Chemotherapy in the Management of Osteosarcoma and Ewing's Sarcoma

Author: Scott M. Schuetze MD, PhD 1
View More View Less
  • 1 From the Department of Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.

Sarcomas of bone are rare malignancies diagnosed in fewer than 3000 individuals yearly in the United States. Ewing's sarcoma and most osteosarcoma are high-grade neoplasms and account for approximately one half of bone sarcoma cases. Fewer than 20% of patients presenting with localized Ewing's sarcoma or osteosarcoma are cured with surgery alone. Current management typically involves collaboration among orthopedic oncologists, medical oncologists, musculoskeletal radiologists, sarcoma pathologists, and radiation oncologists. Modern multidisciplinary management of Ewing's sarcoma and osteosarcoma has improved the cure rate of patients with localized disease to more than 50%. Primary chemotherapy for high-grade bone sarcomas often involves intensive, multiagent regimens, and few secondary chemotherapy options are available to treat refractory or relapsed disease. Patient participation in clinical trials of novel therapies for Ewing's sarcoma and osteosarcoma should be strongly encouraged.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Correspondence: Scott M. Schuetze, MD, PhD, 1500 East Medical Center Drive, C342 Med Inn, Box 0848, Ann Arbor, MI 48109-0848. E-mail: scotschu@med.umich.edu
  • 1.

    Arndt CA, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N Engl J Med 1999;341:342352.

  • 2.

    Jemal A, Murray T, Ward E. Cancer statistics, 2005. CA Cancer J Clin 2005;55:1030.

  • 3.

    Stiller CA, Passmore SJ, Kroll ME. Patterns of care and survival for patients aged under 40 years with bone sarcoma in Britain, 1980–1994. Br J Cancer 2006;94:2229.

    • Search Google Scholar
    • Export Citation
  • 4.

    Bacci G, Mercuri M, Longhi A. Neoadjuvant chemotherapy for the treatment of osteosarcoma of the extremities: a comparison of results obtained in single-institution and multicenter trials. Chir Organi Mov 2004;89:283292.

    • Search Google Scholar
    • Export Citation
  • 5.

    Rougraff BT, Simon MA, Kneisl JS. Limb salvage compared with amputation for osteosarcoma of the distal end of the femur. A long-term oncological, functional, and quality-of-life study. J Bone Joint Surg Am 1994;76:649656.

    • Search Google Scholar
    • Export Citation
  • 6.

    Bramwell VH, Steward WP, Nooij M. Neoadjuvant chemotherapy with doxorubicin and cisplatin in malignant fibrous histiocytoma of bone: a European Osteosarcoma Intergroup study. J Clin Oncol 1999;17:32603269.

    • Search Google Scholar
    • Export Citation
  • 7.

    Meyers PA, Heller G, Healey J. Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience. J Clin Oncol 1992;10:515.

    • Search Google Scholar
    • Export Citation
  • 8.

    Bacci G, Mercuri M, Longhi A. Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution. Eur J Cancer 2005;41:20792085.

    • Search Google Scholar
    • Export Citation
  • 9.

    Bacci G, Longhi A, Ferrari S. Prognostic significance of serum lactate dehydrogenase in osteosarcoma of the extremity: experience at Rizzoli on 1421 patients treated over the last 30 years. Tumori 2004;90:478484.

    • Search Google Scholar
    • Export Citation
  • 10.

    Bramer JA, Abudu AA, Tillman RM. Pre- and post-chemotherapy alkaline phosphatase levels as prognostic indicators in adults with localised osteosarcoma. Eur J Cancer 2005;41:28462852.

    • Search Google Scholar
    • Export Citation
  • 11.

    Davis AM, Bell RS, Goodwin PJ. Prognostic factors in osteosarcoma: a critical review. J Clin Oncol 1994;12:423431.

  • 12.

    Bielack SS, Kempf-Bielack B, Delling G. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 2002;20:776790.

    • Search Google Scholar
    • Export Citation
  • 13.

    Cortes EP, Holland JF, Wang JJ. Amputation and adriamycin in primary osteosarcoma. N Engl J Med 1974;291:9981000.

  • 14.

    Jaffe N, Frei E, Traggis D. Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. N Engl J Med 1974;291:994997.

  • 15.

    Rosen G, Marcove RC, Huvos AG. Primary osteogenic sarcoma: eight-year experience with adjuvant chemotherapy. J Cancer Res Clin Oncol 1983;106(suppl):5567.

    • Search Google Scholar
    • Export Citation
  • 16.

    Sutow WW, Sullivan MP, Fernbach DJ. Adjuvant chemotherapy in primary treatment of osteogenic sarcoma. A Southwest Oncology Group study. Cancer 1975;36:15981602.

