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

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ¹ for more information.)

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

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

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

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

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

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

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

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

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

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



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

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with localized osteosarcoma ² and localized childhood malignant fibrous histiocytoma of bone ³. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁴.

References

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2. Eilber F, Giuliano A, Eckardt J, et al.: Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 5 (1): 21-6, 1987.  [PUBMED Abstract]
   
   
3. Picci P, Bacci G, Ferrari S, et al.: Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors. Ann Oncol 8 (11): 1107-15, 1997.  [PUBMED Abstract]
   
   
4. Bramwell VH, Steward WP, Nooij M, et al.: Neoadjuvant chemotherapy with doxorubicin and cisplatin in malignant fibrous histiocytoma of bone: A European Osteosarcoma Intergroup study. J Clin Oncol 17 (10): 3260-9, 1999.  [PUBMED Abstract]
   
   
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6. Grimer RJ: Surgical options for children with osteosarcoma. Lancet Oncol 6 (2): 85-92, 2005.  [PUBMED Abstract]
   
   
7. Bacci G, Ferrari S, Bertoni F, et al.: Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol 18 (24): 4016-27, 2000.  [PUBMED Abstract]
   
   
8. Scully SP, Ghert MA, Zurakowski D, et al.: Pathologic fracture in osteosarcoma : prognostic importance and treatment implications. J Bone Joint Surg Am 84-A (1): 49-57, 2002.  [PUBMED Abstract]
   
   
9. Bacci G, Ferrari S, Longhi A, et al.: Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: local and systemic control by amputation or limb salvage after preoperative chemotherapy. Acta Orthop Scand 74 (4): 449-54, 2003.  [PUBMED Abstract]
   
   
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16. Meyer WH, Pratt CB, Poquette CA, et al.: Carboplatin/ifosfamide window therapy for osteosarcoma: results of the St Jude Children's Research Hospital OS-91 trial. J Clin Oncol 19 (1): 171-82, 2001.  [PUBMED Abstract]
    
    
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18. Bacci G, Picci P, Avella M, et al.: Effect of intra-arterial versus intravenous cisplatin in addition to systemic adriamycin and high-dose methotrexate on histologic tumor response of osteosarcoma of the extremities. J Chemother 4 (3): 189-95, 1992.  [PUBMED Abstract]
    
    
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20. Voûte PA, Souhami RL, Nooij M, et al.: A phase II study of cisplatin, ifosfamide and doxorubicin in operable primary, axial skeletal and metastatic osteosarcoma. European Osteosarcoma Intergroup (EOI). Ann Oncol 10 (10): 1211-8, 1999.  [PUBMED Abstract]
    
    
21. Ferguson WS, Harris MB, Goorin AM, et al.: Presurgical window of carboplatin and surgery and multidrug chemotherapy for the treatment of newly diagnosed metastatic or unresectable osteosarcoma: Pediatric Oncology Group Trial. J Pediatr Hematol Oncol 23 (6): 340-8, 2001 Aug-Sep.  [PUBMED Abstract]
    
    
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Glossary Terms

Randomized, controlled, nonblinded clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.