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ZO-FAST Trial Shows Early Use of Zoledronic Acid Prevents Bone Loss With Letrozole: Presented at EBCC

By Paula Moyer

NICE, FRANCE -- March 22, 2006 -- Women with oestrogen receptor-positive breast cancer have less bone loss if they start zoledronic acid (Zometa(R)) therapy early in the course of their letrozole (Femara(R)) treatment, according to investigators who presented their findings here at the 5^th European Breast Cancer Conference (EBCC).

"Aromatase inhibitors clearly increase a woman's survival but they leave a woman open to a loss of bone mineral density and subsequent long-term problems," said principal investigator Nigel Bundred, MD, in a presentation on March 22^nd. "It would appear from this study and others that zoledronic acid can prevent that bone mineral density loss, and that it is a useful strategy for women at risk of cancer-associated bone loss."

Dr. Bundred, a professor of surgical oncology, South Manchester University Hospital, Manchester, United Kingdom, reported on the 12-month data of the Zometa-Femara Adjuvant Synergy Trial (ZO-FAST).

The investigators conducted the study because they wanted to see if combining letrozole with zoledronic acid would preserve letrozole's value in preventing breast cancer recurrence as well as minimise the associated bone loss. They also wanted to identify the most effective time to introduce zoledronic acid during the course of letrozole therapy, simultaneously or after treatment with letrozole had been well established.

Therefore, they recruited 1066 patients from 150 centres in 28 countries. The women were postmenopausal and had oestrogen receptor-positive breast cancer in stages I to IIIa. Eligible patients had a bone mineral density (BMD) T score of at least 2 standards of deviation (SD) below normal.

The investigators randomised patients to either begin receiving intravenous zoledronic acid at the same time as the letrozole regimen or to delay the start of the zoledronic acid. The delay group were started on zoledronic acid: 1) when their BMD T score decreased to more than 2 SD below normal; 2) if they had a nontraumatic fracture; 3) if they were found to have an asymptomatic fracture when they were assessed at 36 months after starting letrozole.

The current crossover rate is 15%, Dr. Bundred said. The dose of zoledronic acid was 4 mg daily administered for 6 months.

The investigators used a change in lumbar spine BMD as the primary endpoint, and defined clinically significant bone loss as a 6% reduction in BMD per year, cumulative reduction in BMD of 8% over any period of time, a T-score exceeding 2.5 SD below normal, and a fracture or impending fracture on x-ray.

Among these patients, 573 had had prior adjuvant chemotherapy and 493 had not. The baseline BMD T score was less than 1 SD below normal in 718 patients and 1 to 2 SD below normal in 348 patients. The median age was 58 years.

The most common adverse effect reported was arthralgia, which was seen in 21.3% of the women. Among the original participants, 90 (8%) withdrew from the study, of whom 42 (4%) had experienced adverse events.

At 12 months, the women in the delayed group had lost an average of 3.5% BMD at the lumbar spine and 2% at the hip, compared with a slight increase in BMD at those sites in the group receiving immediate treatment (P <.0001).

Among postmenopausal women, the average total BMD lost in the delayed group was 6%, with virtually no change in women receiving immediate zoledronic acid treatment (P <.0001). Biomarkers such as N-teleopeptide and serum calcium, which can indicate an increased rate of bone resorption and therefore BMD loss, were increased in the delayed group and unchanged in the immediate treatment group.

"At 12 months there is little difference in the groups' fracture rates," Dr. Bundred said. "However, we can see that immediate treatment with zoledronic acid when starting letrozole prevents bone mineral density loss in women with early breast cancer who are being treated with letrozole."

He and his coinvestigators will be following this cohort for several more years, he said.


[Presentation: Zoledronic Acid in the Prevention of Cancer Treatment-Induced Bone Loss in Postmenopausal Women Receiving Letrozole as Adjuvant Therapy for Early Breast Cancer (ZO-FAST Study). Abstract 12]

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