Osteosarcoma: Review of the Past, Impact on the Future. The American Experience

  • Norman JaffeEmail author
Part of the Cancer Treatment and Research book series (CTAR, volume 152)


Major advances have been achieved in the treatment of osteosarcoma with the discovery of several chemotherapeutic agents that were active in the disease. These agents comprise high-dose methotrexate with leucovorin rescue, Adriamycin, cisplatin, ifosfamide and cyclophosphamide. The agents were integrated into various regimens and administered in an effort to destroy silent pulmonary micrometastases which are considered to be present in at least 80% of patients at the time of diagnosis. Their efficacy in achieving this goal was realized and their use was further extended to the application of preoperative (neoadjuvant) chemotherapy to destroy the primary tumor and achieve safe surgical resections. Disease free survival was escalated from <20% prior to the introduction of effective chemotherapy to 55–75% and overall survival to 85%. Further, the opportunity to perform limb salvage was expanded to 80% of patients. Of interest also was an attempt in one series to treat the primary tumor exclusively with chemotherapy, and abrogation of surgery.

Adding to these advances, varieties of subsequently discovered agents are currently undergoing investigations in patients who have relapsed and/or failed conventional therapy. The agents include Gemcitabine, Docetaxel, novel antifolate compounds, and a liposome formulation of adriamycin (Doxil). A biological agent, muramyl tripeptide phosphatidyl ethanolamine (MTPPE) was also recently investigated in a 2×2 factorial design to determine its efficacy in combination with chemotherapy (methotrexate, cisplatin, Adriamycin and ifosfamide).

In circumstances where the tumor was considered inoperable, chemotherapy and radiotherapy were advocated for local control. High dose methotrexate, Adriamycin and cisplatin and Gemcitabine interact with radiation therapy and potentiate its therapeutic effect. This combination is also particularly useful in palliation. Occasionally, the combination of radiation and chemotherapy may render a tumor suitable for surgical ablation. Samarium,153 a radio active agent, is also used as palliative therapy for bone metastases.

However, despite the advances achieved with the multidisciplinary application of chemotherapy, radiotherapy and surgical ablation of the primary tumor over the past 3½ decades, the improved cure rate reported initially has not altered. Particularly vexing is the problem of rescuing patients who develop pulmonary metastases after receiving seemingly effective multidisciplinary treatment. Approximately 15–25% of such patients only are rendered free of disease with the reintroduction of chemotherapy and resection of metastases. Extrapulmonary metastases and multifocal osteosarcoma also constitute a major problem. The arsenal of available agents to treat such patients has not made any substantial impact in improving their survival. New chemotherapeutic agents are urgently required to improve treatment and outcome. Additional strategies to be considered are targeted tumor therapy, anti tumor angiogenesis, biotherapy and therapy based upon molecular profiles.

This communication outlines sequential discoveries in the chemotherapeutic research of osteosarcoma in the United States of America. It also describes the principles regulating the therapeutic application of the regimens and considers the impact of their results on the conduct in the design of future investigations and treatment


Pulmonary Metastasis Limb Salvage Hemorrhagic Cystitis Tumor Destruction Surgical Ablation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Jaffe N, Traggis D, Enriquez C. Evaluation of a combination of mitomycin C (NSC-26980), phenylalanine mustard (NSC-16210) and vincristine (NSC-6757) in the treatment of osteogenic sarcoma. Cancer Chemother Rep. 1971;55:181-191.Google Scholar
  2. 2.
    Sullivan MP, Sutow WW, Taylor G. l-phenylalanine mustard as treatment for metastatic osteogenic sarcoma in children. J Pediatr. 1963;63:227-237.PubMedCrossRefGoogle Scholar
  3. 3.
    Sutow WW, Sullivan MP, Fernbach DJ, et al. Adjuvant chemotherapy in primary treatment of osteogenic sarcoma. Cancer. 1975;36:1598-1602.PubMedCrossRefGoogle Scholar
  4. 4.
