Article: Osteosarcoma/Bone Fibrous Histiocytoma Treatment

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 Cancer.gov 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 Childhood Cancer Therapies 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 the tumors in childhood. In children and adolescents, 50% of these tumors arise from the bones around the knee. 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 only recapitulated the historical experience before 1970; more than half of these patients developed metastases within 6 months of diagnosis, and overall, almost 90% [2] developed recurrent disease within 2 years of diagnosis.[3] Overall survival for patients treated with surgery alone was statistically inferior.[4] The natural history of osteosarcoma has not changed over time, and fewer than 30% of patients with localized resectable primary tumors treated with surgery only can be expected to survive free of relapse.[3,5,6]

Patients with localized disease have a much better prognosis than those with overt metastatic disease. The site of the primary tumor is a significant prognostic factor in localized disease. Axial skeleton primary tumors have the greatest risk of progression and death.[7] Resectability of the tumor is the most important prognostic feature because this tumor is very resistant to radiation therapy. For patients with osteosarcoma of craniofacial bones, complete resection of the primary tumor with negative margins is essential for cure.[8,9] Despite a relatively high rate of poor histologic response to neoadjuvant chemotherapy, very few patients develop systemic metastases with craniofacial primaries.[10-13] Pelvic osteosarcomas make up 7% to 9% of all osteosarcomas; however, they have an overall survival rate of 20% to 47%.[7] 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.[14,15] There have been numerous other identified prognostic features for patients with conventional localized high-grade osteosarcoma. These include age of patient, tumor volume, skip lesions, lactate dehydrogenase level, alkaline phosphatase level, and histologic subtype.[16-22] 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 [23,24] (however, there are conflicting data concerning the prognostic significance of this human epidermal growth factor),[25] tumor cell ploidy, and specific chromosome gains or losses,[26,27] loss of heterozygosity of the RB gene,[28,29] loss of heterozygosity of the p53 locus,[30] and increased expression of p-glycoprotein.[31-34] The only feature that consistently predicts outcome is the degree of histologic necrosis following induction chemotherapy. Patients with greater than 95% necrosis in the primary tumor after induction chemotherapy have a better prognosis than those with lesser amounts of necrosis.[18,35] Imaging modalities such as dynamic magnetic resonance imaging may offer a noninvasive method to assess necrosis.[36]

Up to 20% of patients will have radiographically detectable metastases at diagnosis, with the lung being the most common site.[37] The prognosis for patients with metastatic disease appears to be determined largely by the site(s), the number of metastases, as well as the surgical resectability of the metastatic disease.[6,37-39] Patients who have complete surgical ablation of the primary and metastatic tumor (when confined to the lung) following chemotherapy may attain long-term survival, although overall event-free survival remains about 20% to 30% for patients with metastatic disease at diagnosis.[6,35,37,40] Prognosis appears more favorable for patients with unilateral rather than bilateral pulmonary metastases, and for patients with fewer nodules rather than many nodules.[6,38] The degree of necrosis in the primary tumor after induction chemotherapy remains prognostic in metastatic osteosarcoma.[20] Patients with multifocal osteosarcoma (more than 1 bone lesion at diagnosis) have a poor prognosis.[41]

Malignant fibrous histiocytoma of bone (MFH) is generally treated according to osteosarcoma protocols, and the outcome for patients with resectable MFH receiving cisplatin and doxorubicin is similar to the outcome for patients with osteosarcoma.[42] As with osteosarcoma, patients with a good histological response had a longer survival than those with a poor response.[43]

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. 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. [PUBMED Abstract]

  3. 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]

  4. Link MP: The multi-institutional osteosarcoma study: an update. Cancer Treat Res 62: 261-7, 1993. [PUBMED Abstract]

  5. 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]

  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]

  7. 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]

  8. 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]

  9. 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]

  10. 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]

  11. Kawai A, Huvos AG, Meyers PA, et al.: Osteosarcoma of the pelvis. Oncologic results of 40 patients. Clin Orthop (348): 196-207, 1998. [PUBMED Abstract]

  12. 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]

  13. 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]

  14. 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]

  15. 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]

  16. 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]

  17. Bacci G, Longhi A, Ferrari S, et al.: Prognostic significance of serum alkaline phosphatase in osteosarcoma of the extremity treated with neoadjuvant chemotherapy: recent experience at Rizzoli Institute. Oncol Rep 9 (1): 171-5, 2002 Jan-Feb. [PUBMED Abstract]

  18. 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]

