Treatment of advanced osteosarcoma
Axial primary tumor For the 10% to 15% of patients who present with axial primary osteosarcoma, neoadjuvant chemotherapy should be considered to reduce the tumor burden prior to surgery or radiation therapy. The COSG reported that 11.4% of its patients treated before 1999 had proven metastases at diagnosis. Actuarial survival at 5 and 10 years was 29% and 24%, respectively, when treated with preoperative and postoperative multiagent chemotherapy as well as aggressive surgery for all resectable lesions. Multivariate Cox regression analysis demonstrated that multiple metastases at diagnosis and macroscopically incomplete surgical resection are significantly associated with inferior outcomes in patients with primary metastatic osteosarcoma.

Pulmonary metastasis Patients with metastatic disease to the lungs should be evaluated for resection. Following aggressive pulmonary metastasectomy, < 25% of patients will achieve prolonged relapse-free survival. Hence, these patients may also benefit from aggressive “secondary” adjuvant chemotherapy.

Chemotherapy should also be considered for patients whose pulmonary metastases are unresectable, with the intention of performing surgery in those who have a sufficient response; approximately 10% of such patients may become long-term survivors.

Poor-risk patients or patients with recurrent disease are candidates for clinical trials that evaluate newer therapeutic agents. The COG demonstrated stabilization of disease in patients with recurrent or refractory osteosarcoma employing the combination of cyclophosphamide and topotecan (Hycamtin), although objective responses were rare. A team from the University of Michigan reported that the combination of gemcitabine (Gemzar) and docetaxel (Taxotere) is moderately active in recurrent osteosarcoma, Ewing's sarcoma, and other soft-tissue sarcomas.

The prognosis for patients who develop metachronous skeletal osteosarcoma has been considered grave compared with that for patients with relapse limited to the lungs. Investigators at MSKCC reported that in a small subset of patients who developed metachronous osteosarcoma at 24 months or more from the initial diagnosis (11 of 23 patients with osteosarcoma), combined-modality therapy with surgery and aggressive chemotherapy resulted in a 5-year postmetachronous survival rate of 83%, versus 40% for patients receiving monotherapy (usually surgery) only. These results refute an earlier pessimistic sentiment.

Radiotherapy
Although the routine use of adjuvant radiotherapy for osteosarcoma is unnecessary, certain patients may benefit from treatment. Patients with positive margins and poor response to chemotherapy are particularly at risk for local recurrence. Primary lesions in the axial skeleton are more likely to be difficult to resect with wide margins. DeLaney et al have reported a local control rate of 78% in patients with subtotal resections followed by radiotherapy. Doses in the range of 60 Gy or more are recommended. Patients who have unresectable disease should be considered for high-dose radiotherapy following chemotherapy. Local tumor control may be achieved in 40% to 55% of patients. Sophisticated planning with intensity-modulated radiotherapy and/or proton therapy may be required for lesions located adjacent to radiosensitive structures such as the spinal cord. The use of radiosensitizing chemotherapy has been studied by investigators at MDACC; it may improve the chances of controlling locally advanced disease.

Investigators at the Mayo Clinic reported significant palliation of pain in patients with osteosarcoma and symptomatic bone metastases who were treated with high doses of samarium 153 ethylene diamine tetramethylene phosphonate (¹⁵³Sm EDTMP), a bone-seeking radiopharmaceutical, in conjunction with stem-cell rescue. Escalating doses up to 30mCi/kg were studied. Nonhematologic side effects were minimal. ¹⁵³Sm at a dose of 1 mCi/kg has been used for palliation of bone pain from skeletal metastases without the need for stem-cell support. Investigators at the Johns Hopkins Hospital have determined that a 1.21-mCi/kg dose can be administered to heavily pretreated patients without significant toxicity.

Ewing's sarcoma

Chemotherapy
Prior to the availability of effective chemotherapeutic agents, < 10% of patients with Ewing's sarcoma survived beyond 5 years. The first intergroup Ewing's sarcoma study demonstrated an improved survival rate for patients receiving systemic therapy with the VAC regimen (vincristine, Actinomycin D [dactinomycin], cyclophosphamide, for those receiving the VACA regimen (the VAC regimen plus Adriamycin [doxorubicin]), and for patients receiving VAC plus bilateral pulmonary irradiation. In the future, selection of a specific therapeutic regimen may be influenced by the presence of molecular markers in addition to standard clinical criteria.

In the second intergroup study, the addition of doxorubicin to VAC, when given on an intermittent schedule and at a higher dose, improved the 5-year relapse-free survival rate to 73%; this rate was almost double that of the cohort of patients not receiving doxorubicin as part of their treatment. The worst results were observed in patients with pelvic, proximal extremity, and lumbar vertebral lesions.

In a phase III study, the addition of ifosfamide and etoposide to standard VACA chemotherapy for patients with Ewing's sarcoma and PNET of the bone significantly improved overall survival for patients with localized disease (72% vs 61%), but it did not affect the outcome for patients with metastatic disease (overall survival = 34% vs 35%). In addition to biologic adverse features at presentation (male sex, age, high LDH levels, anemia, fever, axial locations, non-type 1 fusion transcripts, and lack of feasibility of surgical resection), independent prognostic factors also include the type of chemotherapy and degree of tumor necrosis.