n-phenylacetyl-l-prolylglycine ethyl ester Based on these pr

Based on these preliminary clinical results with low-dose, intermittent zoledronic acid, Hu et al. conducted a randomized phase II clinical study in order to clarify the role of metronomic low-dose zoledronic acid. Sixty breast cancer patients with bone metastases were randomized to receive either 1mg intravenous zoledronic n-phenylacetyl-l-prolylglycine ethyl ester weekly for 4 doses, or a single 4mg intravenous dose of zoledronic acid. Administration of other treatments was delayed for 1 month. Serial blood samples were collected on days 1, 15, 29, and at 3 months. Serum VEGF alteration was the primary endpoint. Compared to the conventional arm, the metronomic arm exhibited a significantly greater reduction in serum levels of VEGF and N-telopeptide of type I collagen (NTx) during the first month of treatment. Serum CA 15-3 level stabilized over time in the metronomic arm, but increased in the conventional arm. Independent prognostic factors for PFS included chemotherapy received (HR 8.042, p=0.000), ER status (HR 2.837, p=0.020), VEGF levels at 3 months after intervention (HR 2.026, p=0.045), and baseline NTx (HR 1.051, p=0.001). This is the first study to demonstrate that metronomic weekly low-dose zoledronic acid could be more effective than the conventional zoledronic acid dosing schedule. The weekly regimen resulted in more effective suppression of circulating VEGF and NTx levels, and possibly, more effective stabilization of serum tumor markers. Intervention-related VEGF levels at 3 months after zoledronic acid treatment are an independent prognostic factor for PFS. Further evaluation of the clinical and biomarker parameters of the metronomic (q 1 week) zoledronic acid regimen is clearly warranted [24]. Therefore, the prognostic and predictive effects of clinical and biochemical factors were examined in the aforementioned randomized study of a weekly low dose (metronomic arm) versus a conventional dosage of zoledronic acid (conventional arm) in breast cancer patients with bone metastases. Specifically, treatment outcomes in 60 patients with bone metastases were used to assess the impacts of the following potential prognostic factors: ER status, lymph node status, 2-year disease-free interval (DFI), numbers of chemotherapy regimens administered, interventions, serum levels of VEGF, NTx, CEA, and CA 15-3. In univariate analyses, patients pretreated with 2 or fewer chemotherapy regimens, patients with ER-positive tumors, patients with 3 or fewer lymph nodes, patients with DFI of more than 2 years, patients with serum VEGF of less than 500pg/mL after 3 months of intervention, patients with serum CEA and CA 15-3 of less than ULN, and patients with baseline serum NTx of less than 18nM BCE had significantly longer PFS. Multivariate analysis showed that ER positivity (HR 0.295; 95% CI 0.141–0.618, p=0.001), serum VEGF of less than 500pg/mL after 3 months of intervention (HR 2.220, 95% CI 1.136–4.338, p=0.020), baseline serum NTx of less than 18nM BCE (HR 2.842, 95% CI 1.458–5.539, p=0.001), and 2 or fewer chemotherapy regimens received (HR 7.803, 95% CI 2.884–21.112, p=0.000) were associated with better PFS. When evaluating the predictive effect of the biochemical factors, an interaction between NTx and zoledronic acid intervention was shown (p=0.005). The HR of weekly low dose versus conventional zoledronic acid dosage was estimated to be 2.309 (99% CI 1.067–5.012) in patients with baseline serum NTx of more than 18nM BCE. In conclusion, these results indicate superiority of weekly low dose of zoledronic acid over conventional dosing. ER, serum VEGF level after intervention, and numbers of chemotherapy regimens administered are prognostic but not predictive factors in breast cancer patients with bone metastases. Patients with baseline serum NTx of more than 18nM BCE might benefit more from weekly low-dose of zoledronic acid [26]. Clinical results with low-dose, intermittent zoledronic acid are consistent with those observed in animal models, providing a rationale for further investigations of alternative dosing regimens to optimize the anti-tumor potential of zoledronic acid.