    Wilbur JR, Sutow WW, Sullivan MP, et al. Successful treatment of rhabdomyosarcoma with combination chemotherapy and radiation therapy. Proc ASCO. 1971;7:56.Google Scholar
  5. 5.
    Sutow WW, Sullivan MP, Wilbur JR, et al. The study of adjuvant chemotherapy in osteogenic sarcoma. J Clin Pharmacol. 1975;15:530-533.PubMedGoogle Scholar
  6. 6.
    Pinkel D. Cyclophosphamide in children with cancer. Cancer. 1962;15:42-49.PubMedCrossRefGoogle Scholar
  7. 7.
    Finklestein J, Hittle RE, Hammond CD. Evaluation of a high-dose cyclophosphamide regimen in childhood tumors. Cancer. 1969;23:1239-1242.PubMedCrossRefGoogle Scholar
  8. 8.
    Sutow WW. Chemotherapeutic management of childhood rhabdomyosarcoma. In: Taylor G, Sutow WW, eds. Neoplasia in Childhood. Chicago: Year Book Medical Publishers; 1969:201-208.Google Scholar
  9. 9.
    Cortes EP, Holland JF, Wang JJ, et al. Chemotherapy of advanced osteosarcoma. In: Price CHG, Ross FCM, eds. Colston Paper N.24 Bone-Urban Aspects of Neoplasia. London: Buttersworth; 1972:265-280.Google Scholar
  10. 10.
    Sutow WW. Combination chemotherapy with Adriamycin (NSC-123127) in primary treatment of osteogenic sarcoma (Part III). Cancer Chemother Rep. 1975;6:315-317.Google Scholar
  11. 11.
    Sutow WW, Gehan EA, Dyment PC, et al. Multi-drug adjuvant chemotherapy in osteosarcoma. Interim report of the Southwest Oncology Group studies. Cancer Treat Rep. 1978;62:265-269.Google Scholar
  12. 12.
    Sutow WW. Late metastases in osteosarcoma. Lancet. 1976;1:856.PubMedCrossRefGoogle Scholar
  13. 13.
    Sutow WW, Herson J, Perez C. Survival after metastasis in osteosarcoma. Natl Cancer Inst Monogram. 1981;56:227-231.Google Scholar
  14. 14.
    Perez C, Herson J, Kimball JC, et al. Prognosis after metastases in osteosarcoma. Cancer Clin Trials. 1978;1:315-320.PubMedGoogle Scholar
  15. 15.
    Jaffe N, Smith E, Abelson HT, Frei E III. Osteogenic sarcoma: Alterations in the pattern of pulmonary metastases with adjuvant chemotherapy. J Clin Oncol. 1983;1:251-254.PubMedGoogle Scholar
  16. 16.
    Herson J, Sutow WW, Elder K, et al. Adjuvant chemotherapy in non metastatic osteosarcoma A Southwest Oncology Group Study. Med Pediatr Oncol. 1980;8:343-352.PubMedCrossRefGoogle Scholar
  17. 17.
    Jaffe N, Link M, Traggis D, et al. The role of high-dose methotrexate in osteogenic sarcoma. Sarcomas in soft tissue and bone in childhood. Natl Cancer Inst Monogr. 1981;56:201-206.PubMedGoogle Scholar
  18. 18.
    Goorin AM, Delorey M, Gelber RD, et al. The Dana-Farber Cancer Institute/The Children’s Hospital adjuvant chemotherapy trials for osteosarcoma: Three sequential studies. Cancer Treat Symp. 1986;3:155-159.Google Scholar
  19. 19.
    Rosen G, Marcove RC, Huvos AG, et al. Chemotherapy en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer. 1976;37:1-11.PubMedCrossRefGoogle Scholar
  20. 20.
    Rosen G. Role of chemotherapy in the treatment of primary osteogenic sarcoma. A five-year follow-up of T-10 neoadjuvant chemotherapy. In: Kimura K, Wang Y-M, eds. Methotrexate in Cancer Therapy. New York: Raven Press; 1986:227-238.Google Scholar
  21. 21.
