In the phase AZURE trial women were randomly
In the phase 3 AZURE trial, 3360 women were randomly assigned to receive standard adjuvant systemic treatment alone (control group) or with 4mg intravenous zoledronic VCH-222 every 3–4 weeks for 6 doses, then every 3 months for 8 doses, followed by every 6 months for 5 doses, for a total of 5 years of treatment. The number of DFS events did not differ between the 2 groups. DFS, OS, and distant recurrences were also similar in both groups. However, zoledronic acid reduced the development of bone metastases, both as a first event (HR 0.78, 95% CI 0.63–0.96; p=0.020) and at any time during follow-up (HR 0.81, 95% CI 0.68–0.97; p=0.022). The effects of zoledronic acid on DFS were not affected by estrogen receptor (ER) status. However, zoledronic acid improved IDFS in those who were over 5 years since menopause at trial entry (N=1041; HR 0.77, 95% CI 0.63–0.96) but not in all other (premenopause, perimenopause, and unknown status) menopausal groups (N=2318; HR 1.03, 95% CI 0.89–1.20). For postmenopausal women with stage II or III breast cancer, the absolute DFS benefit at 5 years of around 5% and an osteonecrosis of the jaw rate of 1–2% suggest a favorable risk-to-benefit ratio. Overall, these data do not support the use of adjuvant zoledronic acid in unselected patients with early breast cancer. However, these data suggest that zoledronic acid can be used for postmenopausal women with early breast cancer who are receiving adjuvant treatment [21,22].
Recently, a meta-analysis on 18,766 women with median follow-up 5.6 years showed that by using bisphosphonates including zoledronic acid, the reductions in recurrence (RR 0.·94, 95% CI 0.87–1.01; 2p=0.08), distant recurrence (0.92, 0.85–0.99; 2p=0.03), and breast cancer mortality (0.91, 0.83–0.99; 2p=0.04) were of only borderline significance, but the reduction in bone recurrence was more significant (0.83, 0.73–0·94; 2p=0.004). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by age (2p=0.03) and menopausal status (2p=0.06 for trend with menopausal status), and it was non-significant by bisphosphonate class, treatment schedule, estrogen receptor status, nodes, etc. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0.85, 95% CI 0.75–0.97; 2p=0.02). Hence, adjuvant bisphosphonates including zoledronic acid was able to reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is significant benefit only in postmenopausal women .
Blood half-life based use On the basis of promising data from an in vivo study suggesting that low-dose weekly regimens of zoledronic acid were able to reduce skeletal tumor burden, Santini et al. designed a study to explore the potential anti-angiogenic effect of a weekly low-dose therapy with zoledronic acid in patients with malignancies. Twenty-six patients with solid cancer and bone metastases were administered 1mg of zoledronic acid weekly for 4 times followed by 4mg of zoledronic acid over a standard 4-week schedule, repeated 3 times. The median VEGF basal level showed a statistically significant (p=0.038) decrease 7 days after the first 1mg dose of zoledronic acid, and this effect persisted after 1mg infusions at 14 (p=0.002), 21 (p=0.001), and 28 days (p=0.008). Moreover, the decrease in circulating VEGF levels persisted at each prespecified time point during the second phase of the study (zoledronic acid 4mg every 4 weeks) .
Biomarker-driven dosing Bone turnover biomarkers offer an avenue to evaluate the ongoing rate of skeletal metabolism and interactions between cancer and skeleton in patients. The mutual effect between cancer and bone decouples activities spatially and disturbs otherwise balanced activities resulting in elevated rates of osteolysis and osteogenesis. During this process high levels of distinct biochemical markers are released into blood or urine that are amenable to non-invasive detection . Bone metabolism biochemical markers can provide meaningful evidence that tumor growth influences ongoing bone turnover rate. Such biochemical markers include cross-linked collagen peptides broken from osteolysis, (e.g. the amino [N]- and carboxy [C]-terminal cross-linked telopeptides of type I collagen [NTX and CTX]) and the terminal peptides cleaved from procollagen before its incorporation into newly synthesized bone matrix (e.g. procollagen type I N-terminal and C-terminal peptides [PINP and PICP]). Serum CTX and the urinary NTX are correlated with the ongoing osteolysis rates, whereas serum bone-specific alkaline phosphatase (bone ALP) and PINP are correlated with the ongoing osteogenesis rates . Bone metabolism marker such as osteocalcin is associated with both the processes of osteolysis and osteogenesis. In general, bone metabolism biochemical markers connect with the ongoing rates of osteolysis and osteogenesis. Bone marker level variation is not disease specific, and is independent of the underlying cause of skeletal metabolism alteration . Metabolism biochemical markers, on the whole, may not predict specific lesion site. Emerging evidence suggests that bone markers are helpful in identifying patients with high risk of bone metastasis and bone lesion progression [24,25]. Potential application of bone metabolism biochemical markers should be evaluated in clinical trials to identify the true value in clinical practice [27,28].