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

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Sub-category: Antiangiogenic or Antimetastatic Agents
Category: Developmental Therapeutics: Molecular Therapeutics
Meeting: 2009 ASCO Annual Meeting
Citation: J Clin Oncol 27, 2009 (suppl; abstr e14603)
Abstract No: e14603
Author(s): H. Xi-Chun,
X. Zhao, X. Xu, H. Guo, Z. Wang, X. Guo, J. Chen, J. Wu, Z. Shao, J.
Li, B. Zhu; Cancer Hospital of Fudan University, Shanghai, China
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).
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.