    Delepine N, Delepine G, Jasmine C, et al. Importance of age and methotrexate dosage: Prognosis in children and young adults with high-grade osteosarcoma. Biomed Pharmacother. 1988;42:257-262.PubMedGoogle Scholar
  22. 22.
    Winkler K, Beron G, Dilling G, et al. Neoadjuvant chemotherapy of osteosarcoma. Results of Randomized Cooperative Trial (COSS-82) with salvage. Chemotherapy based on histologic tumor response. J Clin Oncol. 1988;6:329-337.PubMedGoogle Scholar
  23. 23.
    Bacci G, Picci P, Ruggeri P, et al. Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities: The Instituto Rizzoli Experience in 127 patients treated preoperatively with intravenous methotrexate (high versus moderate doses) and intra-arterial cisplatin. Cancer. 1990;65:2539-2553.PubMedCrossRefGoogle Scholar
  24. 24.
    Meyers PA, Heller G, Healey JH, et al. Chemotherapy for non-metastatic osteogenic sarcoma: The Memorial Sloan-Kettering experience. J Clin Oncol. 1992;10:5-15.PubMedGoogle Scholar
  25. 25.
    Bacci G, Picci P, Avella M, et al. The importance of dose intensity in neoadjuvant chemotherapy of osteosarcoma: A retrospective analysis of high-dose methotrexate, cisplatinum and adriamycin used preoperatively. J Chemother. 1990;2:127-135.PubMedGoogle Scholar
  26. 26.
    Provisor AJ, Ettinger LJ, Nachman JB, et al. Treatment of non-metastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: A report from the Children’s Cancer Group. J Clin Oncol. 1997;15:76-84.PubMedGoogle Scholar
  27. 27.
    Meyers PA, Gorlick R, Heller G, et al. Intensification of preoperative chemotherapy for osteogenic sarcoma: Results of the Memorial Sloan-Kettering (T-12) protocol. J Clin Oncol. 1998;16:2452-2458.PubMedGoogle Scholar
  28. 28.
    Krailo M, Ertel I, Makley J, et al. A randomized study comparing high-dose methotrexate with moderate-dose methotrexate as components of adjuvant chemotherapy in childhood nonmetasatic osteosarcoma: A report from the Children’s Cancer Study Group. Med Pediatr. 1987;15:69-77.CrossRefGoogle Scholar
  29. 29.
    Bramwell VH, Berger SM, Sneath R, et al. A comparison of two short intensive adjuvant chemotherapy regimen in operative osteosarcoma of limbs in children and young adults: The first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992;10:1579-1591.PubMedGoogle Scholar
  30. 30.
    Souhami RL, Craft AW, Vander Eijken JW, et al. Randomised trial of two in operable regimens of chemotherapy inoperable osteosarcoma: A study of the European Osteosarcoma Intergroup. Lancet. 1997;350:911-917.PubMedCrossRefGoogle Scholar
  31. 31.
    Grem J, King S, Whittes R, et al. The role of methotrexate in osteosarcoma. J Natl Cancer Inst. 1988;80:626-655.PubMedCrossRefGoogle Scholar
  32. 32.
    Graf N, Winkler K, Betlemovic M, et al. Methotrexate pharmacokinetics and prognosis in osteosarcoma. J Clin Oncol. 1994;12:1443-1451.PubMedGoogle Scholar
  33. 33.
    Wang Y-N, Sutow WW, Romsdahl MM, et al. Age related pharmacokinetics of high-dose methotrexate in patients with osteosarcoma. Cancer Treat Rep. 1979;63:405-410.PubMedGoogle Scholar
  34. 34.
    Jaffe N, Prudich J, Knapp J, et al. Treatment of primary osteosarcoma with intra-arterial and intravenous high-dose methotrexate. J Clin Oncol. 1983;7:428-431.Google Scholar
  35. 35.
    Cohen H, Jaffe N. Pharmacokinetic studies of 24-hour infusions of high-dose methotrexate. Cancer Chemother Pharmacol. 1978;1:61-64.PubMedCrossRefGoogle Scholar
  36. 36.
