Purpose of This PDQ Summary
General Information
Prognostic Factors

Primary Site Tumor Size Presence of Clinically Detectable Metastatic Disease Adequacy of Tumor Resection Necrosis Following Induction or Neoadjuvant Chemotherapy Additional Prognostic Factors

Cellular Classification

Central (Medullary) Tumors Surface (Peripheral) Tumors

Staging and Site Information

Localized Osteosarcoma Metastatic Osteosarcoma

Treatment Option Overview
Localized Osteosarcoma/Malignant Fibrous Histiocytoma of Bone

Biopsy Surgical Removal of Primary Tumor Chemotherapy Treatment Options Under Clinical Evaluation Current Clinical Trials

Osteosarcoma with Metastatic Disease at Diagnosis

Lung Metastases Only Bone Only or Bone with Lung Metastasis Treatment Options Under Clinical Evaluation Malignant Fibrous Histiocytoma of Bone Current Clinical Trials

Recurrent Osteosarcoma

Lung Only Recurrence Bone Metastases Only Local Recurrence Treatment Options Under Clinical Evaluation for Recurrent Osteosarcoma Current Clinical Trials

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Changes to This Summary (04/15/2009)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of osteosarcoma and malignant fibrous histiocytoma of bone. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

• Incidence.
• Prognostic factors.
• Cellular classification.
• Stage information.
• Treatment options.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language, and in Spanish.

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General Information

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, an orthopedic surgeon experienced in bone tumors, a pathologist, radiation oncologists, pediatric oncologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[1] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Osteosarcoma occurs predominantly in adolescents and young adults. It accounts for approximately 5% of childhood tumors. In children and adolescents, more than 50% of these tumors arise from the bones around the knee. Osteosarcoma can rarely be observed in soft tissue or visceral organs. There appears to be no difference in presenting symptoms, tumor location, and outcome for younger patients (<10 years) compared with adolescents.[2,3] Two trials conducted in the 1980s were designed to address the natural history of surgically treated localized, resectable osteosarcoma of the extremity. The outcome of patients in these trials who were treated with surgical removal of the primary tumor recapitulated the historical experience before 1970; more than half of these patients developed metastases within 6 months of diagnosis, and overall, approximately 90% developed recurrent disease within 2 years of diagnosis.[4] Overall survival for patients treated with surgery alone was statistically inferior.[5] The natural history of osteosarcoma has not changed over time, and fewer than 20% of patients with localized resectable primary tumors treated with surgery alone can be expected to survive free of relapse.[4,6,7]

References

1. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.  [PUBMED Abstract]
   
   
2. Bacci G, Longhi A, Bertoni F, et al.: Primary high-grade osteosarcoma: comparison between preadolescent and older patients. J Pediatr Hematol Oncol 27 (3): 129-34, 2005.  [PUBMED Abstract]
   
   
3. Bacci G, Balladelli A, Palmerini E, et al.: Neoadjuvant chemotherapy for osteosarcoma of the extremities in preadolescent patients: the Rizzoli Institute experience. J Pediatr Hematol Oncol 30 (12): 908-12, 2008.  [PUBMED Abstract]
   
   
4. Link MP, Goorin AM, Miser AW, et al.: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314 (25): 1600-6, 1986.  [PUBMED Abstract]
   
   
5. Link MP: The multi-institutional osteosarcoma study: an update. Cancer Treat Res 62: 261-7, 1993.  [PUBMED Abstract]
   
   
6. Eilber F, Giuliano A, Eckardt J, et al.: Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 5 (1): 21-6, 1987.  [PUBMED Abstract]
   
   
7. Bacci G, Ferrari S, Longhi A, et al.: Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: local and systemic control by amputation or limb salvage after preoperative chemotherapy. Acta Orthop Scand 74 (4): 449-54, 2003.  [PUBMED Abstract]
   
   

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Prognostic Factors

Pretreatment factors that influence outcome include site and size of the primary tumor, and presence or absence of clinically detectable metastatic disease. After administration of preoperative chemotherapy, surgical resectability and the degree of tumor necrosis influence outcome. In general, prognostic factors in osteosarcoma have not been helpful in identifying patients who might benefit from treatment intensification or who might require less therapy while maintaining an excellent outcome.

The site of the primary tumor is a significant prognostic factor for patients with localized disease. Among extremity tumors, distal sites have a more favorable prognosis than proximal sites. Axial skeleton primary tumors are associated with the greatest risk of progression and death, primarily related to the inability to achieve a complete surgical resection. Pelvic osteosarcomas make up 7% to 9% of all osteosarcomas; survival rates for patients with pelvic primary tumors are 20% to 47%.[1,2] For patients with osteosarcoma of craniofacial bones, complete resection of the primary tumor with negative margins is essential for cure.[3-5] Despite a relatively high rate of inferior necrosis following neoadjuvant chemotherapy, fewer patients with craniofacial primaries develop systemic metastases than do patients with osteosarcoma originating in the extremities.[6-8] This low rate of metastasis may be related to the relatively smaller size and higher incidence of lower grade tumors in osteosarcoma of the head and neck. There is a better prognosis for patients who have osteosarcoma of the head and neck than for those who have appendicular lesions when treated with surgery alone. While small series have not shown a benefit from adjuvant chemotherapy for patients with osteosarcoma of the head and neck, one meta-analysis concluded that systemic chemotherapy improves the prognosis for these patients. Another large meta-analysis detected no benefit from chemotherapy for patients with osteosarcoma of the head and neck, but suggested that the incorporation of chemotherapy into treatment of patients with high-grade tumors may improve survival. A retrospective analysis identified a trend toward better survival in patients with high-grade osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy.[5,9] Radiation-associated craniofacial osteosarcomas are generally high-grade lesions, usually fibroblastic, which tend to recur locally and have a high rate of metastasis.[10]

Osteosarcoma in extraskeletal sites is rare in children and young adults. With current combined-modality therapy, the outcome for patients with extraskeletal osteosarcoma appears to be similar to that for patients with primary tumors of bone.[11]

Larger tumors have a worse prognosis than smaller tumors. Tumor size has been assessed by the longest single dimension, by the cross-sectional area, or by an estimate of tumor volume; all have correlated with outcome. Serum lactate dehydrogenase (LDH), which also correlates with outcome, is a likely surrogate for tumor volume.

