Osteosarcoma/Malignant Fibrous Histiocytoma of Bone

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of osteosarcoma/malignant fibrous histiocytoma of bone.

Osteosarcoma/Malignant Fibrous Histiocytoma of Bone

General Information

This cancer treatment information summary provides an overview of the prognosis, diagnosis, classification, and treatment of osteosarcoma and malignant fibrous histiocytoma of bone.

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. These summaries are updated regularly according to the latest published research findings by an Editorial Board of pediatric oncology experts.

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 in order to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive Care summaries 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 Late Effects of Treatment for Childhood Cancer summary for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Osteosarcoma is a bone tumor that 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. There appears to be no difference in presenting symptoms, tumor location, and outcome for younger patients (<10 years) compared with adolescents.² 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, almost 90% ³ 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 30% of patients with localized resectable primary tumors treated with surgery alone can be expected to survive free of relapse.^4,6,7,8,

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.

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.

³ Link MP, Goorin AM, Horowitz M, et al.: Adjuvant chemotherapy of high-grade osteosarcoma of the extremity. Updated results of the Multi-Institutional Osteosarcoma Study. Clin Orthop (270): 8-14, 1991.

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.

⁵ Link MP: The multi-institutional osteosarcoma study: an update. Cancer Treat Res 62: 261-7, 1993.

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.

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.

⁸ 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.

Prognostic Factors

Factors that influence prognosis for osteosarcoma include site and size of the primary tumor, presence or absence of clinically detectable metastatic disease, adequacy of resection, and degree of necrosis observed in tumors following initial chemotherapy. The latter two factors are not conventional prognostic factors since they can be assessed only after treatment, not at initial presentation.

Primary Site

The site of the primary tumor is a significant prognostic factor in localized disease. Among tumors of the extremity, distal sites have a more favorable prognosis than proximal sites. Axial skeleton primary tumors are associated with the greatest risk of progression and death.^1,2 Pelvic osteosarcomas make up 7% to 9% of all osteosarcomas; their current overall survival rate is 20% to 47%.¹ For patients with osteosarcoma of craniofacial bones, complete resection of the primary tumor with negative margins is essential for cure.^3,4 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.^5,6,7 However, radiation-associated craniofacial osteosarcomas are high-grade lesions, usually fibroblastic, which tend to recur locally and have a high rate of metastasis.⁸ This 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.^{9 10} 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.¹¹ A retrospective analysis identified a trend toward better survival in patients with high-grade osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy.^12,

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.^13,

Tumor Size

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, which also correlates with outcome, is a likely surrogate for tumor volume.

Presence of Clinically Detectable Metastatic Disease

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.¹⁴ 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.^14,15,16,17 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.^{14,15,18,19,20} Prognosis appears more favorable for patients with fewer pulmonary nodules and for those with unilateral rather than bilateral pulmonary metastases.^15,16 The degree of necrosis in the primary tumor after induction chemotherapy remains prognostic in metastatic osteosarcoma.²¹ Patients with skip metastases (≥2 discontinuous lesions in the same bone) have been reported to have inferior prognoses.²² Analysis of the German Cooperative Osteosarcoma Study (COSS) 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.²³ Patients with multifocal osteosarcoma (>1 bone lesion at diagnosis) have a poor prognosis.^24,

Adequacy of Tumor Resection

Resectability of the tumor is a critical prognostic feature because this tumor is relatively resistant to radiation therapy. Complete resection of tumor-bearing bone with adequate margins is generally considered essential for cure. Skip lesions were previously considered an unfavorable risk factor. Analysis of the German COSS experience, however, suggests that skip lesions do not confer an inferior prognosis if they are included in planned surgical resction.²³ Two studies have examined the outcome for patients with osteosarcoma in the axial skeleton whose tumors were resected with positive margins. In these retrospective analyses of nonrandomized treatments, among patients who had no surgery or intralesional resection, patients who received radiation therapy had better survival than patients who did not receive radiation therapy.^1,25,

Necrosis Following Induction or Neoadjuvant Chemotherapy

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 more than 95% necrosis in the primary tumor after induction chemotherapy have a better prognosis than those with less necrosis.^18,26 Imaging modalities such as dynamic magnetic resonance imaging may offer a noninvasive method to assess necrosis.²⁷ 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.

