New findings from the OPTIMIZE-2 study, a phase III randomized clinical trial supported by Novartis Pharmaceuticals, suggest that after a year of monthly treatment with the bone-building drug zoledronic acid (Zometa?; Novartis), women with breast cancer and bone metastasis can safely scale back treatment to an every-three-month schedule and still get the same benefit.[1][2]
The study shows that a lower-frequency dosing appeared to have comparable efficacy in reducing complications from bone metastases as monthly dosing. The results also suggest that this may decrease the risk of rare, serious side effects associated with the bisphosphonates zoledronic acid. The results were presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), being held in Chicago, May 30 – June 3, 2014.
The study’s objective was to determine the efficacy, translated as the time to first skeletal event, and safety of continued treatment with zoledronic acid every 4 weeks with reduced zoledronic acid dosing frequency (every 12 weeks) or placebo in patients with documented bone metastases from breast cancer, who have been pre-treated with zoledronic acid every 3-4 weeks for 9 to 20 doses during the previous 10 to 15 months.
Women with metastatic breast cancer who require long-term protection against bone fractures now have the option of receiving maintenance bisphosphonate therapy at less frequent intervals without compromising benefit or safety…
Improving care
Bisphosphonates target areas of higher bone turnover. Osteoclast cells, large multinucleated cell responsible for the dissolution and absorption of bone, absorb the bisphosphonate drug, which, in turn, slows down their activity and reduces the breakdown of bone.
?The addition of bisphosphonate drugs like zoledronic acid has dramatically improved the care of patients with bone metastases. But long-term treatment carries the risk of serious side effects, such as osteonecrosis of the jaw and kidney problems,? explained lead study author Gabriel N. Hortobagyi, MD, FACP, a professor of medicine at the MD Anderson Cancer Center in Houston, TX. ?We found that less frequent treatment may reduce the risk of serious side effects, with added benefits in reduced patient inconvenience and cost.?
Complications from bone metastases
Zoledronic acid is commonly used to reduce complications from bone metastases, such as bone fractures and spinal cord compression. Most doctors give zoledronic acid every four weeks for the first year, starting at diagnosis of bone metastases. It is thought that the treatment should continue indefinitely, but doctors have been concerned about the risk of side effects. To date, there has been limited research, and there are no evidence-based guidelines for the optimal treatment schedule after the first year.
Trial design
In the OPTIMIZE-2 study, 403 women with bone metastases from breast cancer who had completed roughly one year of monthly zoledronic acid therapy were randomly assigned to receive zoledronic acid every month vs. every three months for an additional year. Researchers assessed the skeletal event rate or the proportion of patients with one or more skeletal related events ? fractures of long bones and vertebrae, spinal cord compressions, and interventions precipitated by bone metastases.
Limitations and concerns
The skeletal event rates were comparable between the two arms (22% in the monthly arm vs. 23.2% in the every-three-months arm) indicating that less frequent treatment was not inferior to monthly treatment. Other efficacy measures, such as time to first skeletal event and bone turnover markers, were also similar between the two arms. There were no differences in pain levels and use of pain medications between the two treatment schedules. However, due to design limitations and statistical concerns, the efficacy data of OPTIMIZE-2 should be interpreted with caution.
No obvious differences in overall safety profile and in kidney side effects were noted between the two zoledronic acid treatment regimens. Two cases of osteonecrosis of the jaw were reported in the monthly arm, whereas none in the every-three-months treatment arm. Osteonecrosis of the jaw is a condition in which parts of the jawbones weaken and die. The area of necrotic bone is painful and may require surgical removal.
Maintenance therapy
?Women with metastatic breast cancer who require long-term protection against bone fractures now have the option of receiving maintenance bisphosphonate therapy at less frequent intervals without compromising benefit or safety,? noted Patricia Ganz, MD, FASCO, ASCO Expert and director of Cancer Prevention and Control Research at theJonsson Comprehensive Cancer Center, University of California, Los Angeles, CA.
For more information:
[1] Hortobagyi GN, Lipton A, Chew HK, Gradishar WJ, Sauter NP, Mohanlal RW, Zheng M, McGrain B, Van Poznak C et al. Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer: Results of the OPTIMIZE-2 trial. 2014 ASCO Annual Meeting. Oral Abstract Session. Monday June 2, 3:00 PM to 6:00 PM. Abstract No: LBA9500^. Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr LBA9500^)[Abstract]
[2] NCT00320710 – Efficacy and Safety of Zoledronic Acid (Every 4 Weeks vs. Every 12 Weeks) in Patients With Documented Bone Metastases From Bone Cancer. [Study Record Detail]
Photo: Gabriel N. Hortobagyi, MD, FACP, speaks at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO).Photo Courtesy: ?ASCO/Todd Buchanan.
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