Osteosarcoma
        Treatment options under clinical evaluation
Malignant Fibrous Histiocytoma of Bone
Current Clinical Trials

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 with metastatic disease at initial presentation, roughly 20% will remain continuously free of disease and, roughly 30% will survive 5 years from diagnosis.[2] 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.[2] The second most common site of metastasis is another bone that is distant from the primary tumor. Patients with metastasis to other bones distant from the primary tumor experience roughly 10% event-free survival (EFS) and overall survival.[2] In the Italian experience, of the 42 of 1,154 patients who over 16 years presented with primary extremity tumors and synchronous metastasis to other bones, only three patients remained continuously disease-free 5 years later.[3] 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.[4] 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.[4]

Multifocal osteosarcoma is different from osteosarcoma which presents with a clearly delineated primary lesion and limited bone metastasis. Multifocal osteosarcoma classically presents with symmetrical, metaphyseal lesions, and it may be difficult to decide which is the primary lesion. Patients with multifocal bone disease at presentation have an extremely poor prognosis. No patient with synchronous multifocal osteosarcoma has ever been reported to be cured, but systemic chemotherapy and aggressive surgical resection may achieve significant prolongation of life.[5,6]

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. High-dose ifosfamide (17.5 grams per course) in combination with etoposide produced a complete (10%) or partial (49%) response in patients with newly diagnosed metastatic osteosarcoma.[7]

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 EFS than did a carboplatin (560 mg/m²/day)–containing regimen.[8]

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

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



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

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

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

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

References

1. Kaste SC, Pratt CB, Cain AM, et al.: Metastases detected at the time of diagnosis of primary pediatric extremity osteosarcoma at diagnosis: imaging features. Cancer 86 (8): 1602-8, 1999.  [PUBMED Abstract]
   
   
2. Kager L, Zoubek A, Pötschger U, et al.: Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol 21 (10): 2011-8, 2003.  [PUBMED Abstract]
   
   
3. Bacci G, Fabbri N, Balladelli A, et al.: Treatment and prognosis for synchronous multifocal osteosarcoma in 42 patients. J Bone Joint Surg Br 88 (8): 1071-5, 2006.  [PUBMED Abstract]
   
   
4. Kager L, Zoubek A, Kastner U, et al.: Skip metastases in osteosarcoma: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 24 (10): 1535-41, 2006.  [PUBMED Abstract]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. Daw NC, Billups CA, Rodriguez-Galindo C, et al.: Metastatic osteosarcoma. Cancer 106 (2): 403-12, 2006.  [PUBMED Abstract]
   
   
9. Müller CR, Smeland S, Bauer HC, et al.: Interferon-alpha as the only adjuvant treatment in high-grade osteosarcoma: long term results of the Karolinska Hospital series. Acta Oncol 44 (5): 475-80, 2005.  [PUBMED Abstract]
   
   
10. Daw NC, Billups CA, Pappo AS, et al.: Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children's Research Hospital experience. Cancer 97 (11): 2839-47, 2003.  [PUBMED Abstract]
    
    

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