Zoledronic Acid Boosts Antitumor Effects of Chemotherapy


SAN ANTONIO — The addition of the bisphosphonate zoledronic acid to standard neoadjuvant chemotherapy reduces tumor size and results in more patients with a pathologic complete response than does chemotherapy alone, which suggests that the drug has direct antitumor activity, study results showed.

In a retrospective exploratory analysis involving more than 200 women, the adjusted mean residual invasive tumor sizes (RITS) in chemotherapy-alone and chemotherapy plus zoledronic acid groups were 42.4 mm and 28.2 mm, respectively—a significant difference (P = .002), Dr. Robert Coleman reported at the annual San Antonio Breast Cancer Symposium.

The pathologic complete response (pCR) rate (both breast and axilla) was 5.8% in the chemotherapy-alone arm and 10.9% in the combination arm (P = .033). In a multivariate analysis, the difference in pCR significantly favored the combination arm with an odds ratio of 3.7 (P = .03).

“It is the first patient-related evidence that this class of drugs may have direct antitumor activity,” he said at a press conference during the meeting. “What these data suggest is that perhaps zoledronic acid is doing something more than just affecting bone.” Dr. Coleman, an oncologist at the cancer research centre at Weston Park Hospital in Sheffield, England, presented the findings in a poster at the meeting.

“This is not a practice-changing study,” he cautioned. “It's a hypothesis-generating study, which will lead to the design of specific neoadjuvant trials to look at this in more detail.”

In the Neo-Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, 3,360 women with stage II/III breast cancer were recruited to determine whether treatment with zoledronic acid in addition to neoadjuvant therapy improves disease-related outcomes. Women had to have a tumor size greater than 5 cm (T3) or features of locally advanced disease (T4) or biopsy-proven lymph node involvement (N1).

They also had to be scheduled for definitive surgery and/or radical radiotherapy with curative intent within 6 months of starting neoadjuvant therapy. In addition, the time between the start of neoadjuvant treatment and the start of zoledronic acid had to be no greater than 30 days.

In AZURE, eligible patients received neoadjuvant chemotherapy according to local practice and were randomized to also receive 4 mg IV zoledronic acid (every 3–4 weeks for 6 months in the neoadjuvant period) or no additional treatment.

The primary surrogate end point for response was RITS at surgery. Secondary end points included pCR, number of positive axillary nodes, and percentage of patients requiring mastectomy. In a multivariate analysis, the researchers adjusted for T stage, estrogen-receptor and progesterone-receptor status, chemotherapy type (anthracycline/taxane), treatment duration, and menopausal status, Dr. Coleman said.

A total of 205 patients received neoadjuvant chemotherapy—104 in the chemotherapy-alone group and 101 in the chemotherapy plus zoledronic acid group. The baseline characteristics and treatments were similar, and the median number of chemotherapy cycles and treatment duration were the same in both groups.

Most women in both arms were estrogen-receptor positive—64% in the chemotherapy-alone arm and 68% in the combination arm.

In terms of progesterone-receptor status, 46% of the women in the chemotherapy-alone arm were negative, 25% were positive, and 29% were of unknown status; in the zoledronic acid arm, 34% were negative, about a third were positive, and a third were of unknown status.

Almost half of the women in both arms were HER2 positive—47% in the chemotherapy-alone arm and 48% in the combination arm.

The unadjusted median RITS was 30 mm in the chemotherapy-alone group, compared with only 20.5 mm in the combination group. In a multivariate analysis (171 patients with complete data), zoledronic acid, estrogen-receptor status (P = .034), and treatment duration (P = .002) were independent significant predictors of smaller RITS with negative estrogen-receptor status and increasing treatment duration.

There was no significant difference in the median number of positive lymph nodes at surgery. The proportion of patients requiring mastectomy in the chemotherapy-alone and combination arms was 77.9% and 65.3%.

Dr. Coleman reported that he has received grant support from Novartis and he is on the speakers bureau with Novartis and Amgen Inc. Novartis makes Zometa. The study was sponsored in part by Novartis.

'It is the first patient-related evidence that this class of drugs may have direct antitumor activity.' DR. COLEMAN

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