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Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment (PDQ®)

Recurrent Osteosarcoma and MFH of Bone

Approximately 50% of relapses occur within 18 months of therapy termination, and only 5% of recurrences develop beyond 5 years.[1-4] In 564 patients with a recurrence, patients whose disease recurred within 2 years of diagnosis had a worse prognosis than did patients whose disease recurred after 2 years. Patients with a good histologic response to initial preoperative chemotherapy had a better overall survival (OS) after recurrence than did poor responders.[1] The probability of developing lung metastases at 5 years is 28% in patients presenting with localized disease.[5] In two large series, the incidence of recurrence by site was as follows: lung only (65%–80%), bone only (8%–10%), local recurrence only (4%–7%), and combined relapse (10%–15%).[4,6] Abdominal metastases are rare but may occur as late as 4 years after diagnosis.[7]

Patients with recurrent osteosarcoma should be assessed for surgical resectability, because they may sometimes be cured with aggressive surgical resection with or without chemotherapy.[8,6,9-12] Control of osteosarcoma after recurrence depends on complete surgical resection of all sites of clinically detectable metastatic disease. If surgical resection is not attempted or cannot be performed, progression and death are certain. The ability to achieve a complete resection of recurrent disease is the most important prognostic factor at first relapse, with a 5-year survival rate of 20% to 45% after complete resection of metastatic pulmonary tumors and a 20% survival rate after complete resection of metastases at other sites.[4,6,12,13]

The role of systemic chemotherapy for the treatment of patients with recurrent osteosarcoma is not well defined. The selection of further systemic treatment depends on many factors, including the site of recurrence, the patient’s previous primary treatment, and individual patient considerations. Ifosfamide alone with mesna uroprotection, or in combination with etoposide, has been active in as many as one-third of patients with recurrent osteosarcoma who have not previously received this drug.[14-17] Cyclophosphamide and etoposide are active in recurrent osteosarcoma, as is the combination of gemcitabine and docetaxel.[18-20] The Italian Sarcoma Group reported rare objective responses and disease stabilization with sorafenib in patients with recurrent osteosarcoma.[21] Peripheral blood stem cell transplant utilizing high-dose chemotherapy does not appear to improve outcome. High-dose samarium-153-ethylenediamine tetramethylene phosphonic acid (EDTMP) coupled with peripheral blood stem cell support may provide significant pain palliation in patients with bone metastases.[22-25] Toxicity of samarium-153-EDTMP is primarily hematologic.[26][Level of evidence: 3iiDiii]

Lung Only Recurrence

Repeated resections of pulmonary recurrences can lead to extended disease control and possibly cure for some patients.[13,27] Survival for patients with unresectable metastatic disease is less than 5%.[6,28] Five-year event free survival (EFS) for patients who have complete surgical resection of all pulmonary metastases ranges from 20% to 45%.[4,12,13]; [29][Level of evidence: 3iiiA] Factors that suggest a better outcome include fewer pulmonary nodules, unilateral pulmonary metastases, longer intervals between primary tumor resection and metastases, and tumor location in the periphery of the lung.[4-6,30,31]

Resection of metastatic disease followed by observation alone results in low OS and disease-free survival. A high percentage of patients with pulmonary nodules identified in only one lung who underwent staged bilateral thoracotomy were found to have palpable nodules in both lungs that were not visualized on a computed tomography (CT) scan. This suggests that patients with unilateral nodules may benefit from bilateral exploration.[30] A retrospective review of 16 patients who relapsed with single pulmonary metastases on CT scan more than 2 months after therapy showed that no further metastases were found on unilateral thoracotomy, implying that thoracoscopic removal may be adequate to remove all disease in this relatively unusual circumstance (13.9% of patients relapsing in the lung after therapy).[32] There are conflicting recommendations regarding the need for formal thoracotomy for treatment of pulmonary metastases in osteosarcoma. The St. Jude Children’s Research Hospital results suggest that thoracoscopy without exploration of the entire ipsilateral lung is adequate therapy for isolated first pulmonary recurrence more than 2 months from completion of initial planned therapy.[33] The Memorial Sloan-Kettering Cancer Center results suggest that additional nodules will be found in either the ipsilateral or the contralateral lung in patients with pulmonary metastases.[30] The latter experience included both patients with metastases at initial presentation and patients with metastatic recurrence.