    • Search Google Scholar
    • Export Citation
  • 17.

    Eilber F, Giuliano A, Eckardt J. Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 1987;5:2126.

  • 18.

    Link MP, Goorin AM, Miser AW. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986;314:16001606.

    • Search Google Scholar
    • Export Citation
  • 19.

    Rosen G, Caparros B, Huvos AG. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 1982;49:12211230.

    • Search Google Scholar
    • Export Citation
  • 20.

    Souhami RL, Craft AW, Van der Eijken JW. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet 1997;350:911917.

    • Search Google Scholar
    • Export Citation
  • 21.

    Winkler K, Beron G, Kotz R. Neoadjuvant chemotherapy for osteogenic sarcoma: results of a Cooperative German/Austrian study. J Clin Oncol 1984;2:617624.

    • Search Google Scholar
    • Export Citation
  • 22.

    Antman K, Crowley J, Balcerzak SP. A Southwest Oncology Group and Cancer and Leukemia Group B phase II study of doxorubicin, dacarbazine, ifosfamide, and mesna in adults with advanced osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. Cancer 1998;82:12881295.

    • Search Google Scholar
    • Export Citation
  • 23.

    Winkler K, Beron G, Delling G. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol 1988;6:329337.

    • Search Google Scholar
    • Export Citation
  • 24.

    Bramwell VH, Burgers M, Sneath R. 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;10:15791591.

    • Search Google Scholar
    • Export Citation
  • 25.

    Graf N, Winkler K, Betlemovic M. Methotrexate pharmacokinetics and prognosis in osteosarcoma. J Clin Oncol 1994;12:14431451.

  • 26.

    Leung S, Marshall GM, al Mahr M. Prognostic significance of chemotherapy dosage characteristics in children with osteogenic sarcoma. Med Pediatr Oncol 1997;28:179182.

    • Search Google Scholar
    • Export Citation
  • 27.

    Zelcer S, Kellick M, Wexler LH. Methotrexate levels and outcome in osteosarcoma. Pediatr Blood Cancer 2005;44:638642.

  • 28.

    Manoso MW, Healey JH, Boland PJ. De novo osteogenic sarcoma in patients older than forty: benefit of multimodality therapy. Clin Orthop Relat Res 2005;438:110115.

    • Search Google Scholar
    • Export Citation
  • 29.

    Gentet JC, Brunat-Mentigny M, Demaille MC. Ifosfamide and etoposide in childhood osteosarcoma. A phase II study of the French Society of Paediatric Oncology. Eur J Cancer 1997;33:232237.

    • Search Google Scholar
    • Export Citation
  • 30.

    Goorin AM, Harris MB, Bernstein M. Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J Clin Oncol 2002;20:426433.

    • Search Google Scholar
    • Export Citation
  • 31.

    Meyers PA, Schwartz CL, Krailo M. 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;23:20042011.

    • Search Google Scholar
    • Export Citation
  • 32.

    Zalupski MM, Rankin C, Ryan JR. Adjuvant therapy of osteosarcoma—a phase II trial: Southwest Oncology Group study 9139. Cancer 2004;100:818825.

    • Search Google Scholar
    • Export Citation
  • 33.

    Voute PA, Souhami RL, Nooij M. A phase II study of cisplatin, ifosfamide and doxorubicin in operable primary, axial skeletal and metastatic osteosarcoma. European Osteosarcoma Intergroup (EOI). Ann Oncol 1999;10:12111218.

    • Search Google Scholar
    • Export Citation
  • 34.

    Meyers PA, Gorlick R, Heller G. Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the Memorial Sloan-Kettering (T12) protocol. J Clin Oncol 1998;16:24522458.

    • Search Google Scholar
    • Export Citation
  • 35.

    Bacci G, Briccoli A, Rocca M. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol 2003;14:11261134.

    • Search Google Scholar
    • Export Citation
  • 36.

    Bacci G, Briccoli A, Ferrari S. Neoadjuvant chemotherapy for osteosarcoma of the extremity: long-term results of the Rizzoli's 4th protocol. Eur J Cancer 2001;37:20302039.

    • Search Google Scholar
    • Export Citation
  • 37.

    Bacci G, Picci P, Ferrari S. 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;72:32273238.

    • Search Google Scholar
    • Export Citation
  • 38.

    Michelagnoli MP, Lewis IJ, Gattamaneni HR. Ifosfamide/etoposide alternating with high-dose methotrexate: evaluation of a chemotherapy regimen for poor-risk osteosarcoma. Br J Cancer 1999;79:11741178.

    • Search Google Scholar
    • Export Citation
  • 39.

    Kempf-Bielack B, Bielack SS, Jurgens H. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 2005;23:559568.

