Breast-Cancer Adjuvant Therapy with Zoledronic Acid

Academic Unit of Clinical Oncology, Weston Park Hospital, University of Sheffield, United Kingdom.
New England Journal of Medicine (Impact Factor: 55.87). 10/2011; 365(15):1396-405. DOI: 10.1056/NEJMoa1105195
Source: PubMed


Data suggest that the adjuvant use of bisphosphonates reduces rates of recurrence and death in patients with early-stage breast cancer. We conducted a study to determine whether treatment with zoledronic acid, in addition to standard adjuvant therapy, would improve disease outcomes in such patients.
In this open-label phase 3 study, we randomly assigned 3360 patients to receive standard adjuvant systemic therapy either with or without zoledronic acid. The zoledronic acid was administered every 3 to 4 weeks for 6 doses and then every 3 to 6 months to complete 5 years of treatment. The primary end point of the study was disease-free survival. A second interim analysis revealed that a prespecified boundary for lack of benefit had been crossed.
At a median follow-up of 59 months, there was no significant between-group difference in the primary end point, with a rate of disease-free survival of 77% in each group (adjusted hazard ratio in the zoledronic acid group, 0.98; 95% confidence interval [CI], 0.85 to 1.13; P=0.79). Disease recurrence or death occurred in 377 patients in the zoledronic acid group and 375 of those in the control group. The numbers of deaths--243 in the zoledronic acid group and 276 in the control group--were also similar, resulting in rates of overall survival of 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted hazard ratio, 0.85; 95% CI, 0.72 to 1.01; P=0.07). In the zoledronic acid group, there were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1%; 95% CI, 0.6 to 1.7; P<0.001) and 9 suspected cases; there were no cases in the control group. Rates of other adverse effects were similar in the two study groups.
These findings do not support the routine use of zoledronic acid in the adjuvant management of breast cancer. (Funded by Novartis Pharmaceuticals and the National Cancer Research Network; AZURE Current Controlled Trials number, ISRCTN79831382.).

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    • "Clinical investigations have also provided evidence that some N-BP drugs (e.g., 1a) improve the survival of patients with MM via mechanisms that are both related, as well as unrelated to the skeletal benefits (Morgan et al., 2010, 2012). Similar results have been reported for patients with premenopausal breast cancer (Gnant et al., 2009), although these findings seem to be more controversial (Coleman et al., 2011). In spite of all the preliminary evidence, the limited half-life of N-BPs in plasma (i.e., the fast elimination from the blood circulation) and negligible distribution to non-skeletal tissues compromise clinical validation of these compounds as true antineoplastic agents, and consequently, the clinical validation of hFPPS as a therapeutic target for non-skeletal malignancies. "
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    • "Currently , ZOL , a potent inhibitor of FDPS , is used in the treatment of patients with breast and prostate cancers that have metastasised to the bone , to prevent treatment - associated bone loss in breast cancer , as well as to slow the progression of osteoporosis ( Brufsky et al , 2007 ; Gnant et al , 2007 ) . ZOL has also undergone clinical trials as an adjuvant to standard of care for breast cancer , showing mixed efficacy results ( Brufsky et al , 2007 ; Gnant et al , 2007 ; Coleman et al , 2011 ) . ZOL has been seen to radiosensitise fibrosarcoma ( Koto et al , 2013 ) , osteosar - coma ( Ryu et al , 2010 ) , oesophageal squamous cell carcinoma ( You et al , 2014 ) , and breast cancer cells ( Ural et al , 2006 ) in preclinical studies . "
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    • "Several clinical trials have shown the ability of oral and intravenous bisphosphonates to reduce the incidence and frequency of SREs and skeletal morbidity and prevent bone loss in patients with breast cancer bone metastasis when administrated alone or in combination with adjuvant therapy (5,19–24). However, results from the recent AZURE (4) trial, in which over 3000 patients with stage II/III breast cancer were randomized to receive standard therapy (chemotherapy, endocrine therapy, radiation) or standard therapy plus 4 mg of ZOL showed no significant difference between patients receiving ZOL in addition to adjuvant therapy compared to patients receiving only standard therapy, in terms of recurrence of breast cancer or on overall survival. However, a subgroup analysis that evaluated the patients receiving ZOL plus adjuvant therapy by their menopausal status, showed a significant positive effect on both recurrence and survival but only in postmenopausal women compared to patients who were pre- and peri-menopausal. "
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