Recurrence With Bone Metastases Only

Patients with osteosarcoma who develop bone metastases have a poor prognosis. In one large series, the 5-year EFS rate was 11%.[34] Patients with late solitary bone relapse have a 5-year EFS rate of approximately 30%.[34-37] For patients with multiple unresectable bone lesions, samarium-153-EDTMP with or without stem cell support may produce stable disease and/or relief of pain.[26]

Local Recurrence

The postrelapse outcome of patients who have a local recurrence is quite poor.[38-40]

Two retrospective, single-institution series reported 10% to 40% survival following local recurrence without associated systemic metastasis.[41-44] Survival of patients with local recurrence and either previous or concurrent systemic metastases is poor.[43] The incidence of local relapse was higher in patients who had a poor pathologic response to chemotherapy in the primary tumor and in patients with inadequate surgical margins.[38,42]

Second Recurrence of Osteosarcoma

The Cooperative Osteosarcoma Study group reported on 249 patients who had a second recurrence of osteosarcoma. The main feature of therapy was repeated surgical resection of recurrent disease. Of these patients, 197 died, 37 were alive in complete remission (24 after a third complete response and 13 after a fourth or subsequent complete response). Fifteen patients who did not achieve surgical remission remain alive, but follow-up for these patients was extremely short.[45]

Treatment Options Under Clinical Evaluation for Recurrent Osteosarcoma

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

  • EP-ILC-201 (NCT01650090) (Phase 2 Study of Inhaled Lipid Cisplatin in Pulmonary Recurrent Osteosarcoma): This is a phase II study of inhaled lipid-encapsulated cisplatin for patients aged 13 years and older who have a first or second recurrence of osteosarcoma, whose macroscopic disease can be resected, and who have microscopic residual disease.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent osteosarcoma and recurrent childhood malignant fibrous histiocytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