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

  20. 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]

  21. 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]

  22. 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]

  23. 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]

  24. 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]

  25. 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]

  26. Kusuzaki K, Takeshita H, Murata H, et al.: Prognostic value of DNA ploidy response to chemotherapy in human osteosarcomas. Cancer Lett 141 (1-2): 131-8, 1999. [PUBMED Abstract]

  27. 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]

  28. 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]

  29. 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.Â

  30. 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]

  31. 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. [PUBMED Abstract]

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

  33. 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. [PUBMED Abstract]

  34. 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]

  35. 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]

  36. 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]

  37. 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]

  38. 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. [PUBMED Abstract]

  39. 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. [PUBMED Abstract]

  40. 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. [PUBMED Abstract]

  41. 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]

  42. 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]

  43. 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]

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] 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.


  • Periosteal osteosarcoma: low-grade to intermediate-grade osteosarcoma.


  • High-grade surface osteosarcoma.[3]


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] 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. Periosteal osteosarcoma has an intermediate prognosis [5] and treatment is guided by histologic grade. Fibroblastic and hemorrhagic subtypes may be associated with a better prognosis.[6]

Malignant fibrous histiocytoma of bone (MFH) is generally treated according to osteosarcoma 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.[7] One study suggests that event-free survival for MFH and osteosarcoma is similar.[8]

Extraosseous osteosarcoma is a malignant mesenchymal neoplasm without direct attachment to the skeletal system. Treatment for extraosseous osteosarcoma should follow soft tissue sarcoma guidelines rather than guidelines for osteosarcoma of bone.[9] Refer to the PDQ Childhood Soft Tissue Sarcoma Treatment summary for more information about the treatment of soft tissue sarcoma.

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. 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]

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

  6. 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]

  7. 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]

  8. 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]

  9. 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]

Stage Information

Localized Osteosarcoma

Localized tumors are limited to the bone of origin, although local skip-metastases may be apparent within the bone, indicating a worse prognosis.[1] Approximately one half of the tumors arise in the femur, with 80% of these arising adjacent to the knee joint in young patients. Other primary sites in descending order of frequency are tibia, humerus, pelvis, jaw, fibula, and ribs.[2] Osteosarcoma of the head and neck is more likely to be low-grade than osteosarcoma of the appendicular skeleton [3] and is more likely to arise in older patients. The prognosis for osteosarcoma of the head and neck with surgery alone is better than surgery alone for appendicular lesions. While small series have not detected a benefit from adjuvant chemotherapy for osteosarcoma of the head and neck, one meta-analysis concluded that systemic chemotherapy improves the prognosis for osteosarcoma of the head and neck.[3,4] Another large meta-analysis could not detect a benefit from chemotherapy for patients with osteosarcoma of the head and neck, but suggested that incorporation of chemotherapy into treatment of patients with high-grade tumors may improve survival.[5]

Metastatic Osteosarcoma

Radiologic evidence of metastatic tumor deposits in lung, other bones, or other distant sites is found in 10% to 20% of patients at diagnosis; 85% to 90% of metastatic disease is in the lungs. The second most common site of metastasis is another bone.[6] Presentations with multiple bone metastases carry an extremely grave prognosis.[2]

References

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

  2. 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]

  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. 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]

  5. 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]

  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]

Treatment Option Overview

Randomized clinical trials have established that both neoadjuvant and adjuvant chemotherapy are effective in preventing relapse in patients with nonmetastatic occult 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 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.

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]

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] Randomized clinical trials have established that adjuvant chemotherapy is effective in preventing relapse or recurrence in patients with localized resectable primary tumors.[1,2]

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.[3,4] Current chemotherapy protocols include combinations of the following agents: high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin.[4-12] Overall, relapse-free survival ranges between 50% to 75% in these trials.[3,12] One randomized trial found no difference in survival between 2 drugs given for a shorter duration and multiagent regimens, although event-free survival in both arms was less than 50%.[13]

