Addition of Zoledronate to Chemotherapy in Patients with Osteosarcoma Treated with Limb-Sparing Surgery: A Phase III Clinical Trial
Shenglong Li, Peng Chen, Yi Pei, Ke Zheng, Wei Wang, Enduo Qiu, Xiaojing Zhang
(Department of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China (mainland))
Med Sci Monit 2019; 25:1429-1438
Zoledronate has anti-bone resorption activity and is reported to reduce skeletal-related events. The objective of this study was to test the hypothesis that addition of zoledronate in chemotherapy is safe and effective in osteosarcoma.
MATERIAL AND METHODS: A total of 798 patients, age 25 years and above, with newly diagnosed high-grade surgically salvageable malignant osteosarcoma, were included in the trial. All patients had received standard chemotherapies (n=399). In addition, in a standard chemotherapy regimen, patients enrolled in the zoledronate group also received 10 courses of 4 mg intravenous infusions of zoledronate (n=399). Limb-sparing surgery was performed by orthopedic surgeons (n=798). Clinical assessment, laboratory monitoring, overall survival, event-free survival, and treatment-emergent adverse effects were evaluated. The chi-square independence-samples test was used for statistical analysis at 95% confidence level.
RESULTS: The histopathological response was the same for both groups (p=0.12). Addition of zoledronate to chemotherapy improved skeletal event-free survival (p=0.04) but decreased overall survival (p=0.02). Zoledronate induced hypocalcemia (p<0.0001), hypophosphatemia (p<0.0001), cardiotoxicity (p<0.0001), lung metastases (p=0.03), flu-like syndrome (p<0.0001), and ototoxicity (p=0.02), and elevated serum aspartate aminotransferase (p<0.0001) and serum alanine aminotransferase (p<0.0001).
CONCLUSIONS: The addition of zoledronate to standard chemotherapy in high-grade resectable osteosarcoma is detrimental and is not advised.
Keywords: Antineoplastic Combined Chemotherapy Protocols, Disease-Free Survival, Neoplasm Metastasis, Osteosarcoma, Survival Analysis, Survival Rate