Additional Prognostic Factors

Patients with osteosarcoma as a second malignant neoplasm share the same prognosis as patients with newly diagnosed disease if they are treated aggressively with surgery and multiagent chemotherapy.^28,29,30 There have been numerous other identified prognostic features for patients with conventional localized high-grade osteosarcoma. These factors include the age of the patient, lactate dehydrogenase level, alkaline phosphatase level, and histologic subtype.^{21,26,31,32,33,34,35,36} 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);^37,38,39 tumor cell ploidy; specific chromosomal gains or losses;⁴⁰ loss of heterozygosity of the RB gene;^41,42 loss of heterozygosity of the p53 locus;⁴³ and increased expression of p-glycoprotein.^44,45,46,47 In a large COSS study, higher chemotherapy dose intensity did not correlate with improved outcome.⁴⁸ Patients with malignant fibrous histiocytoma of bone (MFH) are treated according to osteosarcoma treatment protocols, and the outcome for patients with resectable MFH is similar to the outcome for patients with osteosarcoma.⁴⁹ As with osteosarcoma, patients with a favorable necrosis had a longer survival than those with an inferior necrosis.⁵⁰

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.

² Donati D, Giacomini S, Gozzi E, et al.: Osteosarcoma of the pelvis. Eur J Surg Oncol 30 (3): 332-40, 2004.

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.

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.

⁵ 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.

⁶ 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.

⁷ Duffaud F, Digue L, Baciuchka-Palmaro M, et al.: Osteosarcomas of flat bones in adolescents and adults. Cancer 88 (2): 324-32, 2000.

⁸ McHugh JB, Thomas DG, Herman JM, et al.: Primary versus radiation-associated craniofacial osteosarcoma: Biologic and clinicopathologic comparisons. Cancer 107 (3): 554-62, 2006.

⁹ Link MP, Goorin AM, Horowitz M, et al.: Adjuvant chemotherapy of high-grade osteosarcoma of the extremity. Updated results of the Multi-Institutional Osteosarcoma Study. Clin Orthop (270): 8-14, 1991.

¹⁰ 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.

¹¹ Link MP: The multi-institutional osteosarcoma study: an update. Cancer Treat Res 62: 261-7, 1993.

¹² 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.

¹³ 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.

¹⁴ 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.

¹⁵ 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.

¹⁶ Bacci G, Briccoli A, Ferrari S, et al.: Neoadjuvant chemotherapy for osteosarcoma of the extremities with synchronous lung metastases: treatment with cisplatin, adriamycin and high dose of methotrexate and ifosfamide. Oncol Rep 7 (2): 339-46, 2000 Mar-Apr.

¹⁷ Bacci G, Briccoli A, Ferrari S, et al.: Neoadjuvant chemotherapy for osteosarcoma of the extremity: long-term results of the Rizzoli's 4th protocol. Eur J Cancer 37 (16): 2030-9, 2001.

¹⁸ 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.

¹⁹ 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.

²⁰ Bacci G, Briccoli A, Mercuri M, et al.: Osteosarcoma of the extremities with synchronous lung metastases: long-term results in 44 patients treated with neoadjuvant chemotherapy. J Chemother 10 (1): 69-76, 1998.

²¹ 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.

²² Sajadi KR, Heck RK, Neel MD, et al.: The incidence and prognosis of osteosarcoma skip metastases. Clin Orthop Relat Res (426): 92-6, 2004.

²³ 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.

²⁴ 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.

²⁵ 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.

²⁶ 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.

²⁷ 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.

²⁸ 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.

²⁹ 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.

³⁰ Gorlick R, Anderson P, Andrulis I, et al.: Biology of childhood osteogenic sarcoma and potential targets for therapeutic development: meeting summary. Clin Cancer Res 9 (15): 5442-53, 2003.

³¹ 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.

³² 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.

³³ Wuisman P, Enneking WF: Prognosis for patients who have osteosarcoma with skip metastasis. J Bone Joint Surg Am 72 (1): 60-8, 1990.

³⁴ Bieling P, Rehan N, Winkler P, et al.: Tumor size and prognosis in aggressively treated osteosarcoma. J Clin Oncol 14 (3): 848-58, 1996.

