Upfront Zoledronic Acid in Breast Cancer Patients on AIs

Zosia Chustecka

November 01, 2011

November 1, 2011 — In postmenopausal breast cancer patients, bisphosphonates are commonly used to counter the adverse effects of aromatase inhibitors (AIs) on bone. Now there is a suggestion that the bisphosphonate should be started upfront, at the same time as the AI, instead of being added when a problem develops.

The use of upfront bisphosphonates has been tested in 3 large trials of zoledronic acid in women with early breast cancer receiving the AI letrozole. All 3 of these studies — Z-FAST, ZO-FAST, and E-ZO-FAST — were funded by Novartis, the manufacturer of both zoledronic acid and letrozole.

The results from all 3 studies, at a follow-up of 36 months, found that the upfront use of zoledronic acid was significantly more effective in preventing bone loss than starting the drug only when a problem developed.

The 5-year results from the Z-FAST trial, published online October 10 in Cancer, confirm the earlier finding that upfront zoledronic acid is significantly more effective than delayed use in preventing bone loss.

"Upfront zoledronic acid seems to be the preferred treatment strategy versus delayed administration, as it significantly and progressively increases [bone mineral density] in postmenopausal women with early breast cancer receiving letrozole for 5 years," the authors conclude.

Lead author Adam Brufsky, MD, PhD, from the Magee-Womens Hospital, Pittsburgh, Pennsylvania, told Medscape Medical News that Z-FAST is the largest of these studies, and clearly shows that the upfront use of the drug gives "better results" than delayed use. These final results also show that the drug is safe over 5 years, he said.

There is also an intriguing finding that hints at an effect of zoledronic acid on the breast cancer itself, which has also been suggested in other studies. There were fewer distant recurrences in the upfront group than in the delayed group (9 vs 19), Dr. Brufsky noted. This was not statistically significant, but the study was not powered to look for this effect, he pointed out.

"This is the story behind the story," Dr. Brufsky told Medscape Medical News. "By giving the drug upfront, we are not only protecting the bones, we may also be protecting against breast cancer."

However, this is a controversial view. Some experts argue that the evidence so far is insufficient to support the use of the drug to protect against breast cancer and that the effects on bone might not be needed in all patients.

Five-Year Results

The Z-FAST trial was conducted in 602 postmenopausal women with early hormone-receptor-positive breast cancer who were receiving oral letrozole (2.5 mg daily for 5 years).

These women were randomized to receive zoledronic acid (4 mg intravenously every 6 months) either upfront, in which case they were given the first dose when they started on letrozole, or when they developed a problem.

In the delayed group, women received zoledronic acid if they developed 1 of the following problems: bone mineral density decreased (T score below –2.0), any clinical nontraumatic fracture occurred, or an asymptomatic vertebral fracture was identified at 36-month follow-up.

In the Z-FAST study, 24.6% (74) of the women in the delayed group had received zoledronic acid by month 61. Most of these patients (66.2%) had been given the drug after meeting protocol-defined criteria, but a few were given the drug at the investigators' discretion, the authors note.

The final results from the Z-FAST study show that bone mineral density decreased significantly at all time points with delayed treatment and progressively increased with upfront treatment.

Fractures occurred in slightly more women in the delayed group than in the upfront group (11% vs 9.3%), but this difference was not statistically significant. Most of these fractures were associated with significant trauma, and the most common fracture sites were the rib and foot.

In addition, the time to first fracture was shorter in the upfront group than in the delayed group (24.7 vs 34.4 months). However, the authors add that these results should be interpreted cautiously because the study was not adequately powered to detect a difference in fracture rates.

Long-term use of letrozole and zoledronic acid was generally well tolerated, the authors add. They note that there were no confirmed cases of osteonecrosis of the jaw (a known adverse effect of zoledronic acid), and only 1% of patients experienced study-related renal impairment.

Commonly Used in Clinical Practice

Although zoledronic acid is not approved to prevent bone loss in women with breast cancer, this and other bisphosphonates are commonly used in this way in clinical practice, and indeed are recommended for such use in both European and American guidelines, Rob Coleman MB, BS, MD, from the Weston Park Hospital, Sheffield, United Kingdom, told Medscape Medical News.

However, the approach tested in these studies — upfront in all women taking an AI — is a new use of zoledronic acid.

Dr. Coleman explained that in routine clinical practice, his team's approach is to stratify patients according to their risk for fracture.

In the Z-FAST study, about a quarter of women in the delayed group were given zoledronic acid during the course of the study. In clinical practice, about a third of women taking AIs develop problems, Dr. Brufsky said.

Medscape Medical News asked Dr. Coleman whether a large proportion of the women in the upfront group, who might never have developed a bone problem, were taking zoledronic acid unnecessarily, and whether upfront treatment with zoledronic acid is really the best strategy for the patient.

His answer: "That depends on whether you believe the AZURE findings in postmenopausal women."

The AZURE study, which was headed by Dr. Coleman, found overall no effect of zoledronic acid on breast cancer, but in a large subgroup of postmenopausal women with breast cancer, there was a significant effect on both recurrence and survival.

In a recent update of these results, Dr. Coleman reported that in this subgroup of postmenopausal women, zoledronic acid reduced both the risk for relapse and the risk of dying by about 25%. In particular, there was a marked reduction in the risk for metastases to extraskeletal sites, he noted.

The finding of a reduction in distant relapses in the Z-FAST study highlighted by Dr. Brufsky ties in with this finding from the AZURE study and from several other studies, which have suggested that bisphosphonates have an effect on breast cancer and on bones.

Dr. Brufsky told Medscape Medical News that he is swayed by the accumulating evidence that zoledronic acid does have an effect on breast cancer, and that this extra effect gives a boost to support its use in postmenopausal women taking AIs.

So far the breast cancer community seems split on this issue, with some experts proclaiming that they already use bisphosphonates for this effect in clinical practice, and others cautioning that such a use is not supported by sufficient evidence and urging clinicians to wait for further results. A heated debate on this subject arose last year after the presentation of the AZURE results at the San Antonio Breast Cancer Symposium; more on the subject is expected when this year's symposium is held next month.

The Z-FAST study was funded by Novartis. Dr. Brufsky has disclosed no relevant financial relationships, but 5 of his coauthors own stock in Novartis, 1 has served on the advisory board and received research funding from Novartis, an 1 reports consulting for and receiving honoraria from Pfzier and Amgen. Dr. Coleman reports consulting for and being on the speakers bureau for Novartis and Amgen.

Cancer. Published online October 10, 2011. Abstract

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