ewing sarcoma. Int J Radiat Oncol Biol Phys 2014; 89:1069.
  67. Bölling 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; 184:193.
  68. Liu AK, Stinauer M, Albano E, et al. Local control of metastatic sites with radiation therapy in metastatic Ewing sarcoma and rhabdomyosarcoma. Pediatr Blood Cancer 2011; 57:169.
  69. 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.
  70. Berry MP, Jenkin RD, Harwood AR, et al. Ewing's sarcoma: a trial of adjuvant chemotherapy and sequential half-body irradiation. Int J Radiat Oncol Biol Phys 1986; 12:19.
  71. Kinsella TJ, Glaubiger D, Diesseroth A, et al. Intensive combined modality therapy including low-dose TBI in high-risk Ewing's Sarcoma Patients. Int J Radiat Oncol Biol Phys 1983; 9:1955.
  72. Razek A, Perez CA, Tefft M, et al. Intergroup Ewing's Sarcoma Study: local control related to radiation dose, volume, and site of primary lesion in Ewing's sarcoma. Cancer 1980; 46:516.
  73. 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.
  74. Gonzalez DG, Breur K. Clinical data from irradiated growing long bones in children. Int J Radiat Oncol Biol Phys 1983; 9:841.
  75. Johnstone PA, Wexler LH, Venzon DJ, et al. Sarcomas of the hand and foot: analysis of local control and functional result with combined modality therapy in extremity preservation. Int J Radiat Oncol Biol Phys 1994; 29:735.
  76. Kinsella TJ, Loeffler JS, Fraass BA, Tepper J. Extremity preservation by combined modality therapy in sarcomas of the hand and foot: an analysis of local control, disease free survival and functional result. Int J Radiat Oncol Biol Phys 1983; 9:1115.
  77. Kuttesch JF Jr, Wexler LH, Marcus RB, et al. Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas. J Clin Oncol 1996; 14:2818.
  78. Lee CT, Bilton SD, Famiglietti RM, et al. Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with other conformal techniques? Int J Radiat Oncol Biol Phys 2005; 63:362.
  79. Isacsson U, Hagberg H, Johansson KA, et al. Potential advantages of protons over conventional radiation beams for paraspinal tumours. Radiother Oncol 1997; 45:63.
  80. Miralbell R, Lomax A, Cella L, Schneider U. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. Int J Radiat Oncol Biol Phys 2002; 54:824.
  81. Chung CS, Keating N, Yock T, Tarbell N. Comparative Analysis of Second Malignancy Risk in Patients Treated with Proton Therapy versus Conventional Photon Therapy, Int J Radiat Oncol Biol Phys 2008; 72:S8.
  82. Tarbell N, 2002, personal communication.
  83. Rombi B, DeLaney TF, MacDonald SM, et al. Proton radiotherapy for pediatric Ewing's sarcoma: initial clinical outcomes. Int J Radiat Oncol Biol Phys 2012; 82:1142.
  84. Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol Phys 2006; 65:1.
  85. Polf JC, Newhauser WD, Titt U. Patient neutron dose equivalent exposures outside of the proton therapy treatment field. Radiat Prot Dosimetry 2005; 115:154.
  86. Schneider U, Agosteo S, Pedroni E, Besserer J. Secondary neutron dose during proton therapy using spot scanning. Int J Radiat Oncol Biol Phys 2002; 53:244.
  87. Paganetti H, Athar BS, Moteabbed M, et al. Assessment of radiation-induced second cancer risks in proton therapy and IMRT for organs inside the primary radiation field. Phys Med Biol 2012; 57:6047.
  88. Mounessi FS, Lehrich P, Haverkamp U, et al. Pelvic Ewing sarcomas. Three-dimensional conformal vs. intensity-modulated radiotherapy. Strahlenther Onkol 2013; 189:308.
  89. Vogin G, Biston MC, Marchesi V, et al. [Localized Ewing sarcoma of the spine: a preliminary dose-escalation study comparing innovative radiation techniques in a single patient]. Cancer Radiother 2013; 17:26.
  90. Merchant TE, Kushner BH, Sheldon JM, et al. Effect of low-dose radiation therapy when combined with surgical resection for Ewing sarcoma. Med Pediatr Oncol 1999; 33:65.
  91. Bolek TW, Marcus RB Jr, Mendenhall NP, et al. Local control and functional results after twice-daily radiotherapy for Ewing's sarcoma of the extremities. Int J Radiat Oncol Biol Phys 1996; 35:687.
  92. Davis AM, Wright JG, Williams JI, et al. Development of a measure of physical function for patients with bone and soft tissue sarcoma. Qual Life Res 1996; 5:508.
  93. Stea B, Kinsella TJ, Triche TJ, et al. Treatment of pelvic sarcomas in adolescents and young adults with intensive combined modality therapy. Int J Radiat Oncol Biol Phys 1987; 13:1797.
  94. Calvo FA, Ortiz de Urbina D, Sierrasesúmaga L, et al. Intraoperative radiotherapy in the multidisciplinary treatment of bone sarcomas in children and adolescents. Med Pediatr Oncol 1991; 19:478.
  95. Thomas PR, Perez CA, Neff JR, et al. The management of Ewing's sarcoma: role of radiotherapy in local tumor control. Cancer Treat Rep 1984; 68:703.
  96. Jentzsch K, Binder H, Cramer H, et al. Leg function after radiotherapy for Ewing's sarcoma. Cancer 1981; 47:1267.
  97. Fuchs B, Valenzuela RG, Inwards C, et al. Complications in long-term survivors of Ewing sarcoma. Cancer 2003; 98:2687.
  98. Tefft M, Lattin PB, Jereb B, et al. Acute and late effects on normal tissues following combined chemo- and radiotherapy for childhood rhabdomyosarcoma and Ewing's sarcoma. Cancer 1976; 37:1201.
  99. McLean TW, Hertel C, Young ML, et al. Late events in pediatric patients with Ewing sarcoma/primitive neuroectodermal tumor of bone: the Dana-Farber Cancer Institute/Children's Hospital experience. J Pediatr Hematol Oncol 1999; 21:486.
  100. Tucker MA, D'Angio GJ, Boice JD Jr, et al. Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 1987; 317:588.
  101. Dunst J, Ahrens S, Paulussen M, et al. Second malignancies after treatment for Ewing's sarcoma: a report of the CESS-studies. Int J Radiat Oncol Biol Phys 1998; 42:379.
  102. Smith LM, Donaldson SS. Incidence and management of secondary malignancies in patients with retinoblastoma and Ewing's sarcoma. Oncology (Williston Park) 1991; 5:135.
  103. Paulussen M, Ahrens S, Lehnert M, et al. Second malignancies after ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study. Ann Oncol 2001; 12:1619.
  104. Strong LC, Herson J, Osborne BM, Sutow WW. Risk of radiation-related subsequent malignant tumors in survivors of Ewing's sarcoma. J Natl Cancer Inst 1979; 62:1401.
  105. Gasparini M, Lombardi F, Ballerini E, et al. Long-term outcome of patients with monostotic Ewing's sarcoma treated with combined modality. Med Pediatr Oncol 1994; 23:406.
  106. Longhi A, Ferrari S, Tamburini A, et al. Late effects of chemotherapy and radiotherapy in osteosarcoma and Ewing sarcoma patients: the Italian Sarcoma Group Experience (1983-2006). Cancer 2012; 118:5050.
  107. Long-term follow-up guidelines after treatment for chioldhood malignancy by the Children's Oncology Group. www.survivorshipguidelines.org (Accessed on September 07, 2011).