Repeated Intermittent Low-Dose Therapy with Zoledronic Acid Induces an Early, Sustained, and Long-Lasting Decrease of Peripheral Vascular Endothelial Growth Factor Levels in Cancer Patients

Abstract

Purpose: On the basis of stimulating data on animals reporting that weekly regimens of zoledronic acid (ZA) were effective in reducing skeletal tumor burden, we designed a study on humans to investigate the potential antiangiogenic role of a weekly low-dose therapy with ZA in patients with malignancies. Experimental Design: Twenty-six consecutive patients with advanced solid cancer and bone metastases received 1mg of ZA every week for four times (days1, 7, 14, and 21) followed by 4 mg of ZA with a standard 28-day schedule repeated thrice (days 28, 56, and 84). Patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) just before the beginning of drug infusion (0) and again at 7, 14, 21, 28, 56, and 84 days after the first ZA infusion. Results: The median VEGF basal value showed an early statistically significant (P = 0.038) decrease 7 days after the first 1-mg infusion of ZA.This effect onVEGF-circulating levels persisted also after the following 1-mg infusions at 14 (P = 0.002), 21 (P = 0.001), and 28 days (P = 0.008). Interestingly, the decrease of VEGF-circulating levels persisted also at each programmed time point during the second phase of the study (ZA 4 mg every 4 weeks). No significant differences were recorded in platelet levels,WBC count, or hemoglobin concentration before and after each ZA infusion. Conclusions: In the present study, we report that a repeated low-dose therapy with ZA is able to induce an early significant and long-lasting decrease of VEGF levels in cancer patients.Bisphosphonates are PP i analogues and differ from one another based on their substituted side chains (1). Nitrogencontaining bisphosphonates (N-BP), including pamidronate and zoledronic acid (ZA), inhibit protein prenylation, which in turn interferes with osteoclast function inducing apoptosis of osteoclasts as well as of myeloma and breast cancer cells in vitro (2 -4). Bisphosphonates have a widely recognized role in the treatment of patients with multiple myeloma and bone metastases secondary to breast cancer (5, 6). ZA recently received broad regulatory approval for the treatment of bone metastases secondary to all solid tumor types and bone lesions from multiple myeloma based on the results of three large, randomized, phase III clinical trials enrolling more than 3,000 patients (7,8). Compelling studies suggest that, besides the strong and well-known antiosteoclastic activity, the efficacy of such compounds in oncology could also be due to their antitumor effect, which is exerted at different levels (9). In detail, growing preclinical evidence supports that at least part of the antitumor activity of bisphosphonates may be attributed to an antiangiogenic effect (10). These findings have been confirmed in vivo; systemic administration of 3 Ag/kg ZA to mice resulted in a potent inhibition of angiogenesis induced by s.c. implants impregnated with h-fibroblast growth factor (11). ZA and ibandronate, but not clodronate, decreased revascularization of the ventral prostat...

Zoledronic acid use in cancer patients

“…42 In another study in patients with bone metastases from solid tumors (N ¼ 26) who were receiving ZOL, VEGF levels were reduced significantly after 84 days of treatment compared with placebo (P ¼ .014). 43 In a second ZOL study in patients with advanced BC who received 1 ZOL dose before chemotherapy (N ¼ 42), the majority had !25% lower circulating VEGF levels compared with baseline. 44 The reduction in VEGF levels was correlated significantly with prolonged time to first SRE (P ¼ .0002), delayed bone disease progression (P ¼ .0024), and maintained or improved performance status (P ¼ .0352) compared with VEGF levels that remained unchanged.…”

Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer

“…Bisphosphonates block angiogenesis via inhibition of cell proliferation and vessel sprouting and are associated with a durable reduction in circulating vascular endothelial growth factor (VEGF) concentrations [17]. A decrease in VEGF concentrations has been described in patients treated with zoledronate [18]. The possible role of angiogenesis in ONJ is supported by the higher incidence of ONJ in patients with multiple myeloma, who are frequently treated with the anti-angiogenic agent, thalidomide.…”

Osteoimmunology and Cancer - Clinical Implications

“…In addition, ZOL stimulates cancer cell apoptosis and expansion of T cells, which play an important role in immune surveillance against neoplasia [94]. Preclinical studies reported that ZOL elicits anticancer activity in various cancer types and exhibits synergy with cytotoxic agents [95][96][97][98][99][100]. Four separate studies reported that ZOL reduced the persistence of DTCs in the bone marrow of patients with breast cancer [101][102][103][104].…”