The role of chemotherapy for metastatic, relapsed and refractory osteosarcoma.

UNLABELLED: Despite a large number of publications on outcomes of second-line chemotherapy for osteosarcoma, there is little consensus on efficacy of the therapy.

OBJECTIVE: Our objective was to systematically categorize published evidence for chemotherapy for metastatic, relapsed and refractory osteosarcoma in order to provide an updated and comprehensive analysis of the clinical outcomes.

METHODS: We performed a search of PubMed and EMBASE to identify published articles reporting on validated clinical outcomes measures (the rate of complete response [CR] and partial response [PR], the rate of stable disease [SD] and progressive disease [PD] and the 5-year overall survival) after chemotherapy in patients with metastatic, relapsed and refractory osteosarcoma. A total of 20 articles were identified and stratified by different regimens. Finally, six regimens that have at least two drugs were reviewed. Weighted averages of each outcome were computed.

RESULTS: The weighted average overall response rate (CR + PR) for the combination of ifosfamide, etoposide and high-dose methotrexate therapy was 62 %, and the tumor control rate (CR + PR + SD) was 92.3 %; the highest of all six regimens. The weighted average overall response rate and tumor control rate of ifosfamide-etoposide therapy (41.7 and 77.9 %, respectively) were the highest of the two-drug regimens. Weighted average overall response rate and tumor control rate for the remaining regimens were 20.5 and 56.8 %, respectively, for cyclophosphamide-etoposide; 30.0 and 73.5 % for ifosfamide, carboplatin, and etoposide; 12.0 and 40.0 % for cyclophosphamide-topotecan; and 14.5 and 36.4 % for gemcitabine-docetaxel.

CONCLUSION: A chemotherapy regimen comprising both a cell cycle-specific drug and a cell cycle-nonspecific drug could increase response rates. The combination of ifosfamide and etoposide therapy is our first choice in two-drug regimens. Regarding three-drug regimens, adding a cell cycle-specific drug to ifosfamide-etoposide therapy may result in a better response rate than adding a cell cycle-nonspecific drug, or any other two-drug regimens in current studies. Hence, we recommend the use of second-line chemotherapy based on the combination ifosfamide-etoposide regimen in patients with metastatic, relapsed and refractory osteosarcoma.