Patients with localized disease have a much better prognosis than those with overt metastatic disease. As many as 20% of patients will have radiographically detectable metastases at diagnosis, with the lung being the most common site.[12] The prognosis for patients with metastatic disease appears to be determined largely by the site(s), the number of metastases, and the surgical resectability of the metastatic disease.[13,14] Patients who have complete surgical ablation of the primary and metastatic tumor (when confined to the lung) following chemotherapy may attain long-term survival, though overall event-free survival remains about 20% to 30% for patients with metastatic disease at diagnosis.[13-16] Prognosis appears more favorable for patients with fewer pulmonary nodules and for those with unilateral rather than bilateral pulmonary metastases;[13] not all patients with suspected pulmonary metastases at diagnosis have osteosarcoma confirmed at the time of lung resection. In one large series, approximately 25% of patients had exclusively benign lesions removed at the time of surgery.[14] The degree of necrosis in the primary tumor after induction chemotherapy remains prognostic in metastatic osteosarcoma.[17] Patients with skip metastases (at least two discontinuous lesions in the same bone) have been reported to have inferior prognoses.[18] Analysis of the German Cooperative Osteosarcoma Study experience, however, suggests that skip lesions in the same bone do not confer an inferior prognosis if they are included in planned surgical resection. Skip lesions across a joint have a worse prognosis.[19] Patients with multifocal osteosarcoma (defined as multiple bone lesions without a clear primary tumor) have an extremely poor prognosis.[20]

Resectability of the tumor is a critical prognostic feature because osteosarcoma is relatively resistant to radiation therapy. Complete resection of the primary tumor and any skip lesions with adequate margins is generally considered essential for cure. For patients with axial skeletal primaries who either do not have surgery for their primary tumor or who have surgery resulting in positive margins, radiation therapy may improve survival.[1,21]

Most treatment protocols for osteosarcoma use an initial period of systemic chemotherapy prior to definitive resection of the primary tumor (or resection of sites of metastases for patients with metastatic disease). The pathologist assesses necrosis in the resected tumor. Patients with at least 90% [22] necrosis in the primary tumor after induction chemotherapy have a better prognosis than those with less necrosis.[22] Patients with less necrosis (<90%) in the primary tumor following initial chemotherapy have a higher rate of recurrence within the first 2 years compared with patients with a more favorable amount of necrosis (≥90%).[23] Imaging modalities such as dynamic magnetic resonance imaging may offer a noninvasive method to assess necrosis.[24] Less necrosis should not be interpreted to mean that chemotherapy has been ineffective; cure rates for patients with little or no necrosis following induction chemotherapy are much higher than cure rates for patients who receive no chemotherapy.

Patients with osteosarcoma as a second malignant neoplasm including those tumors arising in a radiation field, share the same prognosis as patients with de novo osteosarcoma if they are treated aggressively with complete surgical resection and multiagent chemotherapy.[25-27,27,28,28] There have been numerous other identified prognostic features for patients with conventional localized high-grade osteosarcoma. These factors include the age of the patient, LDH level, alkaline phosphatase level, and histologic subtype.[22,29-32] A number of potential prognostic factors have been identified but have not been tested in large numbers of patients. These include the expression of HER2/c-erbB-2 (there are conflicting data concerning the prognostic significance of this human epidermal growth factor);[33-35] tumor cell ploidy; specific chromosomal gains or losses;[36] loss of heterozygosity (LOH) of the RB gene;[37,38] LOH of the p53 locus;[39] and increased expression of p-glycoprotein.[40,41] A prospective analysis of p-glycoprotein expression determined by immunohistochemistry failed to identify prognostic significance for newly diagnosed patients with osteosarcoma, although earlier studies suggested that overexpression of p-glycoprotein predicted for poor outcome.[42]

References

1. Ozaki T, Flege S, Kevric M, et al.: Osteosarcoma of the pelvis: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 21 (2): 334-41, 2003.  [PUBMED Abstract]
   
   
2. Donati D, Giacomini S, Gozzi E, et al.: Osteosarcoma of the pelvis. Eur J Surg Oncol 30 (3): 332-40, 2004.  [PUBMED Abstract]
   
   
3. Patel SG, Meyers P, Huvos AG, et al.: Improved outcomes in patients with osteogenic sarcoma of the head and neck. Cancer 95 (7): 1495-503, 2002.  [PUBMED Abstract]
   
   
4. Smith RB, Apostolakis LW, Karnell LH, et al.: National Cancer Data Base report on osteosarcoma of the head and neck. Cancer 98 (8): 1670-80, 2003.  [PUBMED Abstract]
   
   
5. Fernandes R, Nikitakis NG, Pazoki A, et al.: Osteogenic sarcoma of the jaw: a 10-year experience. J Oral Maxillofac Surg 65 (7): 1286-91, 2007.  [PUBMED Abstract]
   
   
6. Smeele LE, Kostense PJ, van der Waal I, et al.: Effect of chemotherapy on survival of craniofacial osteosarcoma: a systematic review of 201 patients. J Clin Oncol 15 (1): 363-7, 1997.  [PUBMED Abstract]
   
   
7. Ha PK, Eisele DW, Frassica FJ, et al.: Osteosarcoma of the head and neck: a review of the Johns Hopkins experience. Laryngoscope 109 (6): 964-9, 1999.  [PUBMED Abstract]
   
   
8. Duffaud F, Digue L, Baciuchka-Palmaro M, et al.: Osteosarcomas of flat bones in adolescents and adults. Cancer 88 (2): 324-32, 2000.  [PUBMED Abstract]
   
   
9. Canadian Society of Otolaryngology-Head and Neck Surgery Oncology Study Group.: Osteogenic sarcoma of the mandible and maxilla: a Canadian review (1980-2000). J Otolaryngol 33 (3): 139-44, 2004.  [PUBMED Abstract]
   
   
10. McHugh JB, Thomas DG, Herman JM, et al.: Primary versus radiation-associated craniofacial osteosarcoma: Biologic and clinicopathologic comparisons. Cancer 107 (3): 554-62, 2006.  [PUBMED Abstract]
    
    
11. Goldstein-Jackson SY, Gosheger G, Delling G, et al.: Extraskeletal osteosarcoma has a favourable prognosis when treated like conventional osteosarcoma. J Cancer Res Clin Oncol 131 (8): 520-6, 2005.  [PUBMED Abstract]
    
    
12. 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 86 (8): 1602-8, 1999.  [PUBMED Abstract]
    
    
13. Harris MB, Gieser P, Goorin AM, et al.: Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. J Clin Oncol 16 (11): 3641-8, 1998.  [PUBMED Abstract]
    