    Wang YM, Lantin E, Sutow WW. Blood, urinary and cerebral spinal fluid methotrexate levels in children after high-dose methotrexate infusion. Clin Chem. 1976;22:1053-1056.PubMedGoogle Scholar
  37. 37.
    Wang YN, Kim PY, Lantin E, et al. Degradation and clearance of methotrexate in children with osteosarcoma receiving high-dose infusion. Med Pediatr Oncol. 1978;4:221-229.PubMedCrossRefGoogle Scholar
  38. 38.
    Perez C, Wang Y-M, Sutow WW, et al. Significance of 48-hour plasma level in high-dose methotrexate regimens. Cancer Clin Trials. 1978;1:107-111.PubMedGoogle Scholar
  39. 39.
    Jaffe N, Farber S, Traggis D, et al. Favorable response of metastatic osteogenic sarcoma to past high-dose methotrexate with citrovorin rescue and radiation therapy. Cancer. 1973;31:1367-1373.PubMedCrossRefGoogle Scholar
  40. 40.
    Rosen G, Tefft M, Martinez A, et al. Combination chemotherapy and radiation therapy in the treatment of metastatic osteogenic sarcoma. Cancer. 1975;35:622-630.PubMedCrossRefGoogle Scholar
  41. 41.
    Machak GN, Tkachev SI, Solovyev YN, et al. Neoadjuvant chemotherapy and local radiotherapy for high grade osteosarcoma of the extremities. Mayo Clin Proc. 2003;78:147-155.PubMedCrossRefGoogle Scholar
  42. 42.
    Ozaki T, Flege S, Kevric M, et al. Osteosarcoma of the pelvis: Experience of the Osteosarcoma Study Group. J Clin Oncol. 2003;21:334-341.PubMedCrossRefGoogle Scholar
  43. 43.
    Bonnadonna G, Monfardi S, De Lena M, et al. Phase I and preliminary phase II evaluation of Adriamycin (NSC/123127). Cancer Res. 1970;30:2527-2582.Google Scholar
  44. 44.
    Middleman E, Luce L, Frei E. Clinical trials with Adriamycin. Cancer. 1971;28:844-850.PubMedCrossRefGoogle Scholar
  45. 45.
    O’Bryan RN, Luce JK, Talley R, et al. Phase II evaluation of Adriamycin in human neoplasia. Cancer. 1973;32:1-7.PubMedCrossRefGoogle Scholar
  46. 46.
    Cortes EP, Holland JF, Wang JJ, et al. Amputation and Adriamycin in primary osteosarcoma. New Engl J Med. 1974;291:998-1000.PubMedCrossRefGoogle Scholar
  47. 47.
    Cortes EP, Holland JF, Glidewell O. Osteogenic studies by the Cancer and Leukemia Group B. Natl Cancer Inst Monogr. 1975;56:207-209.Google Scholar
  48. 48.
    Cassady JR, Richter NP, Piro AJ, et al. Radiation, Adriamycin interactions – Preliminary clinical observations. Cancer. 1975;36:946-949.PubMedCrossRefGoogle Scholar
  49. 49.
    Eilber FR, Grant T, Morton C. Adjuvant chemotherapy of osteosarcoma: Preoperative treatment. Cancer Treat Rep. 1978;62:213-216.PubMedGoogle Scholar
  50. 50.
    Jaffe N, Watts H, Fellows KE, et al. Local en bloc resection for limb preservation. Cancer Treat Rep. 1978;62:217-273.PubMedGoogle Scholar
  51. 51.
    Basser Rl, Green MD. Strategies for prevention of anthracycline cardiotoxicity. Cancer Treat Rev. 1994;19:57-77.CrossRefGoogle Scholar
  52. 52.
    Seifert CF, Nesser ME, Thompson DF. Dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity. Ann Pharmacother. 1994;28:1063-1072.PubMedGoogle Scholar
  53. 53.
    Smith MA, Ungerleider RS, Horowitz ME, et al. Influence of doxorubicin dose intensity on response and outcome for patients with osteogenic sarcoma and Ewing’s sarcoma. J Natl Cancer Inst. 1991;83:1460-1470.PubMedCrossRefGoogle Scholar
  54. 54.
