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      Possible survival benefits from zoledronic acid treatment in patients with bone metastases from solid tumours and poor prognostic features—An exploratory analysis of placebo-controlled trials

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          Abstract

          Background

          Zoledronic acid (ZOL) is an important component of therapy for patients with metastatic bone disease (MBD) to reduce the risk of skeletal-related events (SREs). We evaluated overall survival (OS) in patients with MBD secondary to solid tumours included in placebocontrolled ZOL trials.

          Patients and methods

          Exploratory analyses were performed using databases from three randomised trials of ZOL versus placebo. 1126 patients (ZOL, n=731; placebo, n=395) with complete baseline data for 18 predefined parameters were evaluated for OS. Relative risks (RRs) with 95% confidence intervals were assessed using stratified and adjusted Cox regression models. Baseline covariates defining patient populations with significantly different effects of ZOL treatment on OS (identified by stepwise backward elimination) were included in multivariate models.

          Results

          Although OS was similar between the overall treatment groups, ZOL significantly improved OS in the subset of patients ( n=423; 38%) with elevated baseline NTX (≥100 nmol/mmol creatinine; RR, 0.692; P=.0028). Notably, this effect was independent of SRE prevention. Additional covariates associated with OS benefits with ZOL (e.g., low albumin, SRE history, elevated lactate dehydrogenase, shorter cancer duration) were characteristic of advanced disease.

          Conclusion

          These exploratory analyses suggest a beneficial effect of ZOL on OS in patients with highly aggressive or advanced MBD.

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          Most cited references20

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          Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid.

          Three large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy. Urinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients-1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non-small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low ( or = 100 nmol/mmol creatinine), and BAP as low ( or = 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates. Patients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes. The bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.
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            The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer

            Background: Pre-clinical studies have demonstrated synergistic anti-tumour effects of chemotherapy (CT) and zoledronic acid (ZOL). Within the AZURE trial, designed to determine whether the addition of ZOL to neoadjuvant therapy improves disease outcomes, a subgroup received neoadjuvant CT. We report a retrospective evaluation comparing pathological response in the primary tumour between treatment groups. Methods: In total, 205 patients received neoadjuvant CT±ZOL (CT+ZOL, n=102; CT, n=103). The primary end point was pathologically assessed residual invasive tumour size (RITS) at surgery. Secondary end points were pathological complete response (pCR) rate and axillary nodal involvement. Following review of surgical pathology reports (n=195), outcome differences between groups were assessed adjusting for potential response modifiers. Results: Baseline characteristics and CT treatments were similar. In multivariate analysis, allowing for biological and clinical factors known to influence tumour response, the adjusted mean RITS in CT and CT+ZOL groups were 27.4 and 15.5 mm, respectively, giving a difference in means of 12 mm (95% confidence interval: 3.5–20.4 mm; P=0.006). The pCR rate was 6.9% in the CT group and 11.7% in the CT+ZOL group (P=0.146). There was no difference in axillary nodal involvement (P=0.6315). Conclusion: These data suggest a possible direct anti-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies.
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              Approval summary for zoledronic acid for treatment of multiple myeloma and cancer bone metastases.

              This article summarizes data submitted to the United States Food and Drug Administration for marketing approval of zoledronic acid (Zol; Novartis Pharmaceuticals, East Hanover, NJ), a bisphosphonate drug for treating patients with bone metastases. We review the chemistry, toxicology, pharmacology, and clinical study results submitted to support the supplemental New Drug Application for Zol for treatment of patients with bone metastases. Four- and 8-mg Zol doses were selected for Phase III trials based on bone resorption markers and clinical efficacy parameters. Patients with bone metastases were randomized in three Phase III studies (prostate cancer, solid tumors, and multiple myeloma or breast cancer) to receive 4 or 8 mg of Zol or to a control arm. The control was a placebo in the prostate cancer study and the other solid tumor study and was 90 mg of pamidronate (Pam) in the study of breast cancer and multiple myeloma. Studies were amended twice because of renal toxicity, initially to increase Zol infusion time from 5 to 15 min and later to decrease the dose in the Zol 8-mg arm to 4 mg. The efficacy end point was skeletal-related events (SREs), a composite end point consisting of pathologic fracture, radiation therapy to bone, changes in antineoplastic therapy for bone pain (prostate cancer only), surgery to bone, or spinal cord compression. This end point was analyzed either as the proportion of patients with SRE or time to first SRE. The breast cancer and myeloma study used a noninferiority statistical analysis methods to determine efficacy. In prostate cancer, both the proportions analysis and time-to-SRE analysis showed significantly less bone morbidity on Zol (4 mg) than placebo, but no significant difference between Zol (8 mg) and placebo in either analysis. In the solid tumor study, the time to SRE analysis but not the proportions analysis showed significantly less skeletal morbidity on Zol (4 mg) than placebo, and Zol (8 mg) was significantly better than placebo in both analyses. The breast cancer and myeloma study demonstrated noninferiority of Zol compared with Pam, with Zol retaining at least 49.3% of the Pam treatment effect previously demonstrated in placebo-controlled trials. Zol was approved on February 22, 2002, by the United States Food and Drug Administration for the "treatment of patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy." The recommended dose and schedule is 4 mg of Zol infused over 15 min every 3-4 weeks. Increased Zol doses and shorter infusions are not recommended because of potential renal toxicity.
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                Author and article information

                Contributors
                Journal
                J Bone Oncol
                J Bone Oncol
                Journal of Bone Oncology
                Elsevier
                2212-1366
                2212-1374
                09 February 2013
                June 2013
                09 February 2013
                : 2
                : 2
                : 70-76
                Affiliations
                [a ]Department of Oncology, Cancer Clinical Trials Centre, University of Sheffield, Weston Park Hospital, Cancer Research Centre, Sheffield, UK
                [b ]College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA
                [c ]Clinical and Translational Oncology Research Unit, Instituto de Medicina Molecular, Lisbon, Portugal
                [d ]Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, ON, Canada
                [e ]Division of Urology, Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame, Montréal, QC, Canada
                [f ]Department of Oncology and Clinical Research, Cancer Research UK Centre, St James’s Hospital, Leeds, UK
                [g ]Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece
                [h ]Department of Oncology, Division of Medical Oncology, McMaster University, Juravinski Cancer Centre, Hamilton, ON, Canada
                [i ]Division of Breast Oncology, Tokyo Medical University, Tokyo, Japan
                [j ]Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center, Boston, MA, USA
                [k ]Department of Medicine, University Hospital Brugmann, ULB, Brussels, Belgium
                Author notes
                [* ]Correspondence to: Department of Oncology, Cancer Clinical Trials Centre, Academic Unit of Clinical Oncology, Weston Park Hospital, University of Sheffield, Whitham Road, Sheffield S10 2SJ, England, United Kingdom Tel.: +44 114 2265213; fax: +44 114 2265364. r.e.coleman@ 123456sheffield.ac.uk
                Article
                S2212-1374(13)00006-7
                10.1016/j.jbo.2013.01.002
                4723367
                26909273
                58b1a262-86a7-4ffb-a10f-a705434b9a36
                © 2013 Elsevier GmbH.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 18 December 2012
                : 14 January 2013
                : 14 January 2013
                Categories
                Research Article

                breast cancer,non-small cell lung cancer,n-telopeptide of type i collagen,prostate cancer,survival,zoledronic acid

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