Recurrent Osteosarcoma and MFH of Bone
Approximately 50% of relapses occur within 18 months of therapy termination, and only 5% of recurrences develop beyond 5 years.[1-4] In 564 patients with a recurrence, patients whose disease recurred within 2 years of diagnosis had a worse prognosis than did patients whose disease recurred after 2 years. Patients with a good histologic response to initial preoperative chemotherapy had a better overall survival (OS) after recurrence than did poor responders. The probability of developing lung metastases at 5 years is 28% in patients presenting with localized disease. In two large series, the incidence of recurrence by site was as follows: lung only (65%–80%), bone only (8%–10%), local recurrence only (4%–7%), and combined relapse (10%–15%).[4,6] Abdominal metastases are rare but may occur as late as 4 years after diagnosis.
Patients with recurrent osteosarcoma should be assessed for surgical resectability, because they may sometimes be cured with aggressive surgical resection with or without chemotherapy.[8,6,9-12] Control of osteosarcoma after recurrence depends on complete surgical resection of all sites of clinically detectable metastatic disease. If surgical resection is not attempted or cannot be performed, progression and death are certain. The ability to achieve a complete resection of recurrent disease is the most important prognostic factor at first relapse, with a 5-year survival rate of 20% to 45% after complete resection of metastatic pulmonary tumors and a 20% survival rate after complete resection of metastases at other sites.[4,6,12,13]
The role of systemic chemotherapy for the treatment of patients with recurrent osteosarcoma is not well defined. The selection of further systemic treatment depends on many factors, including the site of recurrence, the patient’s previous primary treatment, and individual patient considerations. Ifosfamide alone with mesna uroprotection, or in combination with etoposide, has been active in as many as one-third of patients with recurrent osteosarcoma who have not previously received this drug.[14-17] Cyclophosphamide and etoposide are active in recurrent osteosarcoma, as is the combination of gemcitabine and docetaxel.[18-20] The Italian Sarcoma Group reported rare objective responses and disease stabilization with sorafenib in patients with recurrent osteosarcoma. Peripheral blood stem cell transplant utilizing high-dose chemotherapy does not appear to improve outcome. High-dose samarium-153-ethylenediamine tetramethylene phosphonic acid (EDTMP) coupled with peripheral blood stem cell support may provide significant pain palliation in patients with bone metastases.[22-25] Toxicity of samarium-153-EDTMP is primarily hematologic.[Level of evidence: 3iiDiii]
Lung Only Recurrence
Repeated resections of pulmonary recurrences can lead to extended disease control and possibly cure for some patients.[13,27] Survival for patients with unresectable metastatic disease is less than 5%.[6,28] Five-year event free survival (EFS) for patients who have complete surgical resection of all pulmonary metastases ranges from 20% to 45%.[4,12,13]; [Level of evidence: 3iiiA] Factors that suggest a better outcome include fewer pulmonary nodules, unilateral pulmonary metastases, longer intervals between primary tumor resection and metastases, and tumor location in the periphery of the lung.[4-6,30,31]
Resection of metastatic disease followed by observation alone results in low OS and disease-free survival. A high percentage of patients with pulmonary nodules identified in only one lung who underwent staged bilateral thoracotomy were found to have palpable nodules in both lungs that were not visualized on a computed tomography (CT) scan. This suggests that patients with unilateral nodules may benefit from bilateral exploration. A retrospective review of 16 patients who relapsed with single pulmonary metastases on CT scan more than 2 months after therapy showed that no further metastases were found on unilateral thoracotomy, implying that thoracoscopic removal may be adequate to remove all disease in this relatively unusual circumstance (13.9% of patients relapsing in the lung after therapy). There are conflicting recommendations regarding the need for formal thoracotomy for treatment of pulmonary metastases in osteosarcoma. The St. Jude Children’s Research Hospital results suggest that thoracoscopy without exploration of the entire ipsilateral lung is adequate therapy for isolated first pulmonary recurrence more than 2 months from completion of initial planned therapy. The Memorial Sloan-Kettering Cancer Center results suggest that additional nodules will be found in either the ipsilateral or the contralateral lung in patients with pulmonary metastases. The latter experience included both patients with metastases at initial presentation and patients with metastatic recurrence.
Recurrence With Bone Metastases Only
Patients with osteosarcoma who develop bone metastases have a poor prognosis. In one large series, the 5-year EFS rate was 11%. Patients with late solitary bone relapse have a 5-year EFS rate of approximately 30%.[34-37] For patients with multiple unresectable bone lesions, samarium-153-EDTMP with or without stem cell support may produce stable disease and/or relief of pain.
Two retrospective, single-institution series reported 10% to 40% survival following local recurrence without associated systemic metastasis.[41-44] Survival of patients with local recurrence and either previous or concurrent systemic metastases is poor. The incidence of local relapse was higher in patients who had a poor pathologic response to chemotherapy in the primary tumor and in patients with inadequate surgical margins.[38,42]
Second Recurrence of Osteosarcoma
The Cooperative Osteosarcoma Study group reported on 249 patients who had a second recurrence of osteosarcoma. The main feature of therapy was repeated surgical resection of recurrent disease. Of these patients, 197 died, 37 were alive in complete remission (24 after a third complete response and 13 after a fourth or subsequent complete response). Fifteen patients who did not achieve surgical remission remain alive, but follow-up for these patients was extremely short.
Treatment Options Under Clinical Evaluation for Recurrent Osteosarcoma
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- EP-ILC-201 (NCT01650090) (Phase 2 Study of Inhaled Lipid Cisplatin in Pulmonary Recurrent Osteosarcoma): This is a phase II study of inhaled lipid-encapsulated cisplatin for patients aged 13 years and older who have a first or second recurrence of osteosarcoma, whose macroscopic disease can be resected, and who have microscopic residual disease.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent osteosarcoma and recurrent 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.
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