A single dose of 1.0 mCi/kg of 153Sm-EDTMP provided relief from pain associated with bone metastases. Pain relief was observed within 1 week of administration and persisted until at least week 16 in the majority of patients who responded.
The AZURE trial is an ongoing phase III, academic, multi-centre, randomised trial designed to evaluate the role of zoledronic acid (ZOL) in the adjuvant therapy of women with stage II/III breast cancer. Here, we report the safety and tolerability profile of ZOL in this setting. Eligible patients received (neo)adjuvant chemotherapy and/or endocrine therapy and were randomised to receive neither additional treatment nor intravenous ZOL 4 mg. ZOL was administered after each chemotherapy cycle to exploit potential sequence-dependent synergy. ZOL was continued for 60 months post-randomisation (six doses in the first 6 months, eight doses in the following 24 months and five doses in the final 30 months). Serious (SAE) and non-serious adverse event (AE) data generated during the first 36 months on study were analysed for the safety population. 3,360 patients were recruited to the AZURE trial. The safety population comprised 3,340 patients (ZOL 1,665; control 1,675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. SAE were similar in both treatment arms. No significant safety differences were seen apart from the occurrence of osteonecrosis of the jaw (ONJ) in the ZOL group (11 confirmed cases; 0.7%; 95% confidence interval 0.3-1.1%). ZOL in the adjuvant setting is well tolerated, and can be safely administered in addition to adjuvant therapy including chemotherapy. The adverse events were consistent with the known safety profile of ZOL, with a low incidence of ONJ.
Background: The ABCSG XII trial demonstrated a 32% risk reduction in disease-free survival (DFS) events with Zoledronic acid (ZOL) use in a cohort of premenopausal women treated with endocrine therapy at 62 months median follow-up .[1,2] This strategy is increasingly being adopted in the wider breast cancer population. The AZURE trial is an academic study designed to determine whether treatment with ZOL added to standard adjuvant therapy improves DFS and bone metastasis-free survival (BMFS) in a broader range of patients with stage II/III breast cancer. Materials and methods: 3360 patients from 174 centres were randomized to receive (neo) adjuvant chemotherapy (CT) and/or endocrine therapy (ET) +/− ZOL 4mg iv every 3-4 weeks for 6 doses, then 3 monthly x 8 and 6 monthly x 5 to complete 5 years treatment. The primary DFS endpoint was to be determined after 940 DFS events, providing 80% power to detect a 17% reduction in hazard rates (HR) for DFS events. The rate of events on study has been slower than expected, resulting in an estimated final analysis in 2012. In light of the clinical interest in the results of AZURE, the DMEC has agreed to a second interim analysis after 705 events with boundaries set by an independent statistician, unaware of results at the first interim analysis, for both efficacy (HR ∼0.82, alpha spend 1%) and lack of clinical benefit (HR ∼0.935 with a 5% risk of declaring a false negative result). Contingent on DMEC advice, efficacy results that breach either boundary will be presented. A DMEC recommendation not to release the results at the second interim analysis may indicate that the point HR estimate lies between these boundaries.
Results: Patient characteristics including stage, number of positive axillary nodes, CT type, ER status, menopausal status and statin use were well balanced. 3208 patients (96%) received (neo) adjuvant CT (93% anthracyclines, 23% taxanes). 152 patients received ET alone. As of June 9th 2010, with a median follow up of 49 (IQR 42-56) months, there have been 695 DFS events. The safety population comprised 3340 patients (ZOL 1665; control 1675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. Serious adverse events (SAE) were similar in both treatment arms. To date 13 confirmed (0.83%; 95% CI 0.38%, 1.28%) and 12 possible (1.12%; 95% CI 0.39%, 1.85%) cases of osteonecrosis of the jaw (ONJ) in the ZOL arm have occurred. Discussion: AZURE is one of the largest phase III studies of adjuvant bisphosphonates, and the results from this study will help define the role of adjuvant ZOL in the management of early breast cancer.
[1] Gnant M et al. NEJM 2009; 360(7):679-691
[2] Gnant M et al. ASCO 2010 Proceedings; abs #533.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S4-5.
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