    
14. Bacci G, Rocca M, Salone M, et al.: High grade osteosarcoma of the extremities with lung metastases at presentation: treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions. J Surg Oncol 98 (6): 415-20, 2008.  [PUBMED Abstract]
    
    
15. 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]
    
    
16. Bacci G, Mercuri M, Longhi A, et al.: 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 41 (14): 2079-85, 2005.  [PUBMED Abstract]
    
    
17. Meyers PA, Heller G, Healey JH, et al.: Osteogenic sarcoma with clinically detectable metastasis at initial presentation. J Clin Oncol 11 (3): 449-53, 1993.  [PUBMED Abstract]
    
    
18. Sajadi KR, Heck RK, Neel MD, et al.: The incidence and prognosis of osteosarcoma skip metastases. Clin Orthop Relat Res (426): 92-6, 2004.  [PUBMED Abstract]
    
    
19. Kager L, Zoubek A, Kastner U, et al.: Skip metastases in osteosarcoma: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 24 (10): 1535-41, 2006.  [PUBMED Abstract]
    
    
20. Bacci G, Fabbri N, Balladelli A, et al.: Treatment and prognosis for synchronous multifocal osteosarcoma in 42 patients. J Bone Joint Surg Br 88 (8): 1071-5, 2006.  [PUBMED Abstract]
    
    
21. DeLaney TF, Park L, Goldberg SI, et al.: Radiotherapy for local control of osteosarcoma. Int J Radiat Oncol Biol Phys 61 (2): 492-8, 2005.  [PUBMED Abstract]
    
    
22. Bielack SS, Kempf-Bielack B, Delling G, et al.: 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 20 (3): 776-90, 2002.  [PUBMED Abstract]
    
    
23. Kim MS, Cho WH, Song WS, et al.: time dependency of prognostic factors in patients with stage II osteosarcomas. Clin Orthop Relat Res 463: 157-65, 2007.  [PUBMED Abstract]
    
    
24. Reddick WE, Wang S, Xiong X, et al.: Dynamic magnetic resonance imaging of regional contrast access as an additional prognostic factor in pediatric osteosarcoma. Cancer 91 (12): 2230-7, 2001.  [PUBMED Abstract]
    
    
25. Bielack SS, Kempf-Bielack B, Heise U, et al.: Combined modality treatment for osteosarcoma occurring as a second malignant disease. Cooperative German-Austrian-Swiss Osteosarcoma Study Group. J Clin Oncol 17 (4): 1164, 1999.  [PUBMED Abstract]
    
    
26. Tabone MD, Terrier P, Pacquement H, et al.: Outcome of radiation-related osteosarcoma after treatment of childhood and adolescent cancer: a study of 23 cases. J Clin Oncol 17 (9): 2789-95, 1999.  [PUBMED Abstract]
    
    
27. Shaheen M, Deheshi BM, Riad S, et al.: Prognosis of radiation-induced bone sarcoma is similar to primary osteosarcoma. Clin Orthop Relat Res 450: 76-81, 2006.  [PUBMED Abstract]
    
    
28. Bacci G, Longhi A, Forni C, et al.: Neoadjuvant chemotherapy for radioinduced osteosarcoma of the extremity: The Rizzoli experience in 20 cases. Int J Radiat Oncol Biol Phys 67 (2): 505-11, 2007.  [PUBMED Abstract]
    
    
29. Meyers PA, Heller G, Healey J, et al.: Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience. J Clin Oncol 10 (1): 5-15, 1992.  [PUBMED Abstract]
    
    
30. Bacci G, Longhi A, Versari M, et al.: Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer 106 (5): 1154-61, 2006.  [PUBMED Abstract]
    
    
31. Bieling P, Rehan N, Winkler P, et al.: Tumor size and prognosis in aggressively treated osteosarcoma. J Clin Oncol 14 (3): 848-58, 1996.  [PUBMED Abstract]
    
    
32. Ferrari S, Bertoni F, Mercuri M, et al.: Predictive factors of disease-free survival for non-metastatic osteosarcoma of the extremity: an analysis of 300 patients treated at the Rizzoli Institute. Ann Oncol 12 (8): 1145-50, 2001.  [PUBMED Abstract]
    
    
33. Gorlick R, Huvos AG, Heller G, et al.: Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J Clin Oncol 17 (9): 2781-8, 1999.  [PUBMED Abstract]
    
    
34. Onda M, Matsuda S, Higaki S, et al.: ErbB-2 expression is correlated with poor prognosis for patients with osteosarcoma. Cancer 77 (1): 71-8, 1996.  [PUBMED Abstract]
    
    
35. Kilpatrick SE, Geisinger KR, King TS, et al.: Clinicopathologic analysis of HER-2/neu immunoexpression among various histologic subtypes and grades of osteosarcoma. Mod Pathol 14 (12): 1277-83, 2001.  [PUBMED Abstract]
    
    
36. Ozaki T, Schaefer KL, Wai D, et al.: Genetic imbalances revealed by comparative genomic hybridization in osteosarcomas. Int J Cancer 102 (4): 355-65, 2002.  [PUBMED Abstract]
    
    
37. Feugeas O, Guriec N, Babin-Boilletot A, et al.: Loss of heterozygosity of the RB gene is a poor prognostic factor in patients with osteosarcoma. J Clin Oncol 14 (2): 467-72, 1996.  [PUBMED Abstract]
    
    
38. Heinsohn S, Evermann U, Zur Stadt U, et al.: Determination of the prognostic value of loss of heterozygosity at the retinoblastoma gene in osteosarcoma. Int J Oncol 30 (5): 1205-14, 2007.  [PUBMED Abstract]
    
    
39. Goto A, Kanda H, Ishikawa Y, et al.: Association of loss of heterozygosity at the p53 locus with chemoresistance in osteosarcomas. Jpn J Cancer Res 89 (5): 539-47, 1998.  [PUBMED Abstract]
    
    
40. Serra M, Pasello M, Manara MC, et al.: May P-glycoprotein status be used to stratify high-grade osteosarcoma patients? Results from the Italian/Scandinavian Sarcoma Group 1 treatment protocol. Int J Oncol 29 (6): 1459-68, 2006.  [PUBMED Abstract]
    
    
41. Pakos EE, Ioannidis JP: The association of P-glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma. A meta-analysis. Cancer 98 (3): 581-9, 2003.  [PUBMED Abstract]
    
    
42. Schwartz CL, Gorlick R, Teot L, et al.: Multiple drug resistance in osteogenic sarcoma: INT0133 from the Children's Oncology Group. J Clin Oncol 25 (15): 2057-62, 2007.  [PUBMED Abstract]
    
    

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Cellular Classification

Osteosarcoma is a malignant tumor that is characterized by the direct formation of bone or osteoid tissue by the tumor cells. The World Health Organization’s histologic classification [1] of bone tumors separates the osteosarcomas into central (medullary) and surface (peripheral) [2,3] tumors and recognizes a number of subtypes within each group.