    Baum E, Greenberg L, Gaynon P, et al. Use of Cis-diamminedichloroplatinum-II (CPDD) in Osteogenic Sarcoma (OS) in Children (Abstract C-315). Proc AACR-ASCO. 1978;19:385.Google Scholar
  55. 55.
    Nitschke R, Starling KA, Vats T, et al. Cis-diamminedichloroplatin-II (NSC 119875) In Childhood Malignancies. A Southwest Oncology Group Study. Med Pedatr Oncol. 1978;4:127-132.CrossRefGoogle Scholar
  56. 56.
    Ochs JJ, Freeman AR, Douglass HO Jr, et al. Cis-diamminedichloroplatinum (II) in advanced osteogenic sarcoma. Cancer Treat Rep. 1978;62:239-245.PubMedGoogle Scholar
  57. 57.
    Jaffe N, Knapp J, Chuang VP, et al. Osteosarcoma intra-arterial treatment of the primary tumor with Cis-diamminedichloroplatinum-II (CDP). Angiographic, pathologic and pharmacologic studies. Cancer. 1983;51:402-407.PubMedCrossRefGoogle Scholar
  58. 58.
    Jaffe N, Raymond AK, Ayala A, et al. Effect of cumulative courses of intra-arterial Cis-diamminedichloroplatinum II on the primary tumor in osteosarcoma. Cancer. 1989;63:63-67.PubMedCrossRefGoogle Scholar
  59. 59.
    Wright KC, Wallace S, Kim EE, et al. Pulse arterial infusions. Chemotherapeutic complications. Cancer. 1986;57:1952-1956.PubMedCrossRefGoogle Scholar
  60. 60.
    Chuang VP, Benjamin RS, Jaffe N, et al. Radiographic and angiographic changes in osteosarcoma after intra-arterial chemotherapy. Am J Radiol. 1982;139:1065-1069.Google Scholar
  61. 61.
    Shirkoda A, Jaffe N, Wallace S, et al. Computed tomography of osteosarcoma following intra-arterial chemotherapy. Am J Radiol. 1985;144:95-99.Google Scholar
  62. 62.
    Pan G, Raymond AK, Carrasco CH, et al. Osteosarcoma: MR imaging after preoperative chemotherapy. Radiology. 1990;174:517-526.PubMedGoogle Scholar
  63. 63.
    Meyers PA. Osteosarcoma In Pediatric Bone and Soft Tissue Sarcomas. In: Pappo A, ed. Pediatric Bone and Soft Tissue Sarcomas. Berlin, Heidelberg, New York: Springer; 2005:219-233.Google Scholar
  64. 64.
    Ruiz L, Gilden J, Jaffe N, et al. Auditory function in pediatric osteosarcoma patients treated with multiple doses of cis-diamminedichloroplatinum-II (CDP). Cancer Res. 1989;49:742-744.PubMedGoogle Scholar
  65. 65.
    Jaffe N, Keifer R III, Robertson R, et al. Renal toxicity with cumulative doses of cis-diamminedichloroplatinum-II in pediatric patients with osteosarcoma. Cancer. 1987;59:1577-1581.PubMedCrossRefGoogle Scholar
  66. 66.
    Kawai A, Sugihara S, Kunisada T, et al. Imaging assessment of the response of bone tumors to preoperative chemotherapy. Clin Orthop Relat Res. 1997;Apr(337):216-225.CrossRefGoogle Scholar
  67. 67.
    Kunisada T, Ozaki T, Kawai A. Imaging assessment of the responses of osteosarcoma patients to preoperative chemotherapy: Angiography compared with thallium-201 scintigraphy. Cancer. 1999;86(6):949-956.PubMedCrossRefGoogle Scholar
  68. 68.
    Carrasco CH, Charnsangavej C, Raymond AK, et al. Osteosarcoma: Angiographic assessment of response to preoperative chemotherapy. Radiology. 1989;170:839-842.PubMedGoogle Scholar
  69. 69.