³⁵ 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.

³⁶ Bacci G, Longhi A, Fagioli F, et al.: Adjuvant and neoadjuvant chemotherapy for osteosarcoma of the extremities: 27 year experience at Rizzoli Institute, Italy. Eur J Cancer 41 (18): 2836-45, 2005.

³⁷ 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.

³⁸ 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.

³⁹ 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.

⁴⁰ 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.

⁴¹ 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.

⁴² Goorin A, Baker A, Gieser P, et al.: No evidence for improved event free survival [EFS] with presurgical chemotherapy [PRE] for non-metastatic extremity osteogenic sarcoma [OGS]: preliminary results of randomized Pediatric Oncology Group [POG] trial 8651. [Abstract] Proceedings of the American Society of Clinical Oncology 14: A-1420, 444, 1995.

⁴³ 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.

⁴⁴ Serra M, Maurici D, Scotlandi K, et al.: Relationship between P-glycoprotein expression and p53 status in high-grade osteosarcoma. Int J Oncol 14 (2): 301-7, 1999.

⁴⁵ Hornicek FJ, Gebhardt MC, Wolfe MW, et al.: P-glycoprotein levels predict poor outcome in patients with osteosarcoma. Clin Orthop (373): 11-7, 2000.

⁴⁶ Serra M, Scotlandi K, Reverter-Branchat G, et al.: Value of P-glycoprotein and clinicopathologic factors as the basis for new treatment strategies in high-grade osteosarcoma of the extremities. J Clin Oncol 21 (3): 536-42, 2003.

⁴⁷ 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.

⁴⁸ Eselgrim M, Grunert H, Kühne T, et al.: Dose intensity of chemotherapy for osteosarcoma and outcome in the Cooperative Osteosarcoma Study Group (COSS) trials. Pediatr Blood Cancer 47 (1): 42-50, 2006.

⁴⁹ 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.

⁵⁰ 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.

Cellular Classification

Osteosarcoma is a primary malignant tumor of the appendicular skeleton 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.

Central (Medullary) Tumors

• Conventional central osteosarcoma.
• Telangiectatic osteosarcoma.
• Intraosseous well-differentiated (low-grade) osteosarcoma.
• Small cell osteosarcoma.

Surface (Peripheral) Tumors

• Parosteal (juxtacortical) well-differentiated (low-grade) osteosarcoma.^4,
• Periosteal osteosarcoma: low-grade to intermediate-grade osteosarcoma.
• High-grade surface osteosarcoma.^3,5,

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.⁶ 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.⁴ Periosteal osteosarcoma has an intermediate prognosis ⁷ and treatment is guided by histologic grade. ⁸

Malignant fibrous histiocytoma of bone (MFH) 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.⁹ One study suggests similar event-free survival rates for MFH and osteosarcoma.^10,

Extraosseous osteosarcoma is a malignant mesenchymal neoplasm without direct attachment to the skeletal system. Previously, treatment for extraosseous osteosarcoma followed soft tissue sarcoma guidelines,¹¹ though a retrospective analysis of the German Cooperative Osteosarcoma Study identified a favorable outcome for extraosseous osteosarcoma treated with surgery and conventional osteosarcoma therapy.¹²

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.

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.

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.

⁴ Hoshi M, Matsumoto S, Manabe J, et al.: Oncologic outcome of parosteal osteosarcoma. Int J Clin Oncol 11 (2): 120-6, 2006.

⁵ Okada K, Unni KK, Swee RG, et al.: High grade surface osteosarcoma: a clinicopathologic study of 46 cases. Cancer 85 (5): 1044-54, 1999.

⁶ 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.

⁷ Unni KK, Dahlin DC, Beabout JW: Periosteal osteogenic sarcoma. Cancer 37 (5): 2476-85, 1976.

⁸ Grimer RJ, Bielack S, Flege S, et al.: Periosteal osteosarcoma--a European review of outcome. Eur J Cancer 41 (18): 2806-11, 2005.

⁹ 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.

¹⁰ 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.

¹¹ 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.

¹² 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.

Staging and Site Information

There is no formal staging classification for osteosarcoma. There are essentially 2 categories of patients: those who present without clinically detectable metastatic disease (localized osteosarcoma) and those who present with clinically detectable metastatic disease (metastatic osteosarcoma).

