br Bone half life based dosing As zoledronic acid has
Bone half-life based dosing As zoledronic stavudine manufacturer has been shown to have anti-tumor efficacy in both the pre-clinical and clinical settings using the conventional regimen (zoledronic acid 4mg infusion 4 weekly), some studies were designed to explore the anti-tumor effects of zoledronic acid when administered continuously every 6 months. In ABSCG-12, 1803 premenopausal women that compares the efficacy and safety of anastrozole or tamoxifen with or without zoledronic acid (4mg every 6 months) for 3 years. At a median follow-up of 62 months, Zoledronic acid (4mg every 6 months) with adjuvant endocrine therapy significantly improved DFS versus endocrine therapy without zoledronic acid (92% versus 88%, respectively; log-rank p=0.008). This 4% absolute difference in DFS corresponded to a significant reduction in the relative risk of events for patients receiving versus not receiving zoledronic acid, stratified by endocrine therapy (76 versus 110 events; HR 0.68, 95% confidence interval [CI] 0.51–0.91, Cox p=0.009, log-rank p=0.008). Zoledronic acid significantly reduced the relative risk of DFS events both in node-positive (HR 0.67, 95% CI 0.45–0.99) and node-negative patients (HR 0.66, 95% CI 0.43–1.03). Fewer patients receiving zoledronic acid had distant disease recurrence at both bone and non-bone sites (44 versus 56 events), including contralateral breast cancer (6 versus 8 events) and locoregional recurrence (15 versus 30 events). In a subgroup analysis by patient age at study entry, a treatment by-covariate interaction based on patients aged 40 years or younger versus those older than 40 years did not reveal significant heterogeneity (p=0.121). However, in patients who were 40 years or younger at baseline (N=413), zoledronic acid did not significantly reduce the relative risk of DFS events (HR 0.94, 95% CI 0.57–1.56), whereas in those who were older than 40 years at study entry (N=1390), the risk reduction with in patients treated with zoledronic acid was significant (HR 0.58, 95% CI 0.40–0.83). Thirty deaths (3% of 900 patients) occurred in the zoledronic acid group, whereas 43 deaths (5% of 903 patients) occurred in the non-zoledronic acid group; risk of death did not differ significantly between these groups (HR 0.67, 95% CI 0.41–1.07; Cox p=0.09). OS also did not differ significantly between treatment groups in patients with node-positive (HR 0.62, 95% CI 0.34–1.15) and node-negative disease (HR 0.70, 95% CI 0.33–1.52). The addition of zoledronic acid improved DFS in patients taking either anastrozole or tamoxifen. These data show consistent benefits with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer . In the ZO-FAST study, 1065 women were randomly assigned to immediate zoledronic acid 4mg every 6 months for 5 years, or delayed zoledronic acid. Patients were administered letrozole for a median of approximately 60 months. After 5 years of follow-up, patients in the immediate-zoledronic acid group had a 34% relative reduction in the risk of DFS events versus the delayed-zoledronic acid group, HR 0.66, 95% CI 0.44–0.97, p=0.0375). Fewer local and distant disease recurrences occurred in the immediate-zoledronic acid group versus the delayed-zoledronic acid group (local recurrences, 0.9% versus 2.3%, respectively; distant recurrences, 5.5% versus 7.7%, respectively). Bone metastases were more common in the delayed-zoledronic acid group versus the immediate-zoledronic acid group (4.5% versus 2.6%, respectively). Contralateral breast cancers were reported in 3 patients in the immediate-zoledronic acid group versus 6 in the delayed-zoledronic acid group. Immediate use of zoledronic acid substantially improved DFS versus patients in the delayed arm (HR 0.62, 95% CI 0.41–0.93; p=0.0239). Exploratory analyses showed that zoledronic acid initiation in this group (N=144) improved DFS versus no zoledronic acid treatment (HR 0.46, p=0.0334). A larger (non-significant) proportion of patients initiating delayed zoledronic acid treatment were lymph node-positive at diagnosis (70%) compare to those not initiating delayed zoledronic acid (55%), which may contribute to an underestimate of the DFS benefits from delayed introduction of zoledronic acid. Other prognostic factors identified for DFS in the delayed-zoledronic acid arm included tumor stage (HR 2.16, p=0.0416 for ≥T2 versus T0 or T1) and age (HR 1.95, p=0.0236 for age ≥65 versus <65 years). Further exploratory analyses showed trends towards improved DFS with immediate zoledronic acid in recently menopausal (N=177) and truly postmenopausal (N=888) patients (0.05
5 years postmenopausal or >60 years of age at study entry; N=670), immediate zoledronic acid was associated with a trend for improved DFS (HR 0.63, p=0.0516) and demonstrated substantially improved OS (HR 0.50, p=0.0224) versus delayed zoledronic acid. These findings show that, in addition to improving bone health, initiating zoledronic acid immediately may improve DFS compared with delaying zoledronic acid .