    Lang P, Vahlensieck M, Matthay KK. Monitoring neovascularity as an indicator to response to chemotherapy in osteogenic and Ewing sarcoma using magnetic resonance angiography. Med Pediatr Oncol. 1996;26(5):329-333.PubMedCrossRefGoogle Scholar
  70. 70.
    Kumpan W, Lechner G, Wittich GR. The angiographic response of osteosarcoma following pre-operative chemotherapy. Skeletal Radiol. 1986;15(2):96-102.PubMedCrossRefGoogle Scholar
  71. 71.
    Wilkins RM, Cullen JW, Odom L, et al. Superior survival in treatment of primary nonmetastatic pediatric osteosarcoma of the extremity. Ann Surg Oncol. 2003;10:498-507.PubMedCrossRefGoogle Scholar
  72. 72.
    Jaffe N, Spears R, Eftekhari F, et al. Pathologic fracture in osteosarcoma: Effect of chemotherapy in primary Tumor and survival. Cancer. 1987;59:701-709.PubMedCrossRefGoogle Scholar
  73. 73.
    Antman KH, Montella D, Rosenbaum C, et al. Phase II Trial of ifosfamide with mesna in previously treated metastatic osteosarcoma. Cancer Treat Rep. 1985;69:499-504.PubMedGoogle Scholar
  74. 74.
    Bowman LG, Mayer WN, Douglass EC, et al. Activation of ifosfamide in metastatic and unresectable osteosarcoma (Abstract). Proc ASCO. 1987;C-214:844.Google Scholar
  75. 75.
    Meyer WH, Pratt CB, Farham D, et al. The activity of Ifosfamide (IFOS) in previously pretreated patients with osteosarcoma (OS): Preliminary results of SJCRHOS-86 Study. Proc ASCO. 1988;7:261.Google Scholar
  76. 76.
    Grana N, Graham-Pole J, Cassano W, et al. Etoposide (VP-16) infusion plus Cyclophosphamide (CY) pulses: An effective combination for refractory cancer. Proc ASCO. 1989;8:300.Google Scholar
  77. 77.
    Saleh R, Graham-Pole J, Cassano W, et al. Response of osteogenic sarcoma to the combination of rtoposide and cyclophosphamide as neoadjuvant chemotherapy. Cancer. 1990;65:861-865.PubMedCrossRefGoogle Scholar
  78. 78.
    Pratt CB, Luo X, Fay L, et al. Response of pediatric malignant solid tumors following ifosfamide or ifosfamide/carboplatin/etoposide. A single hospital experience. Med Pediatr Oncol. 1996;27:145-148.Google Scholar
  79. 79.
    Harris MB, Cantor AB, Goorin AM. Treatment of osteosarcoma with ifosfamide: Comparison of response in pediatric patients with recurrent disease versus patients previously untreated: A Pediatric Oncology Group study. Med Pediatr Oncol. 2002;20:426-433.Google Scholar
  80. 80.
    Pratt CB, Meyer WH, Dauglass EC, et al. A phase I study of ifosfamide with Mesna given daily for 3 consecutive days to children with malignant solid tumors. Cancer. 1993;71:3661-3665.PubMedCrossRefGoogle Scholar
  81. 81.
    Chawla S, Rosen G, Lowenbraun S, et al. Role of high-dose ifosfamide in recurrent osteosarcoma. Proc ASCO. 1990;9:310.Google Scholar
  82. 82.
    Patel S, Vadhan-Raj S, Papadopolous N, et al. High-dose ifosfamide in bone and soft tissue sarcomas: Results of a Phase II and Pilot Studies – dose-response and schedule dependence. J Clin Oncol. 1997;15:2378-2384.PubMedGoogle Scholar
  83. 83.
    Berrak S, Pearson P, Berbergoglu S, et al. High-dose ifosfamide in relapsed pediatric osteosarcoma: Therapeutic effects and renal toxicity. Pediatr Blood Cancer. 2005;44:215-219.PubMedCrossRefGoogle Scholar
  84. 84.
    Pratt CB, Meyer WH, Rao BN, et al. Osteosarcoma studies at St Jude Children’s Research Hospital from 1968 through 1998. Cancer Treat Res. 1993;62:323-326.PubMedGoogle Scholar
  85. 85.
