No Disease-Free Survival Benefit of Adjuvant Zoledronic Acid in High-Risk Patients With Early Breast Cancer
In the open-label phase III AZURE trial reported in The Lancet Oncology, Coleman et al found that adjuvant zoledronic acid treatment in patients with high-risk early-stage breast cancer provided no overall disease-free survival benefit. A reduction in bone metastases was observed, and women who were > 5 years postmenopause appeared to derive a disease-free survival benefit.
Study Details
In the trial, 3,360 women with stage II or III breast cancer from 174 centers in seven countries were randomly assigned between September 2003 and February 2006 to receive standard systemic adjuvant therapy with or without intravenous zoledronic acid. Zoledronic acid was given at 4 mg every 3 to 4 weeks for six doses, every 3 months for eight doses, and every 6 months for five doses, for a total of 5 years of treatment. The primary endpoint was disease-free survival in the intent-to-treat population.
No Disease-Free Survival Difference Overall
Median follow-up was 84 months. Compared with the control group, the zoledronic acid group had similar disease-free survival (adjusted hazard ratio [HR] = 0.94, P = .30), invasive disease-free survival (HR = 0.93, P = .22), overall survival (HR = 0.93, P = .37), and risk of distant recurrence (HR = 0.93, P = .29). Patients in the zoledronic acid group had reduced risk of bone metastases as a first event (HR = 0.78, P = .020) and at any time during follow-up (HR = .81, P = .022).
Improved Disease-Free Survival in Women > 5 Years Postmenopause
There was no difference in disease-free survival between groups according to estrogen receptor status. Among 1,041 patients who were > 5 years postmenopause, zoledronic acid was associated with a significant improvement in invasive disease-free survival (HR = 0.77, 95% confidence interval [CI] = 0.63–0.96), with no difference observed among the 2,318 patients in all other menopausal status subgroups (HR = 1.03, 95% CI = 0.89–1.20).
Overall, there were 33 suspected cases of osteonecrosis of the jaw; all 26 cases confirmed by central review were in the zoledronic acid group (1.7%).
The investigators concluded, “These results suggest no overall benefit from the addition of zoledronic acid to standard adjuvant treatments for early breast cancer. However, zoledronic acid does reduce the development of bone metastases and, for women with established menopause, improved disease outcomes.
Robert Coleman, FRCP, of Weston Park Hospital, Sheffield, is the corresponding author for The Lancet Oncology article.
The study was funded by Novartis Global and the UK National Institute for Health Research Cancer Research Network. For full disclosures of the study authors, visit www.thelancet.com.
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