Adjuvant zoledronic acid therapy for patients with early stage breast cancer: an updated systematic review and meta-analysis

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Abstract

Background

Zoledronic acid is a potent inhibitor of osteoclast-mediated bone resorption and has been widely used in bone metastasis malignancies and postmenopausal osteoporosis as a preventive therapy against skeletal-related events. The purpose of this study was to evaluate the clinical outcome of zoledronic acid as an adjuvant therapy for patients with early stage breast cancer.

Patients and methods

Entries in the PubMed and EMBASE databases up to 12 July 2013 were systematically reviewed. Online abstracts from the proceedings of the Annual Meetings of the American Society of Clinical Oncology (ASCO) (1992–2013) and the San Antonio Breast Cancer Symposium (SABCS) (2004–2013) were also reviewed. Primary endpoints included overall survival (OS) and disease-free survival (DFS), while secondary endpoints included bone metastasis-free survival (BMFS), distant metastasis-free survival (DMFS), and fracture-free rate (FFR).

Results

A total of eight studies including 3,866 subjects and 3,864 controls met our search criteria and were evaluated. The use of zoledronic acid was found to improve OS (relative risk (RR), 0.88; 95% confidence interval (CI), 0.77–1.01; p-value = 0.06) and DMFS (RR, 0.77; 95% CI, 0.60–1.00; p-value = 0.05). Furthermore, statistically significant benefits were associated with BMFS (RR, 0.81; 95% CI, 0.66–0.99; p-value = 0.04) and FFRs (RR, 0.75; 95% CI, 0.61–0.92; p-value = 0.007). In contrast, there was no significant difference in DFS with the application of zoledronic acid (RR, 0.88; 95% CI, 0.72–1.09; p-value = 0.24). Sensitivity analysis further identified the improvement of 5-year OS for the adjuvant zoledronic acid therapy in early stage breast cancer patients (RR, 0.86; 95% CI, 0.75–0.99; p-value = 0.03), while a borderline statistically significant benefit was observed for 5-year DFS (RR, 0.90; 95% CI, 0.81–1.00; p-value = 0.06).

Conclusion

Zoledronic acid as an adjuvant therapy appears to improve the 5-year OS rate for early stage breast cancer patients, and was associated with a protective effect for the bone metastases and fractures evaluated in more than 7,000 patients. However, further research is needed to confirm our findings, and sub-group analyses according to menopause status or hormone status may provide further insight.

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Most cited references 23

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The clinical course of bone metastases from breast cancer.

R Coleman, R D Rubens (1987)

All patients with carcinoma of the breast seen in this Unit since 1970 were reviewed to study the incidence, prognosis, morbidity and response to treatment of bone metastases. The biological characteristics of the primary tumour were compared in patients relapsing first in bone or liver. Sixty-nine percent of patients dying with breast cancer had bone metastases and bone was the commonest site of first distant relapse. Bone relapse was more common in receptor positive or well differentiated (grade 1) tumours. The median survival was 24 months in those with disease apparently confined to the skeleton compared with 3 months after first relapse in liver. Ten percent of patients with breast cancer developed hypercalcaemia. All had metastatic disease and 85% had widespread skeletal involvement. Fifteen percent of patients with disease confined to the skeleton developed hypercalcaemia. The response in bone to primary endocrine therapy, and chemotherapy, was apparently less than the overall response achieved. A large proportion had apparently static disease reflecting the insensitivity of the UICC assessment criteria. The duration of survival in these patients was similar to responding patients, suggesting a tumour response may occur in the absence of discernable radiological evidence of healing.

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Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results.

R. Coleman, R De Boer, H Eidtmann … (2013)

Aromatase inhibitors are the preferred adjuvant endocrine therapy for the majority of postmenopausal women with hormone-responsive early breast cancer. Although generally more effective than tamoxifen, aromatase inhibitor therapy is associated with increased bone loss and fracture risk. Postmenopausal women receiving adjuvant letrozole (2.5 mg/day for 5 years; N = 1065) were randomly assigned to immediate zoledronic acid (zoledronate) 4 mg every 6 months for 5 years, or delayed zoledronate (initiated for fracture or on-study bone mineral density [BMD] decrease). The primary end point was the change in lumbar spine BMD at 12 months. Lumbar spine and total hip BMD at subsequent follow-up, disease-free survival (DFS), and overall survival were assessed as secondary end points. At 60 months (final analysis), the mean change in lumbar spine BMD was +4.3% with immediate zoledronate and -5.4% with delayed intervention (P < 0.0001). Immediate zoledronate reduced the risk of DFS events by 34% (hazard ratio [HR] = 0.66; P = 0.0375) with fewer local (0.9% versus 2.3%) and distant (5.5% versus 7.7%) recurrences versus delayed zoledronate. In the delayed group, delayed initiation of zoledronate substantially improved DFS versus no zoledronate (HR = 0.46; P = 0.0334). Immediate zoledronate in postmenopausal women receiving letrozole preserved BMD and is associated with improved DFS compared with letrozole alone. Clinical Trials Registration No NCT00171340.