Localized Osteosarcoma

Localized tumors are limited to the bone of origin; local skip metastases may be apparent within the bone and have previously been associated with an inferior prognosis.¹ Analysis of the German Cooperative Osteosarcoma Study (COSS) experience, however, suggests that skip lesions do not confer an inferior prognosis if they are included in 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,

Metastatic Osteosarcoma

Radiologic evidence of metastatic tumor deposits in the lungs, other bones, or other distant sites is found in 10% to 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 tumors in many bones, often with symmetrical metaphyseal involvement. Multifocal osteosarcoma has an extremely grave prognosis.^3,

¹ Wuisman P, Enneking WF: Prognosis for patients who have osteosarcoma with skip metastasis. J Bone Joint Surg Am 72 (1): 60-8, 1990.

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.

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.

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.

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.

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.

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.

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

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.

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.

Localized Osteosarcoma/Malignant Fibrous Histiocytoma of Bone

Complete surgical resection is crucial for patients with localized osteosarcoma; however, at least 80% of patients treated with surgery alone will develop metastatic disease.^1,2 Randomized clinical trials have established that adjuvant chemotherapy is effective in preventing relapse or recurrence in patients with localized resectable primary tumors.^1,3,

A number of single-arm trials evaluated the role of chemotherapy administered both preoperatively and postoperatively. Some of these trials evaluated the necrosis of the primary tumor following chemotherapy and used this information to determine subsequent therapy.^4,5 Current chemotherapy protocols include combinations of the following agents: high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin.^{5,6,7,8,9,10,11,12,13,14,15} Overall, relapse-free survival ranges from 50% to 75% in these trials.^4,13 One randomized trial found no difference in survival between 2 drugs given for a shorter duration and multiagent regimens, though event-free survival (EFS) in both arms was less than 50%.^16,

All patients with osteosarcoma should undergo surgical resection of the primary tumor if possible. The type of surgery required for complete ablation of the primary tumor depends on a number of factors that must be evaluated on an individual basis.¹⁷ 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. While a needle biopsy can often confirm the diagnosis, participation in some clinical trials requires collection of material for biologic studies that can only be obtained via an open biopsy or multiple needle biopsies. Rotationplasty and limb-sparing procedures have been evaluated for both their functional result and their effect on survival.¹⁸ There is no difference in overall survival (OS) between patients initially treated by amputation and those treated with a limb-sparing procedure.¹⁹ One randomized trial noted no difference in disease-free survival (DFS) with preoperative chemotherapy compared with immediate surgery followed by adjuvant chemotherapy.²⁰ Limb-sparing procedures should be planned only when the preoperative staging indicates that it is possible to achieve wide surgical margins. A pathologic fracture noted at diagnosis or during preoperative chemotherapy does not preclude limb-salvage surgery if wide surgical margins can be achieved.²¹ In one series, patients presenting with a pathologic fracture at diagnosis had similar outcomes to those without pathologic fractures at diagnosis.²² 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.¹⁹ In one study, patients undergoing limb-salvage procedures who had poor histologic response and close surgical margins had a high rate of local recurrence.²³ For patients who receive chemotherapy prior to surgery, the degree of tumor necrosis observed postoperatively is highly predictive of DFS, local recurrence, and OS.^7,8,24 Increasing the intensity of preoperative chemotherapy raised the proportion of patients with good histologic response in one study ²⁵ but not in another.²⁶ There is no evidence that increased intensity of preoperative therapy is associated with improved OS.

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. Neither the addition of ifosfamide alone nor L-MTP-PE alone to 3 standard chemotherapy agents improved EFS. The addition of both agents achieved the best EFS in this study, but the difference was not statistically significant when compared with the outcome with the 3 standard chemotherapy agents alone.¹⁵ A joint Scandinavian/Italian study compared standard-dose ifosfamide (9 g/m²/course) with high-dose ifosfamide (15 g/m²/course). All patients received methotrexate, cisplatin, doxorubicin, and ifosfamide. High-dose ifosfamide did not improve EFS but was associated with increased renal and hematologic toxicity.^13,

Patients with primary tumors of the femur have a higher local recurrence rate than do patients with primary tumors of the tibia/fibula. Not surprisingly, patients who undergo amputation have lower local recurrence rates than patients undergoing limb-sparing procedures.²⁴ In general, more than 80% of patients with extremity osteosarcoma can be treated by a limb-sparing operation and do not require amputation.⁴ While limb-sparing tumor 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.²⁷ Patients with osteosarcoma may benefit from radiation therapy if surgical margins are inadequate.^28,29 Information about ongoing clinical trials is available from the NCI Web site.

