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Upfront zoledronic acid best for postmenopausal breast cancer patients
Brufsky AM. Cancer. 2011;doi:10.1002/cncr.26313.
Postmenopausal patients with breast cancer who receive adjuvant aromatase inhibitor therapy benefit from receiving upfront treatment with zoledronic acid, according to the final 5-year results of the Z-FAST trial, published in the journal Cancer.
“Many physicians are concerned about the side effects of bisphosphonates, especially in the long term,” said study researcher Adam M. Brufsky, MD, PhD, professor of medicine at the University of Pittsburgh School of Medicine and a member of the HemOnc Today Editorial Board. “This study clearly shows that these women can be on zoledronic acid for the long term with very few side effects.”
Women who receive therapy with aromatase inhibitors such as letrozole (Femara, Novartis) are at increased risk for bone loss and fractures. These can occur within the first 12 months of therapy, and the risk continues throughout the duration of treatment. However, aromatase inhibitors are related to improved DFS rates and are the preferred adjuvant treatment option for postmenopausal women with hormone receptor-positive breast cancer. According to Brufsky, approximately one-third of women on aromatase inhibitors will require intervention to prevent bone loss and fractures.
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Studies have shown that zoledronic acid increases bone mineral density (BMD) in both premenopausal and postmenopausal women with breast cancer who are at risk for bone loss related to cancer treatment. The drug is indicated for patients with multiple myeloma or patients with bone metastasis from solid tumors. Recent data have also shown that the bisphosphonates have anticancer effects in breast cancer and other cancers.
Several trials have investigated whether patients do better with upfront zoledronic acid administered with letrozole or delayed zoledronic acid administered with a decrease in T-score to less than –2 or occurrence of clinical nontraumatic fracture. The data from all trials indicate that upfront zoledronic acid is significantly more effective at preventing bone loss.
“Most physicians are already offering bisphosphonates to protect women who are on aromatase inhibitors,” Brufsky said. “This study is reinforcing something that physicians are already practicing.”
Z-FAST trial
The Z-FAST trial was a 5-year, open-label, multicenter study that included 602 women who enrolled in the trial between Sept. 28, 2002, and Dec. 5, 2003. All women were postmenopausal and had a history of surgically resectable, early-stage, ER-positive and/or PR-positive breast cancer. The women received letrozole 2.5 mg orally daily for 5 years.
The women were randomly assigned to upfront or delayed-start zoledronic acid, 4 mg IV every 6 months. Patients who received the zoledronic acid upfront received it right after randomization. Patients who received delayed-start zoledronic acid received it when their post-baseline lumbar spine or total hip T-score decreased to less than –2; they had any clinical nontraumatic fracture; or they had an asymptomatic vertebral fracture at the 36-month follow-up.
The primary objective was to measure the difference in lumbar spine BMD from baseline to 12 months in the upfront and delayed groups. Secondary objectives were to compare the lumbar spine BMD between the groups at 24, 36 and 61 months and total hip BMD differences between the groups from baseline to 12, 24, 36 and 61 months.
Five-year results
The researchers found that patients who received upfront zoledronic acid had increases in lumbar spine and total hip BMD, whereas patients who received delayed zoledronic acid had significant decreases in lumbar spine and total hip BMD at all time points. From baseline to month 61, the lumbar spine BMD increased from 4.3% to 8.9%, and the total hip BMD increased from 3.2% to 6.7%. The rates of adverse events were similar between the two groups.
Seventy-four patients in the delayed zoledronic acid group had received the drug by 61 months. A post hoc analysis of the patients in the delayed zoledronic acid group showed that patients who received no zoledronic acid had a larger BMD decrease than the entire group combined. Patients in this group who eventually received zoledronic acid had small BMD increases by month 61. – by Emily Shafer
Disclosure: Dr. Brufsky received research funding from and is a consultant for Novartis.
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This is a study about using zoledronic acid early or late to preserve BMD in postmenopausal women treated with the aromatase inhibitor letrozole in the postoperative adjuvant setting. It uses a surrogate of the risk of fractures, which is the change in BMD, and it demonstrates that earlier and broader use of bisphosphonates is superior to waiting. But given what is already known about bisphosphonates, this is not a surprise. Breast cancer clinicians are advised to follow the ASCO guidelines, which recommend monitoring bone density and responding appropriately. This study shows that if you treat everybody, then you can prevent some of the changes in BMD, although the actual rate of fractures was high and did not vary significantly across the two groups. The study does not address the broader question of whether everybody on aromatase inhibitors should receive a bisphosphonate. Several large trials have not demonstrated any meaningful differences in outcomes in terms of breast cancer itself. The take-home message is that the bisphosphonates work here the same as they work elsewhere: They decrease the rate of BMD loss in people at risk. That is true for all postmenopausal women, including those on aromatase inhibitors.
– Clifford Hudis, MD
Chief, Breast Cancer
Medicine Service, Memorial Sloan-Kettering Cancer Center
Disclosure: Dr. Hudis reports no relevant financial disclosures.
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