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Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy.

Hellmut Samonigg, Florian Fitzal, Christian Marth … (2008)

The Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) bone substudy assesses zoledronic acid for preventing bone loss associated with adjuvant endocrine therapy and reports on long-term findings of bone-mineral density (BMD) during 3 years of treatment and 2 years after completing adjuvant treatment with or without zoledronic acid. The aim of this substudy is to gain insight into bone health in this setting. ABCSG-12 is a randomised, open-label, phase III, 4-arm trial comparing tamoxifen (20 mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days) versus anastrozole (1 mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days), both with or without zoledronic acid (4 mg intravenously every 6 months) for 3 years in premenopausal women with endocrine-responsive breast cancer. This prospective bone subprotocol measured BMD at 0, 6, 12, 36, and 60 months. The primary endpoint of the bone substudy (secondary endpoint in the main trial) was change in BMD at 12 months, assessed by dual-energy X-ray absorptiometry in assessable patients. Analyses were intention to treat. Statistical significance was assessed by t tests. The ABCSG-12 trial is registered on the ClinicalTrials.gov website, number NCT00295646. 404 patients were prospectively included in the bone substudy and randomly assigned to endocrine therapy alone (goserelin and anastrozole or goserelin and tamoxifen; n=199) or endocrine therapy concurrent with zoledronic acid (goserelin, anastrozole, and zoledronic acid or goserelin, tamoxifen, and zoledronic acid; n=205). After 3 years of treatment, endocrine therapy alone caused significant loss of BMD at the lumbar spine (-11.3%, mean difference -0.119 g/cm(2) [95% CI -0.146 to -0.091], p<0.0001) and trochanter (-7.3%, mean difference -0.053 g/cm(2) [-0.076 to -0.030], p<0.0001). In patients who did not receive zoledronic acid, anastrozole caused greater BMD loss than tamoxifen at 36 months at the lumbar spine (-13.6%, mean difference -0.141 g/cm(2) [-0.179 to -0.102] vs -9.0%, mean difference -0.095 g/cm(2) [-0.134 to -0.057], p<0.0001 for both). 2 years after the completion of treatment (median follow-up 60 months [range 15.5-96.6]), patients not receiving zoledronic acid still had decreased BMD at both sites compared with baseline (lumbar spine -6.3%, mean difference -0.067 g/cm(2) [-0.106 to -0.027], p=0.001; trochanter -4.1%, mean difference -0.03 g/cm(2) [-0.062 to 0.001], p=0.058). Patients who received zoledronic acid had stable BMD at 36 months (lumbar spine +0.4%, mean difference 0.004 g/cm(2) [-0.024 to 0.032]; trochanter +0.8%, mean difference 0.006 g/cm(2) [-0.018 to 0.028]) and increased BMD at 60 months at both sites (lumbar spine +4.0%, mean difference 0.039 g/cm(2) [0.005-0.075], p=0.02; trochanter +3.9%, mean difference 0.028 g/cm(2) [0.003-0.058], p=0.07) compared with baseline. Goserelin plus tamoxifen or anastrozole for 3 years without concomitant zoledronic acid caused significant bone loss. Although there was partial recovery 2 years after completing treatment, patients receiving endocrine therapy alone did not recover their baseline BMD levels. Concomitant zoledronic acid prevented bone loss during therapy and improved BMD at 5 years.

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Author and article information

Contributors

Mingfeng He

Weidong Fan

Xianquan Zhang

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central

ISSN (Electronic): 1756-8722

Publication date Collection: 2013

Publication date (Electronic): 23 October 2013

Volume: 6

Page: 80

Affiliations

[1 ]Division of Oncology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China

Article

Publisher ID: 1756-8722-6-80

DOI: 10.1186/1756-8722-6-80

PMC ID: 3874690

PubMed ID: 24283946

SO-VID: 35386f6a-5be6-4478-b2ed-9e6285b1dc49

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 23 July 2013

Date accepted : 16 October 2013

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Adjuvant zoledronic acid therapy for patients with early stage breast cancer: an updated systematic review and meta-analysis

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Abstract

Background

Patients and methods

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Karger: Oncology

Most cited references 23

The clinical course of bone metastases from breast cancer.

Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results.

Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy.

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