Standard Treatment Options

Localized, completely resectable high-grade osteosarcoma
• Most patients receive preoperative (neoadjuvant) chemotherapy followed by extirpative surgery (amputation, limb preservation, or rotationplasty) ¹⁸ and postoperative adjuvant chemotherapy. Limb length inequality is a major potential problem for young children. Treatment options include extensible prostheses, amputation, and rotationplasty for these children.
• Preoperative chemotherapy (either systemically or intra-arterially) followed by extirpative surgery (amputation, limb preservation, or rotationplasty).^9,18,30 After surgery, tumor necrosis is used to determine degree of response to the initial chemotherapy. If tumor necrosis exceeds a preset level (90%–95%), the preoperative chemotherapy regimen is continued; however, if necrosis is inferior, some groups have used alternative regimens that have not been examined in randomized studies.^4,31
• Surgical resection of the primary tumor with adequate margins is an essential component of the curative strategy for patients with localized osteosarcoma. 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. Cure of the patient remains the primary objective. If a complicated reconstruction delays or prohibits the resumption of needed systemic chemotherapy, limb preservation may endanger the chance for cure. For some patients, amputation remains the optimal choice for management of the primary tumor.
• For lesions that cannot be removed, some data from retrospective nonrandomized studies suggest that high-dose radiation therapy may improve local control, especially when there is only microscopic or minimal residual disease.^28,29 Clinical studies are now being conducted using a phase II/phase III approach or using intensive combination chemotherapy and high-dose, very well-collimated and localized radiation.

For patients with malignant fibrous histiocytoma of bone (MFH), wide local excision is recommended regardless of tumor grade. Most patients with MFH will need preoperative chemotherapy to achieve a wide local excision.^32,

Treatment Options Under Clinical Evaluation

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 2 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-α-2b.³³
• Standard Histologic Response (10%–100% viable tumor) : Patients will be randomly assigned to receive postoperative chemotherapy with the same drugs as those given preoperatively ± additional courses of ifosfamide/etoposide.

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.

² Hosalkar HS, Dormans JP: Limb sparing surgery for pediatric musculoskeletal tumors. Pediatr Blood Cancer 42 (4): 295-310, 2004.

³ Eilber F, Giuliano A, Eckardt J, et al.: Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 5 (1): 21-6, 1987.

⁴ 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.

⁵ 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.

⁶ 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.

⁷ Davis AM, Bell RS, Goodwin PJ: Prognostic factors in osteosarcoma: a critical review. J Clin Oncol 12 (2): 423-31, 1994.

⁸ 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.

⁹ 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.

¹⁰ Cassano WF, Graham-Pole J, Dickson N: Etoposide, cyclophosphamide, cisplatin, and doxorubicin as neoadjuvant chemotherapy for osteosarcoma. Cancer 68 (9): 1899-902, 1991.

¹¹ 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.

¹² 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.

¹³ 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.

¹⁴ 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.

¹⁵ 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.

¹⁶ Souhami RL, Craft AW, Van der Eijken JW, et al.: Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet 350 (9082): 911-7, 1997.

¹⁷ Grimer RJ: Surgical options for children with osteosarcoma. Lancet Oncol 6 (2): 85-92, 2005.

¹⁸ Hillmann A, Hoffmann C, Gosheger G, et al.: Malignant tumor of the distal part of the femur or the proximal part of the tibia: endoprosthetic replacement or rotationplasty. Functional outcome and quality-of-life measurements. J Bone Joint Surg Am 81 (4): 462-8, 1999.

¹⁹ 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.

²⁰ Goorin AM, Schwartzentruber DJ, Devidas M, et al.: Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol 21 (8): 1574-80, 2003.