• Conventional central osteosarcomas.



• Telangiectatic osteosarcomas.[4,5]



• Intraosseous well-differentiated (low-grade) osteosarcomas.



• Small cell osteosarcomas.

• Parosteal (juxtacortical) well-differentiated (low-grade) osteosarcomas.[6,7]



• Periosteal osteosarcoma: low-grade to intermediate-grade osteosarcomas.[8,9]



• High-grade surface osteosarcomas.[3,10,11]

The most common pathologic subtype is conventional central osteosarcoma, which is characterized by areas of necrosis, atypical mitoses, and malignant osteoid tissue and/or cartilage. The other subtypes are much less common, each occurring at a frequency of less than 5%. Telangiectatic osteosarcoma may be confused radiographically with an aneurysmal bone cyst or giant cell tumor. This variant should be approached as a conventional osteosarcoma.[4,5] Recognition of intraosseous well-differentiated osteosarcoma and parosteal osteosarcoma is important because these are associated with the most favorable prognosis and can be treated successfully with radical excision of the primary tumor alone.[6,12] Periosteal osteosarcoma has a generally good prognosis [8] and treatment is guided by histologic grade.[9,12]

Malignant fibrous histiocytoma (MFH) of bone is treated according to osteosarcoma treatment protocols. MFH should be distinguished from angiomatoid fibrous histiocytoma, a low-grade tumor that is usually noninvasive, small, and associated with an excellent outcome with surgery alone.[13] One study suggests similar event-free survival rates for MFH and osteosarcoma.[14]

Extraosseous osteosarcoma is a malignant mesenchymal neoplasm without direct attachment to the skeletal system. Previously, treatment for extraosseous osteosarcoma followed soft tissue sarcoma guidelines,[15] though a retrospective analysis of the German Cooperative Osteosarcoma Study identified a favorable outcome for extraosseous osteosarcoma treated with surgery and conventional osteosarcoma therapy.[16]

References

1. Schajowicz F, Sissons HA, Sobin LH: The World Health Organization's histologic classification of bone tumors. A commentary on the second edition. Cancer 75 (5): 1208-14, 1995.  [PUBMED Abstract]
   
   
2. Antonescu CR, Huvos AG: Low-grade osteogenic sarcoma arising in medullary and surface osseous locations. Am J Clin Pathol 114 (Suppl): S90-103, 2000.  [PUBMED Abstract]
   
   
3. Kaste SC, Fuller CE, Saharia A, et al.: Pediatric surface osteosarcoma: clinical, pathologic, and radiologic features. Pediatr Blood Cancer 47 (2): 152-62, 2006.  [PUBMED Abstract]
   
   
4. Bacci G, Ferrari S, Ruggieri P, et al.: Telangiectatic osteosarcoma of the extremity: neoadjuvant chemotherapy in 24 cases. Acta Orthop Scand 72 (2): 167-72, 2001.  [PUBMED Abstract]
   
   
5. Weiss A, Khoury JD, Hoffer FA, et al.: Telangiectatic osteosarcoma: the St. Jude Children's Research Hospital's experience. Cancer 109 (8): 1627-37, 2007.  [PUBMED Abstract]
   
   
6. Hoshi M, Matsumoto S, Manabe J, et al.: Oncologic outcome of parosteal osteosarcoma. Int J Clin Oncol 11 (2): 120-6, 2006.  [PUBMED Abstract]
   
   
7. Han I, Oh JH, Na YG, et al.: Clinical outcome of parosteal osteosarcoma. J Surg Oncol 97 (2): 146-9, 2008.  [PUBMED Abstract]
   
   
8. Rose PS, Dickey ID, Wenger DE, et al.: Periosteal osteosarcoma: long-term outcome and risk of late recurrence. Clin Orthop Relat Res 453: 314-7, 2006.  [PUBMED Abstract]
   
   
9. Grimer RJ, Bielack S, Flege S, et al.: Periosteal osteosarcoma--a European review of outcome. Eur J Cancer 41 (18): 2806-11, 2005.  [PUBMED Abstract]
   
   
10. Okada K, Unni KK, Swee RG, et al.: High grade surface osteosarcoma: a clinicopathologic study of 46 cases. Cancer 85 (5): 1044-54, 1999.  [PUBMED Abstract]
    
    
11. Staals EL, Bacchini P, Bertoni F: High-grade surface osteosarcoma: a review of 25 cases from the Rizzoli Institute. Cancer 112 (7): 1592-9, 2008.  [PUBMED Abstract]
    
    
12. Schwab JH, Antonescu CR, Athanasian EA, et al.: A comparison of intramedullary and juxtacortical low-grade osteogenic sarcoma. Clin Orthop Relat Res 466 (6): 1318-22, 2008.  [PUBMED Abstract]
    
    
13. Daw NC, Billups CA, Pappo AS, et al.: Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children's Research Hospital experience. Cancer 97 (11): 2839-47, 2003.  [PUBMED Abstract]
    
    
14. Picci P, Bacci G, Ferrari S, et al.: Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors. Ann Oncol 8 (11): 1107-15, 1997.  [PUBMED Abstract]
    
    
15. Wodowski K, Hill DA, Pappo AS, et al.: A chemosensitive pediatric extraosseous osteosarcoma: case report and review of the literature. J Pediatr Hematol Oncol 25 (1): 73-7, 2003.  [PUBMED Abstract]
    
    
16. Goldstein-Jackson SY, Gosheger G, Delling G, et al.: Extraskeletal osteosarcoma has a favourable prognosis when treated like conventional osteosarcoma. J Cancer Res Clin Oncol 131 (8): 520-6, 2005.  [PUBMED Abstract]
    
    

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Staging and Site Information

The Enneking staging system for musculoskeletal neoplasms is based on grade, site, and presence of metastases.[1] All conventional osteosarcomas are high grade; site is graded as intracompartmental or extracompartmental. To be intracompartmental, an osteosarcoma must be confined within the periosteum; such lesions are IIA in the Enneking system. The great majority of osteosarcomas extend beyond the periosteum, which makes them IIB. The presence of clinically detectable metastases is graded as stage III in this system. For practical purposes, there are essentially two classes of patients: those who present without clinically detectable metastatic disease (localized osteosarcoma) and those who present with clinically detectable metastatic disease (metastatic osteosarcoma).

