Zoledronate Fails to Improve Outcomes With Chemo in Osteosarcoma

Zoledronate in combination with chemotherapy failed to improve outcomes over chemotherapy alone in patients with osteosarcoma, according to a randomized phase III trial. The finding came in contrast to preclinical data that suggested benefit with zoledronate.

“The evolution of systemic treatments for osteosarcoma over the past two decades has been disappointing,” wrote study authors led by Sophie Piperno-Neumann, MD, of Institut Curie in Paris. “Among the several new drugs associated with preclinical activity, bisphosphonates seem to be one of the most promising.”

Bisphosphonates inhibit osteoclastic bone resorption, and preclinical evidence suggested direct anticancer activity. Zoledronate in particular has been found to have antitumor effects in osteosarcoma cell lines, and enhanced tumor regression and tissue repair when combined with ifosfamide.

The OS2006 trial was an open-label, randomized, phase III trial including 318 patients with localized or metastatic high-grade osteosarcoma. Patients either received standard chemotherapy alone (methotrexate-based in patients under 18 years of age; doxorubicin, ifosfamide, and cisplatin in patients older than 25 years; and either regimen in patients between those ages) (158 patients) or in combination with 10 zoledronate infusions (4 before surgery and 6 postoperatively; 160 patients). The results were published in Lancet Oncology.

After a second interim analysis, the trial was stopped for futility. The 3-year event-free survival rate was 63.4% in the control group and 57.1% in the zoledronate group. The risk of failure was not reduced by zoledronate, and there was a trend toward a higher risk in that group, with a hazard ratio of 1.36 (95% CI, 0.95–1.96; P = .094).

There were 74 deaths in the study, 32 of which were control patients and 42 of which were zoledronate patients. Two deaths, one in each group, were deemed treatment-related. The 3-year overall survival rate was 84.4% in the control group and 73.4% in the zoledronate patients.

The only excess acute toxicities with zoledronate compared with chemotherapy alone were hypocalcemia and hypophosphatemia, as well as a slight increase in thrombocytopenia. Fractures and wound-healing complications after surgery were similar across the groups.

The total enrollment in the study was lower than planned, but the authors concluded that “the absence of a positive effect of zoledronate on event-free survival in our patients is incontestable.” They offered several possibilities for why zoledronate failed to live up to its preclinical promise, including that the dose used might be inadequate. Also, zoledronate-induced reduction of osteoclasts could increase the risk of lung metastases, as other research has suggested that osteoclasts could inhibit migration of the osteosarcoma cells.

“In conclusion, from the results observed in this study, zoledronate cannot be recommended in patients with osteosarcoma,” the authors wrote.