²¹ 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.

²² 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.

²³ Grimer RJ, Taminiau AM, Cannon SR, et al.: Surgical outcomes in osteosarcoma. J Bone Joint Surg Br 84 (3): 395-400, 2002.

²⁴ 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.

²⁵ Meyers PA, Gorlick R, Heller G, et al.: Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the Memorial Sloan-Kettering (T12) protocol. J Clin Oncol 16 (7): 2452-8, 1998.

²⁶ Bacci G, Forni C, Ferrari S, et al.: Neoadjuvant chemotherapy for osteosarcoma of the extremity: intensification of preoperative treatment does not increase the rate of good histologic response to the primary tumor or improve the final outcome. J Pediatr Hematol Oncol 25 (11): 845-53, 2003.

²⁷ Nagarajan R, Neglia JP, Clohisy DR, et al.: Limb salvage and amputation in survivors of pediatric lower-extremity bone tumors: what are the long-term implications? J Clin Oncol 20 (22): 4493-501, 2002.

²⁸ 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.

²⁹ 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.

³⁰ Wilkins RM, Cullen JW, Camozzi AB, et al.: Improved survival in primary nonmetastatic pediatric osteosarcoma of the extremity. Clin Orthop Relat Res 438: 128-36, 2005.

³¹ 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.

³² 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.

³³ 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.

Metastatic Disease at Diagnosis

Osteosarcoma

Osteosarcoma at diagnosis can present with clinically detectable metastases. The prognosis for osteosarcoma metastatic at diagnosis varies according to the site(s) and number of metastases. As many as 20% of patients will have radiographically detectable metastases at diagnosis, with the lung being the most common site of metastasis.¹ For patients who present with primary osteosarcoma and metastases limited to the lungs, multiple metastatic nodules confer a worse prognosis than one or two nodules, and bilateral lung involvement is worse than unilateral. The second most common site of metastasis is another bone that is distant from the primary tumor. Bony metastasis is associated with a very poor prognosis. Previously, noncontiguous involvement in the same bone as the primary tumor (a skip lesion) was felt to confer a prognosis similar to that of distant bony metastasis. Analysis of the German Cooperative Osteosarcoma Study Group experience suggests that skip lesions do not confer an inferior prognosis if they are included in planned surgical resction and in the same bone.² Patients with skip lesions who have transarticular lesions and/or whose tumors respond poorly to neoadjuvant chemotherapy have a significantly lower survival probability than other patients.² 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, but systemic chemotherapy and aggressive surgical resection may achieve significant prolongation of life.^3,

The most frequently used approach is preoperative chemotherapy followed by surgical ablation of the primary tumor and resection of all overt metastatic disease. This is followed by postoperative combination chemotherapy. The chemotherapeutic agents used include high-dose methotrexate, doxorubicin, cisplatin, high-dose ifosfamide, etoposide, and in some reports, carboplatin or cyclophosphamide.

An alternative approach is surgical ablation of the primary tumor and metastases, where possible, followed by combination chemotherapy. This approach may be appropriate in patients with intractable pain, pathologic fracture, or uncontrolled infection of the tumor where initiation of chemotherapy could create risk of sepsis. The chemotherapeutic regimens utilized in the treatment of metastatic osteosarcoma include high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin. For patients with lung metastases as the only site of metastatic disease, a cisplatin (100 mg/m²/day)–containing regimen produced a better event-free survival than did a carboplatin (560 mg/m²/day)–containing regimen.^4,

Treatment options under clinical evaluation

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 2 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-α-2b.^5,
• Standard Histologic Response (10%–100% viable tumor): Patients will be randomly assigned to receive postoperative chemotherapy with the same drugs as those given preoperatively ± additional courses of ifosfamide/etoposide.

Information about ongoing clinical trials is available from the NCI Web site.

Malignant Fibrous Histiocytoma of Bone

The treatment for malignant fibrous histiocytoma of bone (MFH) 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.^6,

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.

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.

³ 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.

⁴ Daw NC, Billups CA, Rodriguez-Galindo C, et al.: Metastatic osteosarcoma. Cancer 106 (2): 403-12, 2006.

⁵ 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.

⁶ 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.