Localized tumors are limited to the bone of origin. Patients with skip lesions confined to the bone which includes the primary tumor should be considered to have localized disease if the skip lesions can be included in the planned surgical resection.[2] Approximately one-half of the tumors arise in the femur; of these, 80% are in the distal femur. Other primary sites in descending order of frequency are the proximal tibia, proximal humerus, pelvis, jaw, fibula, and ribs.[3] Compared with osteosarcoma of the appendicular skeleton, osteosarcoma of the head and neck is more likely to be low grade [4] and to arise in older patients. A retrospective analysis identified a trend toward better survival in patients with osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy.[5]

Radiologic evidence of metastatic tumor deposits in the lungs, other bones, or other distant sites is found in approximately 20% of patients at diagnosis, with 85% to 90% of metastatic disease presenting in the lungs. The second most common site of metastasis is another bone.[6] Metastasis to other bones may be solitary or multiple. The syndrome of multifocal osteosarcoma refers to a presentation with multiple foci of osteosarcoma without a clear primary tumor, often with symmetrical metaphyseal involvement. Multifocal osteosarcoma has an extremely grave prognosis.[3]

References

1. Enneking WF: A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res (204): 9-24, 1986.  [PUBMED Abstract]
   
   
2. Kager L, Zoubek A, Kastner U, et al.: Skip metastases in osteosarcoma: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 24 (10): 1535-41, 2006.  [PUBMED Abstract]
   
   
3. Longhi A, Fabbri N, Donati D, et al.: Neoadjuvant chemotherapy for patients with synchronous multifocal osteosarcoma: results in eleven cases. J Chemother 13 (3): 324-30, 2001.  [PUBMED Abstract]
   
   
4. Patel SG, Meyers P, Huvos AG, et al.: Improved outcomes in patients with osteogenic sarcoma of the head and neck. Cancer 95 (7): 1495-503, 2002.  [PUBMED Abstract]
   
   
5. Canadian Society of Otolaryngology-Head and Neck Surgery Oncology Study Group.: Osteogenic sarcoma of the mandible and maxilla: a Canadian review (1980-2000). J Otolaryngol 33 (3): 139-44, 2004.  [PUBMED Abstract]
   
   
6. Harris MB, Gieser P, Goorin AM, et al.: Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. J Clin Oncol 16 (11): 3641-8, 1998.  [PUBMED Abstract]
   
   

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Treatment Option Overview

Successful treatment generally requires the combination of effective systemic chemotherapy and complete resection of all clinically detectable disease. Protective weight bearing is recommended for patients with tumors of weight-bearing bones to prevent pathological fractures that could preclude limb-preserving surgery.

Randomized clinical trials have established that both neoadjuvant and adjuvant chemotherapy are effective in preventing relapse in patients with clinically nonmetastatic tumors.[1,2] It is imperative that patients with proven or suspected osteosarcoma have an initial evaluation by an orthopedic oncologist familiar with the surgical management of this disease. This evaluation, which includes imaging studies, should be done prior to the initial biopsy, since an inappropriately performed biopsy may jeopardize a limb-sparing procedure.

References

1. Eilber F, Giuliano A, Eckardt J, et al.: Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 5 (1): 21-6, 1987.  [PUBMED Abstract]
   
   
2. Link MP, Goorin AM, Miser AW, et al.: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314 (25): 1600-6, 1986.  [PUBMED Abstract]
   
   

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Localized Osteosarcoma/Malignant Fibrous Histiocytoma of Bone

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Complete surgical resection is crucial for patients with localized osteosarcoma; however, at least 80% of patients treated with surgery alone will develop metastatic disease.[1] Randomized clinical trials have established that adjuvant chemotherapy is effective in preventing relapse or recurrence in patients with localized resectable primary tumors.[1,2] Patients with malignant fibrous histiocytoma (MFH) of bone are treated according to osteosarcoma treatment protocols, and the outcome for patients with resectable MFH is similar to the outcome for patients with osteosarcoma.[3] As with osteosarcoma, patients with a favorable necrosis had a longer survival than those with an inferior necrosis.[4] MFH of bone is seen more commonly in older adults. Many patients with MFH will need preoperative chemotherapy to achieve a wide local excision.[5]

While a needle biopsy can often make the diagnosis of osteosarcoma, participation in clinical trials may require collection of material for biologic studies that can only be obtained via an open biopsy or multiple needle biopsies. If limb sparing (removal of the malignant bone tumor without amputation and replacement of bones or joints with allografts or prosthetic devices) is contemplated, the biopsy should be performed by the surgeon who will do the definitive operation, since incision placement is crucial.

Surgical resection of the primary tumor with adequate margins is an essential component of the curative strategy for patients with localized osteosarcoma. The type of surgery required for complete ablation of the primary tumor depends on a number of factors that must be evaluated on a case-by-case basis.[6] In general, more than 80% of patients with extremity osteosarcoma can be treated by a limb sparing procedure and do not require amputation.[7] Limb sparing procedures should be planned only when the preoperative staging indicates that it would be possible to achieve wide surgical margins. Reconstruction after surgery can be accomplished with many options including metallic endoprosthesis, allograft, vascularized autologous bone graft, and rotationplasty. The choice of optimal surgical reconstruction involves many factors, including the site and size of the primary tumor, the ability to preserve the neurovascular supply of the distal extremity, the age of the patient and potential for additional growth, and the needs and desires of the patient and family for specific function, such as sports participation. If a complicated reconstruction delays or prohibits the resumption of systemic chemotherapy, limb preservation may endanger the chance for cure. For some patients, amputation remains the optimal choice for management of the primary tumor. A pathologic fracture noted at diagnosis or during preoperative chemotherapy does not preclude limb-salvage surgery if wide surgical margins can be achieved.[8] In one series, patients presenting with a pathologic fracture at diagnosis had similar outcomes to those without pathologic fractures at diagnosis, while in a second series, pathologic fracture at diagnosis was associated with a worse overall outcome.[9,10] If the pathologic examination of the surgical specimen shows inadequate margins, an immediate amputation should be considered, especially if the histologic necrosis following preoperative chemotherapy was poor.[11] In one study, patients undergoing limb-salvage procedures who had poor histologic response and close surgical margins had a high rate of local recurrence.[12]

Not surprisingly, patients who undergo amputation have lower local recurrence rates than patients who undergo limb salvage procedures. Patients with tumors of the femur have a higher local recurrence rate than patients with primary tumors of the tibia/fibula. Rotationplasty and other limb salvage procedures have been evaluated for both their functional outcome and their effect on survival. There is no difference in overall survival (OS) between patients initially treated by amputation and those treated with a limb sparing procedure. While limb sparing resection is the current practice for local control at most pediatric institutions, there are few data to indicate that limb-salvage of the lower limb is substantially superior to amputation with regard to patient quality of life.

