Elsevier

The Lancet Oncology

Volume 14, Issue 7, June 2013, Pages 663-670
The Lancet Oncology

Articles
Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial

https://doi.org/10.1016/S1470-2045(13)70174-8Get rights and content

Summary

Background

Zoledronic acid reduces skeletal-related events in patients with breast cancer, but concerns have been raised about prolonged monthly administration. We assessed the efficacy and safety of a reduced dosing frequency of zoledronic acid in women treated previously with monthly zoledronic acid.

Methods

We did this non-inferiority, phase 3 trial in 62 centres in Italy. We enrolled patients with breast cancer who had one or more bone metastases and had completed 12–15 months of monthly treatment with zoledronic acid. Patients were randomly assigned with a permutated block (size four to eight) random list stratified by centre in a 1:1 ratio to zoledronic acid 4 mg once every 12 weeks or once every 4 weeks, and followed up for at least 1 year. Neither patients nor investigators were masked to treatment allocation. The primary outcome was skeletal morbidity rate (skeletal-related events per patient per year) in the intention-to-treat population. We used a non-inferiority margin of 0·19. The trial is registered with EudraCT, number 2005-004942-15.

Findings

We screened 430 patients and enrolled 425, of whom 209 were assigned to the 12-week group and 216 to the 4-week group. The skeletal morbidity rate was 0·26 (95% CI 0·15–0·37) in the 12-week group versus 0·22 (0·14–0·29) in the 4-week group. The between-group difference was 0·04 and the upper limit of one-tailed 97·5% CI was 0·17, which is lower than the non-inferiority margin. The most common grade 3–4 adverse events were bone pain (56 [27%] patients in the 12-week group vs 65 [30%] in the 4-week group), nausea (24 [11%] vs 33 [15%]), and asthenia (18 [9%] vs 33 [15%]). Renal adverse events occurred in one patient (<1%) in the 12-week group versus two (1%) in the 4-week group. One patient (<1%) in the 4-week group had grade 1 acute renal failure. Osteonecrosis of the jaw occurred in four patients in the 12-week group versus three in the 4-week group. No treatment-related deaths were reported. Median N-terminal telopeptide concentration changed from baseline more in the 12-week group than in the 4-week group after 12 months (12·2% vs 0·0%; p=0·011).

Interpretation

Our results raise the possibility of decreasing administration of zoledronic acid to a 12-weekly regimen to reduce exposure during the second year, while maintaining its therapeutic effects. However, the effects on N-terminal telopeptide should be investigated further before changing current practice.

Funding

Novartis Farma.

Introduction

About 65–75% of patients with advanced breast cancer develop bone metastases,1 making bone the most common site of breast cancer advancement.2 Malignant bone disease severely impairs normal skeletal homoeostasis and can result in debilitating pain and skeletal-related events, including pathological fractures, spinal cord compression, severe bone pain, the need for palliative radiotherapy or surgery, and hypercalcaemia.3 Without treatment to inhibit bone resorption, about two-thirds of patients with bone-metastatic breast cancer develop skeletal-related events (roughly three or four per year per patient),4 which can limit functional independence and reduce quality of life.5, 6 Moreover, patients with pathological fractures have an increased risk of death.7

Zoledronic acid (4 mg intravenously every 3–4 weeks) is a well-established antiresorptive drug approved for use in patients with bone-metastatic breast cancer to delay the onset and reduce the risk of skeletal-related events.8, 9, 10

Although the optimum duration of treatment has not yet been established, zoledronic acid has been shown to reduce skeletal complications for up to 2 years in some studies,10, 11, 12, 13, 14 and even longer in others.15, 16, 17 Because of the paucity of evidence for treatment beyond 2 years, clinical practice guidelines of the American Society of Clinical Oncology recommend continuation of treatment until there is evidence of a substantial fall in general health status.18, 19 An expert panel has recommended treatment beyond 2 years based on individual risk assessment, since skeletal complications can occur repeatedly throughout the disease course and the risk of complications exists for as long as bone metastases are present.20 Prolonged treatment with zoledronic acid increases the risk of osteonecrosis of the jaw. Therefore, as new cancer treatments extend the life expectancy of patients with advanced breast cancer,21 better strategies for treatment with zoledronic acid are needed for long-term reduction and prevention of skeletal-related events.

We investigated whether reduced-frequency dosing of zoledronic acid after 1 year of standard dosing might provide the same efficacy as the standard schedule while improving adherence and safety. Our hypothesis is supported by studies22 of treatment of postmenopausal osteoporosis, in which only a few doses of zoledronic acid suppressed bone turnover for many years because of the potency of osteoclast inhibition and skeletal accumulation of zoledronic acid.

Section snippets

Study design and participants

We did this phase 3, prospective, randomised, open-label, non-inferiority, trial in 62 hospitals in Italy. Eligible patients were women (age ≥18 years) with stage IV breast cancer, one or more radiologically confirmed bone metastases, and treated with zoledronic acid every 3–4 weeks for 12–15 months before enrolment. Exclusion criteria were: more than 3 months since the last infusion of zoledronic acid, use of bisphosphonates other than zoledronic acid, serum creatinine concentration more than

Results

Enrolment started on Feb 20, 2006. 425 patients were enrolled and randomly assigned to treatment (209 to the 12-weekly group, 216 to the 4-weekly group; figure 1). The last patient completed treatment on Feb 17, 2010. Treatment groups were well-balanced for baseline characteristics (table 1). Mean age was 60 years (range 28–89). The number and type of previous skeletal-related events was much the same in each group. Most patients received concurrent cancer treatment. The majority of patients

Discussion

Our findings indicate that a 12-weekly zoledronic acid regimen was not inferior to a 4-weekly schedule in patients with bone-metastatic breast cancer who had previously completed 1 year of on-label treatment with zoledronic acid. The skeletal morbidity rate was low and much the same in both groups. However, one should note that, although significant, the proximity of the upper limit of the one-tailed 97·5% CI to the adjusted non-inferiority margin suggests that the non-inferiority of 12-weekly

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