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Adjuvant Use of Zoledronic Acid Fails to Extend Survival in Stage II/III Breast Cancer (AZURE Trial Results)

Laino, Charlene

doi: 10.1097/01.COT.0000396394.75144.dc
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Adjuvant use of the bisphosphonate zoledronic acid did not improve disease-free or overall survival rates in a broad population of women with Stage II/III breast cancer, researchers reported here at the CTRC-AACR San Antonio Breast Cancer Symposium.

Long-awaited esults of the study—the AZURE, Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial—of more than 3,000 women also showed that the bisphosphonate did not improve recurrence rates when added to adjuvant chemotherapy.

In a prespecified subgroup analysis, however, a highly significant heterogeneity of effect by menopausal status was seen, with improved disease-free survival and overall survival rates in women more than five years post-menopause.

“This wasn't a small subgroup,” said lead researcher Robert E. Coleman, MD, Professor of Medical Oncology at the University of Sheffield. “1,101 women fell into the category. The benefit was so great we don't think it's a chance finding.”

Still, he said, the results of a subgroup analysis cannot be considered conclusive.

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Austrian Trial Suggests Benefit

Leading up to the report, in vitro and animal research had originally suggested that bisphosphonates may have a direct anti-cancer effect—inducing apoptosis, reducing angiogenesis, and stimulating memory T cells, noted Rowan T. Chlebowski, MD, PhD, Professor and Chief of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center.

MICHAEL GNANT, MD, principal investigator of the ABCSG XII trial, said that the results of his study showed that zoledronic acid has a role in the treatment of premenopausal women who are treated with goserelin to induce artificial menopause, and that the new data extend that to postmenopausal women

MICHAEL GNANT, MD, principal investigator of the ABCSG XII trial, said that the results of his study showed that zoledronic acid has a role in the treatment of premenopausal women who are treated with goserelin to induce artificial menopause, and that the new data extend that to postmenopausal women

ROBERT E

ROBERT E

The new results suggest it may have an indirect effect on the host, modifying the bone marrow in such a way as to improve outcomes, Dr. Coleman said.

The medical community has been awaiting the results of AZURE since the Austrian Breast and Colorectal Cancer Study Group (ABCSG ) XII trial showed that the addition of zoledronic acid to adjuvant endocrine therapy improved disease-free survival rates in premenopausal patients with estrogen-responsive early breast cancer (Gnant et al: NEJM 2009;360:679-691).

Also, at the 2009 San Antonio Breast Cancer Symposium, Dr. Chlebowski presented an analysis of data on some 150,000 women in the Women's Health Initiative that showed that there were 31% fewer cases of breast cancer among women who took oral bisphosphonates than among women who did not.

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AZURE Largest Study to Date

AZURE enrolled 3,360 patients with Stage II/III breast cancer, making it the largest study to date on the use of bisphosphonates in breast cancer.

Nearly all patients had adjuvant chemotherapy, and some received endocrine therapy. The women were randomized in a one-to-one fashion to either placebo or zoledronic acid (4 mg intravenously over three to four weeks for six doses, and then every three months for eight doses and every six months for five doses).

After a median follow-up period of 59 months, the disease-free survival rates were virtually identical between the two arms. There were 404 events in the zoledronic acid group and 403 in the control arm.

There were 243 deaths in the zoledronic acid arm compared with 276 in the placebo arm, resulting in a nonsignificant trend favoring the bisphosphonate.

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Prespecified Subset Analysis

In the preplanned subset analysis based on menopausal status, zoledronic acid was associated with a significant 29% reduction in risk of death in women who were more than five years postmenopausal. There was no significant effect in premenopausal or perimenopausal women.

“Adjuvant bisphosphonate efficacy may be dependent on a low estrogen concentration within the bone microenvironment,” Dr. Coleman said.

The most significant toxicity was osteonecrosis of the jaw, confirmed in 17 women on zoledronic acid and suspected in another nine women.

Other serious adverse events that occurred more frequently in the zoledronic acid arm were pyrexia (2.2% vs. 1.4%) and vomiting (2.1% vs. 1.4%).

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Routine Use ‘Not Indicated’

Commenting on the results, Sharon H. Giordano, MD, MPH, Associate Professor of Medicine in the Division of Breast Medical Oncology at The University of Texas M.D. Anderson Cancer Center, said the apparent benefit in postmenopausal women “is intriguing, but not definitive.”

“Routine adjuvant use of zoledronic acid to prevent recurrence is not indicated,” she said.

Alan Coates, MD, Clinical Professor of Public Health at the University of Sydney School of Public Health, concurred. Results from the subset analysis should be considered exploratory, he said.

“It would be irresponsible” to use them as the basis for treating postmenopausal women with adjuvant zoledronic acid.”

Michael Gnant, MD, Professor of Surgery at the Medical University of Vienna and principal investigator of the ABCSG XII trial, disagreed.

The Austrian trial showed that zoledronic acid has a role in the treatment of premenopausal women who are given goserelin to induce artificial menopause, and the new findings extend that to postmenopausal women, he said. “Before, I would say that I would treat my wife, who is 42. Now I would also treat my mother, who is 82.”

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ABCSG XII Update

Later at the meeting in a poster study, Dr. Gnant presented updated results from the ABCSG XII trial, which originally showed that zoledronic acid was associated with a 36% improvement in disease-free survival rates after 48 months.

After 14 more months of follow-up, adjuvant endocrine therapy plus zoledronic acid continued to be associated with significantly better outcomes than endocrine therapy alone, he reported.

The population of women in this study was quite different from those in AZURE: They were premenopausal women with Stage I/II breast cancer. None received chemotherapy, and zoledronic acid was infused once every six months.

“Zoledronic acid's anticancer benefits are consistent with the seed-and-soil hypothesis. Bisphosphonates may modify the bone marrow microenvironment and thereby contribute to the disease-free survival results seen in and outside of bone,” Dr. Gnant said.

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Still Indicated for Bone Loss

Four trials are under way that should better define bisphosphonates' role as an adjuvant treatment, Dr. Giordano said.

The AZURE results do not affect bisphosphonates' “important role in treating bone loss among women with breast cancer,” she stressed.

Novartis Pharmaceuticals, which funded AZURE, released a statement after the results were reported that the company is withdrawing U.S. and European applications for approval of zoledronic acid as adjuvant therapy for breast cancer, pending further review of the data.

© 2011 Lippincott Williams & Wilkins, Inc.
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