Effect of metronomic use of zoledronic acid (ZOL) on antitumor and antiosteoclastic effects in breast cancer patients with bone metastasis

Abstract

e14603 Background: Zoledronic acid (ZOL) can reduce the risk of skeletal-related events (SREs) and may have direct and indirect antitumor effects, which have been shown in animal models, pilot clinical studies as well as in recent phase III randomized trials. However, the pharmacokinetics of the drug in breast cancer patients remains to be elucidated and optimized. The purpose of this randomized study was to compare the effects of ZOL on osteoclasts and angiogenesis between a weekly low-dose versus a conventional dosage. Methods: Sixty breast cancer patients with bone metastases were recruited in this randomized phase II clinical study. The participants either received ZOL 1mg IV weekly for 4 doses or a single dose of ZOL 4mg IV. No other antitumor treatments were administered. During the first month after initial infusion of ZOL, serial blood samples were collected on day 1, 15 and 29 measuring markers for bone resorption (NTx), angiogenesis (VEGF), and tumor burden (CEA and CA15–3). Results: Compared to a single-dose administration, weekly low dose of ZOL resulted in a greater reduction in serum levels of VEGF and NTx, with a significant trend over time during one month observation. There were no statistically significant differences in circulating levels of CEA and CA15–3 between the two dosing regimens. Patients who received metronomic ZOL had a longer median time to disease progression (TTP) (7.0 months, 95%CI, 6.1–7.9 months) than those who had a single dose of ZOL (2.8 months, 95%CI, 0–5.7 months; p=0.076). Conclusions: The metronomic use of low-dose ZOL 1 mg appeared to be more effective than the conventional regimen in the long-lasting reduction of VEGF and NTx, and in prolonging TTP. This dosing schedule should be further assessed in phase III trials as we demonstrated that ZOL 1mg has greater antitumor properties in our study. No significant financial relationships to disclose.