French Phase III Trial Shows No Benefit of Adding Zoledronate to Chemotherapy and Surgery in Osteosarcoma
In the French phase III OS2006 trial reported by Piperno-Neumann et al in The Lancet Oncology, the addition of zoledronate to chemotherapy and surgery provided no event-free survival benefit in the treatment of patients with newly diagnosed high-grade osteosarcoma.
Study Details
In the open-label trial, 318 patients aged 5 to 50 years (median = 15.5 years) from 40 French sites were randomized between April 2007 and March 2014 to receive standard chemotherapy with (n = 160) or without (n = 158) 10 zoledronate intravenous (IV) infusions (four preoperative and six postoperative). Zoledronate was given at 4 mg per infusion in patients aged > 25 years, 0.05 mg/kg for the first two infusions and 4 mg for eight infusions in those aged 18 to 25 years, and 0.05 mg/kg per infusion in younger patients. Chemotherapy consisted of high-dose methotrexate-based chemotherapy in patients aged < 18 years; doxorubicin, ifosfamide, and cisplatin in those aged > 25 years; and either regimen in those aged 18 to 25 years at investigator discretion. Among all patients 15% had possible metastases, and 17% had definite metastases. The primary endpoint was event-free survival.
Outcomes
The trial was stopped for futility after the second interim analysis. Median follow-up was 3.9 years. Three-year event-free survival was 57.1% (95% confidence interval [CI] = 48.8%–65.0%) in the zoledronate group vs 63.4% (55.2%–70.9%) in the control group (hazard ratio [HR] = 1.36, P = .094). The hazard ratio in a post-hoc sensitivity analysis excluding patients with definite metastases was similar (1.3, P = .17). No significant heterogeneity of treatment effect was observed according to age, chemotherapy regimen, risk group, or tumor size. Three-year overall survival was 73.4% vs 84.4% (HR = 1.61, P = .052).
Toxicity
No marked increases in grade ≥ 3 adverse events were associated with zoledronate, except for anticipated increases in hypocalcemia (29% vs 6%) and hypophosphatemia (40% vs 17%). There was no difference in the number of orthopedic complications in the two groups (29 and 27).
The investigators concluded: “From the results observed in this study, we do not recommend zoledronate in osteosarcoma patients. Further biological studies are required to understand the discordance between the results of OS2006 trial and preclinical data.”
The study was funded by the French National Cancer Institute, Novartis, Chugai, Ligue Nationale contre le Cancer, Fédération Enfants et Santé, and Société Française des Cancers et Leucémies de l’Enfant.
Sophie Piperno-Neumann, MD, of the Institut Curie, Paris, France, is the corresponding author of The Lancet Oncology article.
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