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

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Localized Osteosarcoma and MFH of Bone

Biopsy
Surgical Removal of Primary Tumor
Chemotherapy
Osteosarcoma of the Head and Neck
Current Clinical Trials

Patients with localized osteosarcoma undergoing surgery and chemotherapy have a 5-year overall survival (OS) of 62% to 65%.[1] Complete surgical resection is crucial for patients with localized osteosarcoma; however, at least 80% of patients treated with surgery alone will develop metastatic disease.[2] Randomized clinical trials have established that adjuvant chemotherapy is effective in preventing relapse or recurrence in patients with localized resectable primary tumors.[2]; [3][Level of evidence: 1iiA]

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.[4] As with osteosarcoma, patients with a favorable necrosis (≥90% necrosis) had a longer survival than those with an inferior necrosis (<90% necrosis).[5] MFH of bone is seen more commonly in older adults. Many patients with MFH will need preoperative chemotherapy to achieve a wide local excision.[6]

Biopsy

The diagnosis of osteosarcoma can be made by needle biopsy, core needle biopsy, or open surgical biopsy. It is preferable that the biopsy be done by a surgeon skilled in the techniques of limb sparing (removal of the malignant bone tumor without amputation and replacement of bones or joints with allografts or prosthetic devices). In these cases, the original biopsy incision placement is crucial. Inappropriate alignment of the biopsy or inadvertent contamination of soft tissues can render subsequent limb-preserving reconstructive surgery impossible.

Surgical Removal of Primary Tumor

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.[7]

In general, more than 80% of patients with extremity osteosarcoma can be treated by a limb-sparing procedure and do not require amputation.[8] Limb-sparing procedures are planned only when the preoperative staging indicates that it would be possible to achieve wide surgical margins. In one study, patients undergoing limb-salvage procedures who had poor histologic response and close surgical margins had a high rate of local recurrence.[9] 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. Retrospective analyses have shown that delay (≥ 21 days) in resumption of chemotherapy after definitive surgery is associated with increased risk of tumor recurrence and death.[10][Level of evidence: 1iiA]

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.[11] In two series, patients presenting with a pathologic fracture at diagnosis had similar outcomes to patients without pathologic fractures at diagnosis, while in a third series, pathologic fracture at diagnosis was associated with a worse overall outcome.[12,13]; [14][Level of evidence: 3iiiA] If the pathologic examination of the surgical specimen shows inadequate margins, an immediate amputation should be considered, especially if the histologic necrosis after preoperative chemotherapy was poor.[15]

The German Cooperative Osteosarcoma Study performed a retrospective analysis of 1,802 patients with localized and metastatic osteosarcoma who underwent surgical resection of all clinically detectable disease.[16][Level of evidence: 3iiA] Local recurrence (n = 76) was associated with a high risk of death from osteosarcoma. Factors associated with an increased risk of local recurrence included nonparticipation in a clinical trial, pelvic primary site, limb-preserving surgery, soft tissue infiltration beyond the periosteum, poor pathologic response to initial chemotherapy, failure to complete planned chemotherapy, and performance of the biopsy at an institution different from the institution performing definitive surgery.

Not surprisingly, patients who undergo amputation have lower local recurrence rates than do patients who undergo limb-salvage procedures. There is no difference in OS between patients initially treated with amputation and those treated with a limb-sparing procedure. Patients with tumors of the femur have a higher local recurrence rate than do 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. While limb-sparing resection is the current practice for local control at most pediatric institutions, there are few data to indicate that 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 (RT) may improve the local control rate.[17,18]; [19][Level of evidence: 3iiA] While it is accepted that the standard approach is primary surgical resection, a retrospective analysis of a small group of highly selective patients reported long-term event-free survival with external-beam RT for local control in some patients.[20][Level of evidence: 3iiiA] RT should be considered in patients with osteosarcoma of the head and neck who have positive or uncertain resection margins.[21][Level of evidence: 3iiA]

Chemotherapy

Almost all patients receive intravenous preoperative chemotherapy as initial treatment. However, a specific standard chemotherapy regimen has not been determined. Current chemotherapy protocols include combinations of the following agents: high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin.[22-30] A meta-analysis of protocols for the treatment of osteosarcoma concluded that regimens containing three active chemotherapy agents were superior to regimens containing two active agents.[31] The same meta-analysis concluded that regimens with four active agents were not superior to regimens with three active agents. The meta-analysis suggested that three-drug regimens that did not include high-dose methotrexate were inferior to three-drug regimens that did include high-dose methotrexate.

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 (MSKCC) that suggested that adding cisplatin to postoperative chemotherapy improved the outcome for patients with less than 90% tumor necrosis. With longer follow-up, 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.[23,32]

The Children's Oncology Group 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 L-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).[33][Level of evidence: 1iiA] There has been speculation regarding the potential contribution of postrelapse treatment, although there were no differences in the postrelapse surgical approaches in the relapsed patients. The appropriate role of L-MTP-PE in the treatment of osteosarcoma remains under discussion.

The degree of necrosis observed in the primary tumor after an initial period of chemotherapy correlates with subsequent EFS and OS. An international consortium (European and American Osteosarcoma Study Group) was formed to conduct a large prospective randomized trial. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate. Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon. The addition of interferon did not improve the probability of EFS.[34] Patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to recieve the same chemotherapy with the addition of high-dose ifosfamide and etoposide. The results of the randomization for these patients is not yet available.

The Italian Sarcoma Group and the Scandinavian Sarcoma Group performed a clinical trial in patients with osteosarcoma who presented with clinically detectable metastatic disease.[35] Consolidation with high-dose etoposide and carboplatin followed by autologous stem cell reconstitution did not appear to improve outcome and the investigators do not recommend this strategy for the treatment of osteosarcoma.

Osteosarcoma of the Head and Neck

Osteosarcoma of the head and neck occurs in an older population compared with osteosarcoma of the extremities.[21,36-39] In the pediatric age group, osteosarcomas of the head and neck are more likely to be low or intermediate grade than are tumors of the extremities.[40,41] All reported series stress the need for complete surgical resection.[21,36-41][Level of evidence: 3iiiA] Osteosarcoma of the head and neck has a higher risk for local recurrence and a lower risk for distant metastasis than osteosarcoma of the extremities.[36,38,39,42] The probability for cure with surgery alone is higher for osteosarcoma of the head and neck than it is for extremity osteosarcoma. Primary sites in the mandible and maxilla are associated with a better prognosis than are other primary sites in the head and neck.[37,38,42] When surgical margins are positive, there is a trend for improved survival with adjuvant radiation therapy.[21,38][Level of evidence: 3iiiA] There are no randomized trials to assess the benefit of chemotherapy in osteosarcoma of the head and neck, but several series suggest a benefit.[36,43] Chemotherapy should be considered for younger patients with high-grade osteosarcoma of the head and neck.[40,41]

Current Clinical Trials

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

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

References
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