ArticlesEfficacy 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
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.
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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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