  1. Gelderblom H, Jinks RC, Sydes M, et al.: Survival after recurrent osteosarcoma: data from 3 European Osteosarcoma Intergroup (EOI) randomized controlled trials. Eur J Cancer 47 (6): 895-902, 2011. [PUBMED Abstract]
  2. Hauben EI, Bielack S, Grimer R, et al.: Clinico-histologic parameters of osteosarcoma patients with late relapse. Eur J Cancer 42 (4): 460-6, 2006. [PUBMED Abstract]
  3. Ferrari S, Briccoli A, Mercuri M, et al.: Late relapse in osteosarcoma. J Pediatr Hematol Oncol 28 (7): 418-22, 2006. [PUBMED Abstract]
  4. Kempf-Bielack B, Bielack SS, Jürgens H, et al.: Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 23 (3): 559-68, 2005. [PUBMED Abstract]
  5. Aljubran AH, Griffin A, Pintilie M, et al.: Osteosarcoma in adolescents and adults: survival analysis with and without lung metastases. Ann Oncol 20 (6): 1136-41, 2009. [PUBMED Abstract]
  6. Bacci G, Briccoli A, Longhi A, et al.: Treatment and outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated with neoadjuvant chemotherapy. Acta Oncol 44 (7): 748-55, 2005. [PUBMED Abstract]
  7. Rejin K, Aykan OA, Omer G, et al.: Intra-abdominal metastasis in osteosarcoma: survey and literature review. Pediatr Hematol Oncol 28 (7): 609-15, 2011. [PUBMED Abstract]
  8. Goorin AM, Shuster JJ, Baker A, et al.: Changing pattern of pulmonary metastases with adjuvant chemotherapy in patients with osteosarcoma: results from the multiinstitutional osteosarcoma study. J Clin Oncol 9 (4): 600-5, 1991. [PUBMED Abstract]
  9. Harting MT, Blakely ML: Management of osteosarcoma pulmonary metastases. Semin Pediatr Surg 15 (1): 25-9, 2006. [PUBMED Abstract]
  10. Pastorino U, Gasparini M, Tavecchio L, et al.: The contribution of salvage surgery to the management of childhood osteosarcoma. J Clin Oncol 9 (8): 1357-62, 1991. [PUBMED Abstract]
  11. Skinner KA, Eilber FR, Holmes EC, et al.: Surgical treatment and chemotherapy for pulmonary metastases from osteosarcoma. Arch Surg 127 (9): 1065-70; discussion 1070-1, 1992. [PUBMED Abstract]
  12. Chou AJ, Merola PR, Wexler LH, et al.: Treatment of osteosarcoma at first recurrence after contemporary therapy: the Memorial Sloan-Kettering Cancer Center experience. Cancer 104 (10): 2214-21, 2005. [PUBMED Abstract]
  13. 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 41 (1): 194-9, 2006. [PUBMED Abstract]
  14. Harris MB, Cantor AB, Goorin AM, et al.: 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 24 (2): 87-92, 1995. [PUBMED Abstract]
  15. Miser JS, Kinsella TJ, Triche TJ, et al.: 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 5 (8): 1191-8, 1987. [PUBMED Abstract]
  16. Kung FH, Pratt CB, Vega RA, et al.: Ifosfamide/etoposide combination in the treatment of recurrent malignant solid tumors of childhood. A Pediatric Oncology Group Phase II study. Cancer 71 (5): 1898-903, 1993. [PUBMED Abstract]
  17. Berrak SG, Pearson M, Berberoğlu S, et al.: High-dose ifosfamide in relapsed pediatric osteosarcoma: therapeutic effects and renal toxicity. Pediatr Blood Cancer 44 (3): 215-9, 2005. [PUBMED Abstract]
  18. Massimo B, Giovanni G, Stefano F, et al.: Phase 2 trial of two courses of cyclophosphamide and etoposide for relapsed high-risk osteosarcoma patients. Cancer 115 (13): 2980-7, 2009. [PUBMED Abstract]
  19. Navid F, Willert JR, McCarville MB, et al.: Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer 113 (2): 419-25, 2008. [PUBMED Abstract]
  20. Qi WX, He AN, Tang LN, et al.: Efficacy and safety of gemcitabine-docetaxel combination therapy for recurrent or refractory high-grade osteosarcoma in China: a retrospective study of 18 patients. Jpn J Clin Oncol 42 (5): 427-31, 2012. [PUBMED Abstract]
  21. Grignani G, Palmerini E, Dileo P, et al.: A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol 23 (2): 508-16, 2012. [PUBMED Abstract]
  22. 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 20 (1): 189-96, 2002. [PUBMED Abstract]
  23. Franzius C, Bielack S, Flege S, et al.: High-activity samarium-153-EDTMP therapy followed by autologous peripheral blood stem cell support in unresectable osteosarcoma. Nuklearmedizin 40 (6): 215-20, 2001. [PUBMED Abstract]
  24. Sauerbrey A, Bielack S, Kempf-Bielack B, et al.: High-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (ASCT) as salvage therapy for relapsed osteosarcoma. Bone Marrow Transplant 27 (9): 933-7, 2001. [PUBMED Abstract]