    • Search Google Scholar
    • Export Citation
  • 40.

    Leu KM, Ostruszka LJ, Shewach D. Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol 2004;22:17061712.

    • Search Google Scholar
    • Export Citation
  • 41.

    Laverdiere C, Kolb EA, Supko JG. Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma. Cancer 2003;98:832840.

    • Search Google Scholar
    • Export Citation
  • 42.

    Chawla SP, Tolcher AW, Staddon AP. Updated results of a phase II trial of AP23573, a novel mTOR inhibitor, in patients with advanced soft tissue or bone sarcomas [abstract]. J Clin Oncol 2006;24:521s. Abstract 9505.

    • Search Google Scholar
    • Export Citation
  • 43.

    Schuetze SM, Baker LH, Maki RG. Sirolimus reduced tumor-related morbidity and resulted in biochemical and radiographic response in patients with progressive sarcoma [abstract]. J Clin Oncol 2006;24:520s. Abstract 9503.

    • Search Google Scholar
    • Export Citation
  • 44.

    Bacci G, Ferrari S, Comandone A. Neoadjuvant chemotherapy for Ewing's sarcoma of bone in patients older than thirty-nine years. Acta Oncol 2000;39:111116.

    • Search Google Scholar
    • Export Citation
  • 45.

    Fizazi K, Dohollou N, Blay JY. Ewing's family of tumors in adults: multivariate analysis of survival and long-term results of multimodality therapy in 182 patients. J Clin Oncol 1998;16:37363743.

    • Search Google Scholar
    • Export Citation
  • 46.

    Bacci G, Ferrari S, Bertoni F. Prognostic factors in nonmetastatic Ewing's sarcoma of bone treated with adjuvant chemotherapy: analysis of 359 patients at the Istituto Ortopedico Rizzoli. J Clin Oncol 2000;18:411.

    • Search Google Scholar
    • Export Citation
  • 47.

    Grier HE, Krailo MD, Tarbell NJ. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 2003;348:694701.

    • Search Google Scholar
    • Export Citation
  • 48.

    Hoffmann C, Ahrens S, Dunst J. Pelvic Ewing's sarcoma: a retrospective analysis of 241 cases. Cancer 1999;85:869877.

  • 49.

    Paulussen M, Ahrens S, Dunst J. Localized Ewing's tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86 J Clin Oncol 2001;19:18181829.

    • Search Google Scholar
    • Export Citation
  • 50.

    Bacci G, Forni C, Longhi A. 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;40:7383.

    • Search Google Scholar
    • Export Citation
  • 51.

    Huang HY, Illei PB, Zhao Z. Ewing's sarcomas with p53 mutation or p16/p14ARF homozygous deletion: a highly lethal subset associated with poor chemoresponse. J Clin Oncol 2005;23:548558.

    • Search Google Scholar
    • Export Citation
  • 52.

    Nesbit ME, Gehan EA, Burgert EO. 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;8:16641674.

    • Search Google Scholar
    • Export Citation
  • 53.

    Burgert EO Jr, Nesbit ME, Garnsey LA. Multimodal therapy for the management of nonpelvic, localized Ewing's sarcoma of bone: intergroup study IESS-II. J Clin Oncol 1990;8:15141524.

    • Search Google Scholar
    • Export Citation
  • 54.

    Paulussen M, Ahrens S, Craft AW. Ewing's tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing's Sarcoma Studies patients. J Clin Oncol 1998;16:30443052.

    • Search Google Scholar
    • Export Citation
  • 55.

    Bernstein ML, Devidas M, Lafreniere D. Intensive therapy with growth factor support for patients with Ewing's 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;24:152159.

    • Search Google Scholar
    • Export Citation
  • 56.

    Meyers PA, Krailo MD, Ladanyi M. 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;19:28122820.

    • Search Google Scholar
    • Export Citation
  • 57.

    Horowitz ME, Kinsella TJ, Wexler LH. Total-body irradiation and autologous bone marrow transplant in the treatment of high-risk Ewing's sarcoma and rhabdomyosarcoma. J Clin Oncol 1993;11:19111918.

    • Search Google Scholar
    • Export Citation
  • 58.

    Miser JS, Kinsella TJ, Triche TJ. Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol 1987;5:11911198.

    • Search Google Scholar
    • Export Citation
  • 59.

    Saylors RL, Stine KC, Sullivan J. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 2001;19:34633469.

    • Search Google Scholar
    • Export Citation
  • 60.

    Barker LM, Pendergrass TW, Sanders JE. Survival after recurrence of Ewing's sarcoma family of tumors. J Clin Oncol 2005;23:43544362.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 157 79 4
PDF Downloads 96 62 5
EPUB Downloads 0 0 0