Almost all patients with osteosarcoma should undergo surgical resection of the primary tumor. 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. 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 functional result and effect on survival.[14] There is no difference in overall survival between patients treated by amputation and those treated with a limb-sparing procedure.[15] One randomized trial has suggested that there is no difference in disease-free survival between preoperative chemotherapy and immediate surgery followed by adjuvant chemotherapy.[16] 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.[17] In one series, patients presenting with a pathologic fracture at diagnosis had similar outcomes to those without pathologic fractures at diagnosis.[18] If the pathologic examination of the surgical specimen shows inadequate margins, an immediate amputation should be considered, especially if the histologic response to preoperative chemotherapy was poor.[15] In 1 study, patients undergoing limb-salvage procedures who had poor histologic response and close surgical margins had a high rate of local recurrence.[19] For patients who receive chemotherapy prior to surgery, the degree of tumor necrosis observed postoperatively is highly predictive of disease-free survival, local recurrence, and overall survival.[6,7,20] Increasing intensity of preoperative chemotherapy increased the proportion of patients with good histologic response in one study,[21] but not in another.[22] There is no evidence that increased intensity of preoperative therapy is associated with an increase in overall survival. Patients with primary tumors of the femur have the highest local recurrence rate as compared to 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.[20] In general, more than 80% of patients with extremity osteosarcomas can be treated by a limb-sparing operation and do not require amputation.[3] 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 in regard to patient quality of life.[23] Patients with pelvic osteosarcoma may benefit from radiotherapy if surgical margins are inadequate.[24] Information about ongoing clinical trials is available from the NCI Cancer.gov Web site.

Treatment options

Nonmetastatic, completely-resectable high-grade osteosarcoma

  • Most patients receive preoperative (neoadjuvant) chemotherapy followed by extirpative surgery (amputation, limb salvage, or rotationplasty) [14] and postoperative adjuvant chemotherapy. In some trials, the type of postoperative adjuvant chemotherapy is determined by the degree of necrosis observed in the primary tumor.


  • Preoperative chemotherapy (either systemically or intra-arterially) followed by extirpative surgery (amputation, limb salvage, or rotationplasty).[8,14] 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; if necrosis is inferior, an alternative regimen is used.[3,25] This approach has not been examined in a randomized study.


For lesions that cannot be removed, clinical studies are now being conducted using a phase II/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.[26]

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. 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]

  4. 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]

  5. 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]

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

  7. 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]

  8. 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]

  9. 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]

  10. 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]

  11. 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]

  12. Bacci G, Ferrari S, Longhi A, et al.: High dose ifosfamide in combination with high dose methotrexate, adriamycin and cisplatin in the neoadjuvant treatment of extremity osteosarcoma: preliminary results of an Italian Sarcoma Group/Scandinavian Sarcoma Group pilot study. J Chemother 14 (2): 198-206, 2002. [PUBMED Abstract]

  13. 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. [PUBMED Abstract]

  14. 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. [PUBMED Abstract]

  15. 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]

  16. 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. [PUBMED Abstract]

  17. 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]

  18. 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]

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

  20. Weeden S, Grimer RJ, Cannon SR, et al.: The effect of local recurrence on survival in resected osteosarcoma. Eur J Cancer 37 (1): 39-46, 2001. [PUBMED Abstract]

  21. 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. [PUBMED Abstract]

  22. 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. [PUBMED Abstract]

  23. 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. [PUBMED Abstract]

  24. 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]

  25. 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]

  26. 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]

Metastatic Disease

Osteosarcoma

The progression-free survival rate for patients with metastatic osteosarcoma is approximately 20%.[1-4] Patients with pulmonary metastatic disease only may have a better survival rate (approximately 40%).[2,3] Prognosis for these patients appears to be more favorable with unilateral rather than bilateral pulmonary metastases, and for patients with fewer nodules and lobes involved. [3,5,6] 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.[7] Multifocal osteosarcoma classically presents with symmetrical, metaphyseal lesions, and it may be difficult to decide which is the primary lesion. Patients with a more conventional presentation of a large primary lesion may have 1 or more bone metastases in the same bone (“skip lesions”) or in distant bones. Patients with bony metastases have a poor prognosis.[7] Aggressive management, including surgical removal of primary and all metastatic disease at the time of diagnosis or after intensive multiagent regimens, is necessary. All patients should receive intensive multiagent chemotherapy whether or not the primary and metastatic lesions are surgically resectable.[4] Information about ongoing clinical trials is available from the NCI Cancer.gov Web site.

Treatment options that are accepted approaches include the following:

  • Preoperative chemotherapy followed by surgical ablation of the primary tumor and resection of metastatic disease. This is followed by postoperative combination chemotherapy. The chemotherapeutic regimens utilized include high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, high-dose ifosfamide (17.5 g/m2), etoposide, and carboplatin.[8]


  • Surgical ablation of the primary tumor and metastases, where possible, followed by combination chemotherapy. The chemotherapeutic regimens utilized in the treatment of metastatic osteosarcoma include high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin.