  25. Fagioli F, Aglietta M, Tienghi A, et al.: High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian sarcoma group study. J Clin Oncol 20 (8): 2150-6, 2002. [PUBMED Abstract]
  26. Loeb DM, Garrett-Mayer E, Hobbs RF, et al.: Dose-finding study of 153Sm-EDTMP in patients with poor-prognosis osteosarcoma. Cancer 115 (11): 2514-22, 2009. [PUBMED Abstract]
  27. Briccoli A, Rocca M, Salone M, et al.: Resection of recurrent pulmonary metastases in patients with osteosarcoma. Cancer 104 (8): 1721-5, 2005. [PUBMED Abstract]
  28. Tabone MD, Kalifa C, Rodary C, et al.: Osteosarcoma recurrences in pediatric patients previously treated with intensive chemotherapy. J Clin Oncol 12 (12): 2614-20, 1994. [PUBMED Abstract]
  29. Briccoli A, Rocca M, Salone M, et al.: High grade osteosarcoma of the extremities metastatic to the lung: long-term results in 323 patients treated combining surgery and chemotherapy, 1985-2005. Surg Oncol 19 (4): 193-9, 2010. [PUBMED Abstract]
  30. Su WT, Chewning J, Abramson S, et al.: Surgical management and outcome of osteosarcoma patients with unilateral pulmonary metastases. J Pediatr Surg 39 (3): 418-23; discussion 418-23, 2004. [PUBMED Abstract]
  31. Letourneau PA, Xiao L, Harting MT, et al.: Location of pulmonary metastasis in pediatric osteosarcoma is predictive of outcome. J Pediatr Surg 46 (7): 1333-7, 2011. [PUBMED Abstract]
  32. Fernandez-Pineda I, Daw NC, McCarville B, et al.: Patients with osteosarcoma with a single pulmonary nodule on computed tomography: a single-institution experience. J Pediatr Surg 47 (6): 1250-4, 2012. [PUBMED Abstract]
  33. Karplus G, McCarville MB, Smeltzer MP, et al.: Should contralateral exploratory thoracotomy be advocated for children with osteosarcoma and early unilateral pulmonary metastases? J Pediatr Surg 44 (4): 665-71, 2009. [PUBMED Abstract]
  34. Bacci G, Longhi A, Bertoni F, et al.: Bone metastases in osteosarcoma patients treated with neoadjuvant or adjuvant chemotherapy: the Rizzoli experience in 52 patients. Acta Orthop 77 (6): 938-43, 2006. [PUBMED Abstract]
  35. Aung L, Gorlick R, Healey JH, et al.: Metachronous skeletal osteosarcoma in patients treated with adjuvant and neoadjuvant chemotherapy for nonmetastatic osteosarcoma. J Clin Oncol 21 (2): 342-8, 2003. [PUBMED Abstract]
  36. Jaffe N, Pearson P, Yasko AW, et al.: Single and multiple metachronous osteosarcoma tumors after therapy. Cancer 98 (11): 2457-66, 2003. [PUBMED Abstract]
  37. Franke M, Hardes J, Helmke K, et al.: Solitary skeletal osteosarcoma recurrence. Findings from the Cooperative Osteosarcoma Study Group. Pediatr Blood Cancer 56 (5): 771-6, 2011. [PUBMED Abstract]
  38. Weeden S, Grimer RJ, Cannon SR, et al.: The effect of local recurrence on survival in resected osteosarcoma. Eur J Cancer 37 (1): 39-46, 2001. [PUBMED Abstract]
  39. Bacci G, Ferrari S, Lari S, et al.: Osteosarcoma of the limb. Amputation or limb salvage in patients treated by neoadjuvant chemotherapy. J Bone Joint Surg Br 84 (1): 88-92, 2002. [PUBMED Abstract]
  40. Rodriguez-Galindo C, Shah N, McCarville MB, et al.: Outcome after local recurrence of osteosarcoma: the St. Jude Children's Research Hospital experience (1970-2000). Cancer 100 (9): 1928-35, 2004. [PUBMED Abstract]
  41. Grimer RJ, Sommerville S, Warnock D, et al.: Management and outcome after local recurrence of osteosarcoma. Eur J Cancer 41 (4): 578-83, 2005. [PUBMED Abstract]
  42. Bacci G, Forni C, Longhi A, et al.: Local recurrence and local control of non-metastatic osteosarcoma of the extremities: a 27-year experience in a single institution. J Surg Oncol 96 (2): 118-23, 2007. [PUBMED Abstract]
  43. Bacci G, Longhi A, Cesari M, et al.: Influence of local recurrence on survival in patients with extremity osteosarcoma treated with neoadjuvant chemotherapy: the experience of a single institution with 44 patients. Cancer 106 (12): 2701-6, 2006. [PUBMED Abstract]
  44. 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 107 (7): 1607-16, 2006. [PUBMED Abstract]
  45. Bielack SS, Kempf-Bielack B, Branscheid D, et al.: Second and subsequent recurrences of osteosarcoma: presentation, treatment, and outcomes of 249 consecutive cooperative osteosarcoma study group patients. J Clin Oncol 27 (4): 557-65, 2009. [PUBMED Abstract]
  • Updated: December 4, 2014