If complete surgical resection is not feasible or if surgical margins are inadequate, radiation therapy may improve the local control rate.[13,14]

Almost all patients receive intravenous preoperative chemotherapy as initial treatment. Current chemotherapy protocols include combinations of the following agents: high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin.[15-24] Although most patients with osteosarcoma receive high-dose methotrexate as part of initial therapy, patients treated with doxorubicin, cisplatin, cyclophosphamide, and vincristine (without high-dose methotrexate) have a similar outcome to that of patients receiving high-dose methotrexate.[25]

In certain trials, extent of tumor necrosis is used to determine postoperative chemotherapy. In general, if tumor necrosis exceeds 90%, the preoperative chemotherapy regimen is continued. If tumor necrosis is less than 90%, some groups have incorporated drugs not previously utilized in the preoperative therapy. This approach is based on early reports from Memorial Sloan-Kettering Cancer Center (MMSKC) which suggested that adding cisplatin to postoperative chemotherapy improved the outcome for patients with less than 90% tumor necrosis. With longer followup, the outcome for patients with less than 90% tumor necrosis treated at MSKCC was the same whether they did or did not receive cisplatin in the postoperative phase of treatment. Subsequent trials performed by other groups have failed to demonstrate improved event-free survival (EFS) when drugs not included in the preoperative regimen were added to postoperative therapy.

The Children's Oncology Group (COG) performed a prospective randomized trial in newly diagnosed children and young adults with localized osteosarcoma. All patients received cisplatin, doxorubicin, and high-dose methotrexate. One-half of the patients were randomly assigned to receive ifosfamide. In a second randomization, one-half of the patients were assigned to receive the biological compound muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) beginning after definitive surgical resection. The addition of ifosfamide did not improve outcome. The addition of MTP-PE produced improvement in EFS which did not meet the conventional test for statistical significance (p = .08), and a significant improvement in OS (78% vs. 70%; p = .03).[26][Level of evidence: 1iiA] There has been speculation regarding the potential contribution of postrelapse treatment, although there was no differences in the postrelapse surgical approaches in the relapsed patients. The appropriate role of MTP in the treatment of osteosarcoma remains under discussion.

The COG, in collaboration with several European groups, has opened a trial in which all patients receive preoperative therapy with doxorubicin, cisplatin, and high-dose methotrexate. Patients are then divided into the following two strata on the basis of histologic necrosis in the resected primary tumor:

• Favorable histologic response (<10% viable tumor): All patients receive postoperative therapy with the same drugs as those given preoperatively. Patients will be randomly assigned to receive additional therapy with pegylated interferon alpha-2b.[27]



• Standard histologic response (10%–100% viable tumor): Patients will be randomly assigned to receive postoperative chemotherapy with the same drugs as those given preoperatively plus or minus additional courses of ifosfamide/etoposide.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with localized osteosarcoma and localized 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.

References

1. Link MP, Goorin AM, Miser AW, et al.: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314 (25): 1600-6, 1986.  [PUBMED Abstract]
   
   
2. Eilber F, Giuliano A, Eckardt J, et al.: Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 5 (1): 21-6, 1987.  [PUBMED Abstract]
   
   
3. Picci P, Bacci G, Ferrari S, et al.: Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors. Ann Oncol 8 (11): 1107-15, 1997.  [PUBMED Abstract]
   
   
4. Bramwell VH, Steward WP, Nooij M, et al.: Neoadjuvant chemotherapy with doxorubicin and cisplatin in malignant fibrous histiocytoma of bone: A European Osteosarcoma Intergroup study. J Clin Oncol 17 (10): 3260-9, 1999.  [PUBMED Abstract]
   
   
5. Daw NC, Billups CA, Pappo AS, et al.: Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children's Research Hospital experience. Cancer 97 (11): 2839-47, 2003.  [PUBMED Abstract]
   
   
6. Grimer RJ: Surgical options for children with osteosarcoma. Lancet Oncol 6 (2): 85-92, 2005.  [PUBMED Abstract]
   
   
7. 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 according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol 18 (24): 4016-27, 2000.  [PUBMED Abstract]
   
   
8. Scully SP, Ghert MA, Zurakowski D, et al.: Pathologic fracture in osteosarcoma : prognostic importance and treatment implications. J Bone Joint Surg Am 84-A (1): 49-57, 2002.  [PUBMED Abstract]
   
   
9. Bacci G, Ferrari S, Longhi A, et al.: Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: local and systemic control by amputation or limb salvage after preoperative chemotherapy. Acta Orthop Scand 74 (4): 449-54, 2003.  [PUBMED Abstract]
   
   
10. Bramer JA, Abudu AA, Grimer RJ, et al.: Do pathological fractures influence survival and local recurrence rate in bony sarcomas? Eur J Cancer 43 (13): 1944-51, 2007.  [PUBMED Abstract]
    
    
11. 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]
    
    
12. Grimer RJ, Taminiau AM, Cannon SR, et al.: Surgical outcomes in osteosarcoma. J Bone Joint Surg Br 84 (3): 395-400, 2002.  [PUBMED Abstract]
    
    
13. Ozaki T, Flege S, Kevric M, et al.: Osteosarcoma of the pelvis: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 21 (2): 334-41, 2003.  [PUBMED Abstract]
    
    
14. DeLaney TF, Park L, Goldberg SI, et al.: Radiotherapy for local control of osteosarcoma. Int J Radiat Oncol Biol Phys 61 (2): 492-8, 2005.  [PUBMED Abstract]
    
    
15. Fuchs N, Bielack SS, Epler D, et al.: Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group's protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol 9 (8): 893-9, 1998.  [PUBMED Abstract]
    