Malignant Fibrous Histiocytoma of Bone

Patients with unresectable or metastatic malignant fibrous histiocytoma of bone have a very poor outcome.[9]

References

  1. 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]

  2. Bacci G, Mercuri M, Briccoli A, et al.: Osteogenic sarcoma of the extremity with detectable lung metastases at presentation. Results of treatment of 23 patients with chemotherapy followed by simultaneous resection of primary and metastatic lesions. Cancer 79 (2): 245-54, 1997. [PUBMED Abstract]

  3. 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]

  4. Bacci G, Briccoli A, Rocca M, et al.: Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol 14 (7): 1126-34, 2003. [PUBMED Abstract]

  5. 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. [PUBMED Abstract]

  6. 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]

  7. 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]

  8. 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]

  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. [PUBMED Abstract]

Recurrent Osteosarcoma

Recurrence of osteosarcoma is most common 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.[1-5] 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.[5] Survival for patients with unresectable metastatic disease is less than 5%.[5,6] Factors that suggest a better outcome include fewer pulmonary nodules, unilateral pulmonary metastases, or longer intervals between primary tumor resection and metastases.[5,7] In a series of 59 patients who relapsed after multiagent preoperative chemotherapy, surgery, and postoperative chemotherapy, 36 (approximately 60%) had isolated lung metastases, 7 (approximately 10%) had lung/other site, 8 (approximately 15%) had isolated bone metastases and 4 had other combinations. Four patients had local recurrence. The 4-year disease-free survival (DFS) and overall survival (OS) were 6% and 23%, respectively. Factors associated with improved DFS and OS included unilateral pulmonary recurrence, solitary pulmonary nodule >24 months from initial diagnosis, and achieving a second complete remission.[8,9] In a small series, patients with metachronous bone recurrence have an approximate 40% salvage rate; late metachronous recurrence >24 months from initial diagnosis is more favorable than early metachronous recurrence.[10-12] The postrelapse outcome of patients who have a local recurrence is worse than that for patients who relapse with metastases alone.[13,14] The incidence of local relapse was higher in those patients who had a poor pathologic response of the primary to chemotherapy in the primary tumor.[13] The selection of further treatment depends on many factors, including the site of recurrence, the patient's previous primary treatment, and individual patient considerations. Ifosfamide with mesna uroprotection, alone or in combination with etoposide, has shown activity in up to one third of patients with recurrent osteosarcoma who have not previously received this drug.[15-17] Cyclophosphamide and etoposide have activity in recurrent osteosarcoma.[18] Peripheral blood stem cell transplant utilizing high-dose chemotherapy does not appear to improve outcome.[19,20] Clinical trials (phases I and II) are appropriate for patients with unresectable metastatic disease and should be considered. High-dose samarium-153-EDTMP coupled with peripheral blood stem cell support may provide significant pain palliation in patients with bone metastases.[21,22]

References

  1. 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]

  2. 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. [PUBMED Abstract]

  3. 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]

  4. 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]

  5. Ferrari S, Briccoli A, Mercuri M, et al.: Postrelapse survival in osteosarcoma of the extremities: prognostic factors for long-term survival. J Clin Oncol 21 (4): 710-5, 2003. [PUBMED Abstract]

  6. 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]

  7. 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]

  8. Hawkins DS, Arndt CA: Pattern of disease recurrence and prognostic factors in patients with osteosarcoma treated with contemporary chemotherapy. Cancer 98 (11): 2447-56, 2003. [PUBMED Abstract]

  9. Duffaud F, Digue L, Mercier C, et al.: Recurrences following primary osteosarcoma in adolescents and adults previously treated with chemotherapy. Eur J Cancer 39 (14): 2050-7, 2003. [PUBMED Abstract]

  10. 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]

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

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

  13. Weeden S, Grimer RJ, Cannon SR, et al.: The effect of local recurrence on survival in resected osteosarcoma. Eur J Cancer 37 (1): 39-46, 2001. [PUBMED Abstract]

  14. 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]

  15. 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]

  16. 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]

  17. 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]

  18. 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]

  19. 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]

  20. 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]

  21. 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]

  22. 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]

Changes to This Summary 08/18/2004

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.

Localized Osteosarcoma/Malignant Fibrous Histiocytoma of Bone

Revised text to state that patients with pulmonary metastatic disease only may have a better survival rate (approximately 40%).

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Source: National Cancer Institute
Cache Date: December 10, 2004