    Harris MB, Gieser P, Goorin AM, et al. Treatment of metastatic osteosarcoma at diagnosis: A Pediatric Oncology Group Study. J Clin Oncol. 1998;16:3641-3648.PubMedGoogle Scholar
  86. 86.
    Goorin AM, Harris MB, Bernstein M, et al. Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: A Pediatric Oncology Group Trial. J Clin Oncol. 2002;20:426-433.PubMedCrossRefGoogle Scholar
  87. 87.
    Daw NC, Billups CA, Rodroguez-Galindo C, et al. Metastatic osteosarcoma. Cancer. 2006;106:403-412.PubMedCrossRefGoogle Scholar
  88. 88.
    Meyer WH, Pratt CB, Poquette CA, et al. Carboplatin/Ifosfamide window therapy for osteosarcoma: Results of the St Jude Children’s Research Hospital OS-91 Trial. J Clin Oncol. 2001;19:171-182.PubMedGoogle Scholar
  89. 89.
    Fergusen WS, Harris MB, Goorin AM, et al. Presurgical window of carboplatin and surgery and multi-drug chemotherapy for the treatment of newly diagnosed metastatic or unresectable osteosarcoma: Pediatric Oncology Group trial. J Pediatr Hematol Oncol. 2001;23:340-348.CrossRefGoogle Scholar
  90. 90.
    Petrilli AS, de Camargo B, Filho VO, et al. Results of the osteosarcoma treatment group studies III and IV: Prognostic factors and impact on survival. J Clin Oncol. 2006;24:1161-1168.PubMedCrossRefGoogle Scholar
  91. 91.
    Merimsky O, Meller I, Flusser G, et al. Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: A phase II study. Cancer Chemother Pharmacol. 2000;45:177-181.PubMedCrossRefGoogle Scholar
  92. 92.
    Navid F, Willert JR, Mc Carville MB, et al. Combination of gemcitibine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008;113:419-425.PubMedCrossRefGoogle Scholar
  93. 93.
    Anderson PM, Wiseman GA, Dispenzieri A, et al. High-dose samarium-153 ethylene diamine tetramethylene phosphonate: Low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol. 2002;20:189-196.PubMedCrossRefGoogle Scholar
  94. 94.
    Meyers P, Schwartz CL, Krailo M, et al. Osteosarcoma: A randomized prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol. 2005;23:2004-2011.PubMedCrossRefGoogle Scholar
  95. 95.
    Lu L, Lu L. Junovan fails to win ODAC nod for osteosarcoma treatment. ONI. 2007;16:1632.Google Scholar
  96. 96.
    Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival – a report from the Children’s Oncology Group. J Clin Oncol. 2008;26:633-638.PubMedCrossRefGoogle Scholar
  97. 97.
    Bielack SS, Marina N, Ferrari S, et al. Osteosarcoma: The same old drugs or more? Journal Clin Oncol. 2008;26:3192-3193.Google Scholar
  98. 98.
    Hunsberger S, Freidlin B, Smith MA. Complexities in interpretation of osteosarcoma clinical trial results. Journal Clin Oncol. 2008;26:3193-3194.Google Scholar
  99. 99.
    Meyers PA, Schwartz CL, Krailo MD, et al. In Reply Journal. Clin Oncol. 2008;26:3194-3195.Google Scholar
  100. 100.
    Gitelis S, Neel MD, Wilkins RM, et al. The use of a closed expandable prosthesis for pediatric sarcomas. Chir Organi Mov. 2003;88:327-333.PubMedGoogle Scholar
  101. 101.
    Hudson M, Jaffe MR, Jaffe N, et al. Pediatric osteosarcoma: Therapeutic strategies, results and prognostic factors derived from a 10-year experience. J Clin Oncol. 1990;8:1988-1997.PubMedGoogle Scholar
  102. 102.
    Hosalkar HS, Dormans JP. Limb sparing surgery for pediatric musculoskeletal tumors. Pediatr Blood Cancer. 2004;42(4):295-310.PubMedCrossRefGoogle Scholar
  103. 103.