    
16. 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 19 (1): 171-82, 2001.  [PUBMED Abstract]
    
    
17. 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 15 (1): 76-84, 1997.  [PUBMED Abstract]
    
    
18. Bacci G, Picci P, Avella M, et al.: Effect of intra-arterial versus intravenous cisplatin in addition to systemic adriamycin and high-dose methotrexate on histologic tumor response of osteosarcoma of the extremities. J Chemother 4 (3): 189-95, 1992.  [PUBMED Abstract]
    
    
19. Cassano WF, Graham-Pole J, Dickson N: Etoposide, cyclophosphamide, cisplatin, and doxorubicin as neoadjuvant chemotherapy for osteosarcoma. Cancer 68 (9): 1899-902, 1991.  [PUBMED Abstract]
    
    
20. Voûte PA, Souhami RL, Nooij M, et al.: A phase II study of cisplatin, ifosfamide and doxorubicin in operable primary, axial skeletal and metastatic osteosarcoma. European Osteosarcoma Intergroup (EOI). Ann Oncol 10 (10): 1211-8, 1999.  [PUBMED Abstract]
    
    
21. Ferguson WS, Harris MB, Goorin AM, et al.: Presurgical window of carboplatin and surgery and multidrug chemotherapy for the treatment of newly diagnosed metastatic or unresectable osteosarcoma: Pediatric Oncology Group Trial. J Pediatr Hematol Oncol 23 (6): 340-8, 2001 Aug-Sep.  [PUBMED Abstract]
    
    
22. Ferrari S, Smeland S, Mercuri M, et al.: Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol 23 (34): 8845-52, 2005.  [PUBMED Abstract]
    
    
23. Zalupski MM, Rankin C, Ryan JR, et al.: Adjuvant therapy of osteosarcoma--A Phase II trial: Southwest Oncology Group study 9139. Cancer 100 (4): 818-25, 2004.  [PUBMED Abstract]
    
    
24. Meyers PA, 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 23 (9): 2004-11, 2005.  [PUBMED Abstract]
    
    
25. Tunn PU, Reichardt P: Chemotherapy for osteosarcoma without high-dose methotrexate: a 12-year follow-up on 53 patients. Onkologie 30 (5): 228-32, 2007.  [PUBMED Abstract]
    
    
26. 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 26 (4): 633-8, 2008.  [PUBMED Abstract]
    
    
27. Müller CR, Smeland S, Bauer HC, et al.: Interferon-alpha as the only adjuvant treatment in high-grade osteosarcoma: long term results of the Karolinska Hospital series. Acta Oncol 44 (5): 475-80, 2005.  [PUBMED Abstract]
    
    

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Osteosarcoma with Metastatic Disease at Diagnosis

Approximately 20% to 25% of patients with osteogenic sarcoma present with clinically detectable metastatic disease. The lung is the most common site of initial metastatic disease.[1] For patients with metastatic disease at initial presentation, roughly 20% will remain continuously free of disease, and roughly 30% will survive 5 years from diagnosis.[2] Patients with metastases limited to the lungs have a better outcome than patients with metastases to other sites or to the lungs combined with other sites.[2,3] The chemotherapeutic agents used include high-dose methotrexate, doxorubicin, cisplatin, high-dose ifosfamide, etoposide, and in some reports, carboplatin or cyclophosphamide. High-dose ifosfamide (17.5 grams per course) in combination with etoposide produced a complete (10%) or partial (49%) response in patients with newly diagnosed metastatic osteosarcoma.[4]

Patients with metastatic lung lesions as the sole site of metastatic disease should have the lung lesions resected if at all possible. Generally, this is done following administration of preoperative chemotherapy. In approximately 10% of patients, all lung lesions disappear following preoperative chemotherapy.[3] Complete resection of pulmonary metastatic disease can be achieved in a high percentage of patients with residual lung nodules following preoperative chemotherapy. The cure rate is essentially zero without complete resection of residual pulmonary metastatic lesions.

For patients who present with primary osteosarcoma and metastases limited to the lungs and who achieve complete surgical remission, 5-year event-free survival (EFS) is approximately 20% to 25%. Multiple metastatic nodules confer a worse prognosis than one or two nodules, and bilateral lung involvement is worse than unilateral.[2] Patients with fewer than three nodules confined to one lung may achieve a 5-year EFS of approximately 40% to 50%.

The second most common site of metastasis is another bone that is distant from the primary tumor. Patients with metastasis to other bones distant from the primary tumor experience roughly 10% EFS and overall survival.[2] In the Italian experience, of the patients who presented with primary extremity tumors and synchronous metastasis to other bones, only three patients remained continuously disease-free 5 years later.[5] Patients who have transarticular skip lesions have a poor prognosis.[6]

Multifocal osteosarcoma is different from osteosarcoma which presents with a clearly delineated primary lesion and limited bone metastasis. Multifocal osteosarcoma classically presents with symmetrical, metaphyseal lesions, and it may be difficult to decide which is the primary lesion. Patients with multifocal bone disease at presentation have an extremely poor prognosis. No patient with synchronous multifocal osteosarcoma has ever been reported to be cured, but systemic chemotherapy and aggressive surgical resection may achieve significant prolongation of life.[7,8]

When the usual treatment course of preoperative chemotherapy followed by surgical ablation of the primary tumor and resection of all overt metastatic disease (usually lungs) followed by postoperative combination chemotherapy cannot be used, an alternative treatment approach may be used. This alternative treatment approach begins with surgery for the primary tumor, followed by chemotherapy and then surgical resection of metastatic disease (usually lungs). This alternative approach may be appropriate in patients with intractable pain, pathologic fracture, or uncontrolled infection of the tumor when initiation of chemotherapy could create risk of sepsis.

The Children's Oncology Group, in collaboration with several European groups, has opened a trial in which all patients with sites of metastatic disease amenable to surgical resection receive preoperative therapy with doxorubicin, cisplatin, and high-dose methotrexate. Patients are then divided into the following two strata on the basis of necrosis observed in the resected primary tumor:

• Favorable histologic response (<10% viable tumor): All patients receive postoperative therapy with the same drugs as those given preoperatively. Patients will be randomly assigned to receive additional therapy with pegylated interferon alpha-2b.[9]



• Standard histologic response (10%–100% viable tumor): Patients will be randomly assigned to receive postoperative chemotherapy with the same drugs as those given preoperatively plus or minus additional courses of ifosfamide/etoposide.