Recurrent Osteosarcoma

Most recurrences of osteosarcoma develop within 2 to 3 years after treatment completion. Late recurrences are rare, occuring in 0.6% to 3.7% of patients.^1,2,3 Recurrence of osteosarcoma is most often in the lung. Patients with recurrent osteosarcoma should be assessed for surgical resectability, as they may sometimes be cured with aggressive surgical resection with or without chemotherapy.^4,5,6,7,8,9 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 20% following complete resection of metastases at other sites.^8,9,10,11 Repeated resections of pulmonary recurrences can lead to extended disease control and possibly cure for some patients.^11,12 Survival for patients with unresectable metastatic disease is less than 5%.^8,13 Factors that suggest a better outcome include fewer pulmonary nodules, unilateral pulmonary metastases,¹⁴ or longer intervals between primary tumor resection and metastases.^8,10,15 Resection of metastatic disease followed by observation alone results in low overall and disease-free survival. In several small series, patients with metachronous bone recurrence have an approximate 40% salvage rate; late metachronous recurrence more than 24 months from initial diagnosis is more favorable than early metachronous recurrence.^16,17,18 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.¹⁴ The postrelapse outcome of patients who have a local recurrence is worse than that for patients who relapse with metastases alone.^19,20,21

Two retrospective, single-institution series reported 10% to 40% survival following local recurrence without associated systemic metastasis.^22,23,24 The survival for patients with local recurrence and either prior or concurrent systemic metastases is poor.²³ The incidence of local relapse was higher in patients who had a poor pathologic response to chemotherapy in the primary tumor.^19,

The role of systemic chemotherapy 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.^25,26,27 Cyclophosphamide and etoposide have activity in recurrent osteosarcoma.²⁸ 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.^29,30,31,32 Clinical trials (phases I and II) are appropriate for patients with unresectable metastatic disease and should be considered.

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.

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.

³ Ferrari S, Briccoli A, Mercuri M, et al.: Late relapse in osteosarcoma. J Pediatr Hematol Oncol 28 (7): 418-22, 2006.

⁴ 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.

⁵ Meyer WH, Schell MJ, Kumar AP, et al.: Thoracotomy for pulmonary metastatic osteosarcoma. An analysis of prognostic indicators of survival. Cancer 59 (2): 374-9, 1987.

⁶ 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.

⁷ 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.

⁸ 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.

⁹ 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.

¹⁰ 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.

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.

¹² Briccoli A, Rocca M, Salone M, et al.: Resection of recurrent pulmonary metastases in patients with osteosarcoma. Cancer 104 (8): 1721-5, 2005.

¹³ 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.

¹⁴ 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.

¹⁵ 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.

¹⁶ 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.

¹⁷ Jaffe N, Pearson P, Yasko AW, et al.: Single and multiple metachronous osteosarcoma tumors after therapy. Cancer 98 (11): 2457-66, 2003.

¹⁸ Rodriguez EK, Hornicek FJ, Gebhardt MC, et al.: Metachronous osteosarcoma: a report of five cases. Clin Orthop (411): 227-35, 2003.

¹⁹ 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.

²⁰ 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.

²¹ 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.

²² Grimer RJ, Sommerville S, Warnock D, et al.: Management and outcome after local recurrence of osteosarcoma. Eur J Cancer 41 (4): 578-83, 2005.

²³ 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.

²⁴ 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.

²⁵ 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.

²⁶ 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.

²⁷ 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.

²⁸ 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.

²⁹ 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.

³⁰ 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.

³¹ 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.

³² 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.

Changes to This Summary (04/27/2007)

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.

Prognostic Factors

Added text on radiation-associated craniofacial osteosarcomas (cited McHugh et al. as reference 8).

Added text on results of a COSS study (cited Eselgrim et al. as reference 48).

Cellular Classification

Added Kaste et al. as reference 3.

Added Hoshi et al. as reference 4.

Metastatic Disease at Diagnosis

Updated text on sites of metastases (cited Kager et al. as reference 2).

Recurrent Osteosarcoma

Added Hauben et al. as reference 2, Ferrari et al. as reference 3, and Harting et al. as reference 11.

Updated text on survival following local recurrence with or without systematic metastases (cited Bacci et al. as reference 23 and Nathan et al. as reference 24).

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