    Jaffe N, Carrasco H, Raymond K, et al. Can cure in patients with osteosarcoma be achieved exclusively with chemotherapy and abrogation of surgery? Cancer. 2002;95:2202-2210.PubMedCrossRefGoogle Scholar
  104. 104.
    Kaste SC, Pratt CB, Cain AM, et al. Metastases detected at the time of diagnosis of primary pediatric extremity osteosarcoma at diagnosis: Imaging features. Cancer. 1999;86(8):1602-1608.PubMedCrossRefGoogle Scholar
  105. 105.
    Meyers PA, Heller G, Healy JH, et al. Osteogenic sarcoma with clinically detectable pulmonary metastases at initial presentation. J Clin Oncol. 1993;11:449-453.PubMedGoogle Scholar
  106. 106.
    Su WT, Chewning J, Abramson S, et al. Surgical management and outcome of osteosarcoma patients with unilateral pulmonary metastases. J Pediatr Surg. 1994;39(3):1849-1858.Google Scholar
  107. 107.
    Meyer WH, Schell MJ, Kumar AP, et al. Thoracotomy for pulmonary metastatic osteosarcoma. An analysis of prognostic indicators of survival. Cancer. 1987;59(2):374-379.PubMedCrossRefGoogle Scholar
  108. 108.
    Skinner KA, Eilber FR, Holmes E, et al. Surgical treatment and chemotherapy for pulmonary metastases from osteosarcoma. Arch Surg. 1992;127(90):1065-1070. discussion 1070-71.PubMedGoogle Scholar
  109. 109.
    Chou AJ, Merola P, Wexler LH, et al. Treatment of osteosarcoma at first recurrence after contemporary therapy: The Memorial Sloan-Kettering Cancer Center experience. Cancer. 2005;104(10):2214-2221.PubMedCrossRefGoogle Scholar
  110. 110.
    Harting MT, Blakely ML, Jaffe N, et al. Long-term survival after aggressive resection of pulmonary metastases among children and adolescents with osteosarcoma. J Pediatr Surg. 2006;41(1):194-199.PubMedCrossRefGoogle Scholar
  111. 111.
    Ward WG, Mikaelian K, Dorey F, et al. Pulmonary metastases of stage IIB extremity osteosarcoma and subsequent pulmonary metastases. J Clin Oncol. 1994;12(9):1849-1858.PubMedGoogle Scholar
  112. 112.
    Bacci G, Ferrari S, Bertoni F, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the Istituto Ortopedico Rizzoli/osteosarcoma-2 protocol: An updated report. J Clin Oncol. 2000;18(24):4016-4027.PubMedGoogle Scholar
  113. 113.
    Nathan SS, Gorlick R, Bukata S, et al. Treatment algorithm for locally recurrent osteosarcoma based on local disease-free interval and the presence of lung metastasis. Cancer. 2006;107(7):1607-1616.PubMedCrossRefGoogle Scholar
  114. 114.
    Bielack SS, Kempf-Bielack B, Branscheid D, et al. Second and subsequent recurrences of osteosarcoma: Presentation and treatment outcomes of 249 Consecutive Cooperative Osteosarcoma Study Group patients. J Clin Oncol. 2008;27:557-565.PubMedCrossRefGoogle Scholar
  115. 115.
    McCarten KM, Jaffe N, Kirkpatrick JA. The changing radiographic appearance of osteosarcoma. Ann Radiol. 1980;23:203-208.PubMedGoogle Scholar
  116. 116.
    Lockhart SK, Coan JD, Jaffe N, et al. Osteosarcoma metastatic to the kidney. Clin Imaging. 1989;13:154-156.PubMedCrossRefGoogle Scholar
  117. 117.
    Baram TZ, Van Tassel P, Jaffe N. Brain metastases in osteosarcoma: Incidence, clinical and neurological findings and management options. J Neuro Oncol. 1988;6:45-52.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Children’s Cancer HospitalUniversity of Texas M.D. Anderson Cancer CenterHoustonUSA

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