The treatment for malignant fibrous histiocytoma (MFH) of bone with metastasis at initial presentation is the same as the treatment for osteosarcoma with metastasis. Patients with unresectable or metastatic MFH have a very poor outcome.[10]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with metastatic osteosarcoma and metastatic 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.

References

1. 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 86 (8): 1602-8, 1999.  [PUBMED Abstract]
   
   
2. Kager L, Zoubek A, Pötschger U, et al.: Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol 21 (10): 2011-8, 2003.  [PUBMED Abstract]
   
   
3. Bacci G, Rocca M, Salone M, et al.: High grade osteosarcoma of the extremities with lung metastases at presentation: treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions. J Surg Oncol 98 (6): 415-20, 2008.  [PUBMED Abstract]
   
   
4. 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 20 (2): 426-33, 2002.  [PUBMED Abstract]
   
   
5. Bacci G, Fabbri N, Balladelli A, et al.: Treatment and prognosis for synchronous multifocal osteosarcoma in 42 patients. J Bone Joint Surg Br 88 (8): 1071-5, 2006.  [PUBMED Abstract]
   
   
6. Kager L, Zoubek A, Kastner U, et al.: Skip metastases in osteosarcoma: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 24 (10): 1535-41, 2006.  [PUBMED Abstract]
   
   
7. Harris MB, Gieser P, Goorin AM, et al.: Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. J Clin Oncol 16 (11): 3641-8, 1998.  [PUBMED Abstract]
   
   
8. Longhi A, Fabbri N, Donati D, et al.: Neoadjuvant chemotherapy for patients with synchronous multifocal osteosarcoma: results in eleven cases. J Chemother 13 (3): 324-30, 2001.  [PUBMED Abstract]
   
   
9. Müller CR, Smeland S, Bauer HC, et al.: Interferon-alpha as the only adjuvant treatment in high-grade osteosarcoma: long term results of the Karolinska Hospital series. Acta Oncol 44 (5): 475-80, 2005.  [PUBMED Abstract]
   
   
10. Daw NC, Billups CA, Pappo AS, et al.: Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children's Research Hospital experience. Cancer 97 (11): 2839-47, 2003.  [PUBMED Abstract]
    
    

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Recurrent Osteosarcoma

Approximately 50% of relapses occur within 18 months of therapy termination and only 5% of recurrences develop beyond 5 years.[1-4] 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%).[4,5] Patients with recurrent osteosarcoma should be assessed for surgical resectability, as they may sometimes be cured with aggressive surgical resection with or without chemotherapy.[6,5,7-10] 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% following complete resection of metastatic pulmonary tumors and a 20% survival rate following complete resection of metastases at other sites.[4,5,10,11]

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 shown activity in as many as one-third of patients with recurrent osteosarcoma who have not previously received this drug.[12-15] Cyclophosphamide and etoposide have activity in recurrent osteosarcoma [16] as does the combination of gemcitabine and docetaxel.[17] Peripheral blood stem cell transplant utilizing high-dose chemotherapy does not appear to improve outcome. High-dose samarium-153-EDTMP coupled with peripheral blood stem cell support may provide significant pain palliation in patients with bone metastases.[18-21]

Repeated resections of pulmonary recurrences can lead to extended disease control and possibly cure for some patients.[11,22] Survival for patients with unresectable metastatic disease is less than 5%.[5,23] Five-year event free survical (EFS) for patients who have complete surgical resection of all pulmonary metastases ranges from 20% to 45%.[4,5,10,11] Factors that suggest a better outcome include fewer pulmonary nodules, unilateral pulmonary metastases,[24] or longer intervals between primary tumor resection and metastases.[4,5,25] Resection of metastatic disease followed by observation alone results in low overall survival 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 scan. This suggests that patients with unilateral nodules may benefit from bilateral exploration.[24]

Patients with osteosarcoma who develop bone metastases have a poor prognosis. In one large series, the 5-year EFS rate was 11%.[26] Patients with late solitary bone relapse have a 5-year EFS rate of approximately 30%.[26-28]

The postrelapse outcome of patients who have a local recurrence is worse than that for patients who relapse with metastases alone.[29-31]

Two retrospective, single-institution series reported 10% to 40% survival following local recurrence without associated systemic metastasis.[32-35] The survival for patients with local recurrence and either prior or concurrent systemic metastases is poor.[34] 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.[29,33]

Clinical trials (phases I and II) are appropriate for patients with unresectable metastatic disease and should be considered.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References

1. Strauss SJ, McTiernan A, Whelan JS: Late relapse of osteosarcoma: implications for follow-up and screening. Pediatr Blood Cancer 43 (6): 692-7, 2004.  [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. 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]
   
   
6. 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]
   
   
7. Harting MT, Blakely ML: Management of osteosarcoma pulmonary metastases. Semin Pediatr Surg 15 (1): 25-9, 2006.  [PUBMED Abstract]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    
16. Rodríguez-Galindo C, Daw NC, Kaste SC, et al.: Treatment of refractory osteosarcoma with fractionated cyclophosphamide and etoposide. J Pediatr Hematol Oncol 24 (4): 250-5, 2002.  [PUBMED Abstract]
    
    
17. 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]
    
    
18. 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]
    
    
19. 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]
    
    
20. 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]
    
    
21. 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]
    
    
22. 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]
    
    
23. 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]
    
    
24. 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]
    
    
25. Ward WG, Mikaelian K, Dorey F, et al.: Pulmonary metastases of stage IIB extremity osteosarcoma and subsequent pulmonary metastases. J Clin Oncol 12 (9): 1849-58, 1994.  [PUBMED Abstract]
    
    
26. 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]
    
    
27. 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]
    
    
28. Jaffe N, Pearson P, Yasko AW, et al.: Single and multiple metachronous osteosarcoma tumors after therapy. Cancer 98 (11): 2457-66, 2003.  [PUBMED Abstract]
    
    
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Get More Information From NCI

Call 1-800-4-CANCER

For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. Deaf and hard-of-hearing callers with TTY equipment may call 1-800-332-8615. The call is free and a trained Cancer Information Specialist is available to answer your questions.

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The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 9:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.

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For more information from the NCI, please write to this address:

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Search the NCI Web site

The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use our “Best Bets” search box in the upper right hand corner of each Web page. The results that are most closely related to your search term will be listed as Best Bets at the top of the list of search results.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237), TTY at 1-800-332-8615.

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Changes to This Summary (04/15/2009)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

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More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database.

  Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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