Lung Metastases Only
Bone Only or Bone with Lung Metastasis
Treatment Options Under Clinical Evaluation
Malignant Fibrous Histiocytoma of Bone
Current Clinical Trials

Approximately 20% to 25% of patients with osteogenic sarcoma present with clinically detectable metastatic disease. The lung is the most common site of initial metastatic disease.[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] Patients with metastases limited to the lungs have a better outcome than patients with metastases to other sites or to the lungs combined with other sites.[2,3] 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.[4]

Patients with metastatic lung lesions as the sole site of metastatic disease should have the lung lesions resected if at all possible. Generally, this is done following administration of preoperative chemotherapy. In approximately 10% of patients, all lung lesions disappear following preoperative chemotherapy.[3] Complete resection of pulmonary metastatic disease can be achieved in a high percentage of patients with residual lung nodules following preoperative chemotherapy. The cure rate is essentially zero without complete resection of residual pulmonary metastatic lesions.

For patients who present with primary osteosarcoma and metastases limited to the lungs and who achieve complete surgical remission, 5-year event-free survival (EFS) is approximately 20% to 25%. Multiple metastatic nodules confer a worse prognosis than one or two nodules, and bilateral lung involvement is worse than unilateral.[2] Patients with fewer than three nodules confined to one lung may achieve a 5-year EFS of approximately 40% to 50%.

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% EFS and overall survival.[2] In the Italian experience, of the patients who presented with primary extremity tumors and synchronous metastasis to other bones, only three patients remained continuously disease-free 5 years later.[5] Patients who have transarticular skip lesions have a poor prognosis.[6]

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.[7,8]

When the usual treatment course of preoperative chemotherapy followed by surgical ablation of the primary tumor and resection of all overt metastatic disease (usually lungs) followed by postoperative combination chemotherapy cannot be used, an alternative treatment approach may be used. This alternative treatment approach begins with surgery for the primary tumor, followed by chemotherapy and then surgical resection of metastatic disease (usually lungs). This alternative approach may be appropriate in patients with intractable pain, pathologic fracture, or uncontrolled infection of the tumor when initiation of chemotherapy could create risk of sepsis.

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 ¹ and metastatic childhood malignant fibrous histiocytoma of bone ². 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 ³.

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, Rocca M, Salone M, et al.: High grade osteosarcoma of the extremities with lung metastases at presentation: treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions. J Surg Oncol 98 (6): 415-20, 2008.  [PUBMED Abstract]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
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.  [PUBMED Abstract]
   
   
8. 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]
   
   
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]