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Less frequent zoledronic acid treatments effective for women with bone metastases from breast cancer
The incidence of skeletal-related events was comparable among women with bone metastases from breast cancer who received zoledronic acid every 12 weeks or every 4 weeks, according to results of the double blind, phase 3 OPTIMIZE-2 trial published in JAMA Oncology.
“For patients with breast cancer and other not-so-aggressive malignancies who are likely to live for years with metastatic disease, these results can be applied today and reduce cost, inconvenience and the risk for complications,” Gabriel N. Hortobagyi, MD, FACP, professor of medicine in the breast medical oncology division of The University of Texas MD Anderson Cancer Center, told HemOnc Today.
Zoledronic acid is a potent bisphosphonate that inhibits osteoclast-mediated bone resorption. It has been approved for treatment of patients with bone metastases from solid tumors or multiple myeloma and for the management of tumor-induced hypercalcemia.
Because skeletal-related events (SREs) can occur repeatedly in patients with metastatic disease that involves the bone, ASCO clinical guidelines recommend zoledronic acid be taken indefinitely as IV infusion every 3 to 4 weeks until there is deterioration of the general health of patients. However, concern exists that long-term administration of zoledronic acid leads to preferential binding and accumulation in bone, thus prolonging its pharmacologic activity after treatment discontinuation.
Hortobagyi and colleagues assessed whether a 12-week dosing of zoledronic acid was noninferior to dosing every 4 weeks in women who had already completed 1 year of treatment.
The analysis included 416 women with bone metastases from breast cancer who previously received nine or more doses of zoledronic acid or pamidronate during the first 10 to 15 months of therapy.
Overall, 200 patients (mean age, 59.2 years; 86.5% white) received 4 mg IV zoledronic acid every 4 weeks and 203 patients (mean age, 58.6 years; 87.7% white) received the same dose every 12 weeks. Because the original trial design included a placebo arm, 13 patients (mean age, 60.8 years; 100% white) received placebo. However, this arm was eliminated because bisphosphonates were already approved for this indication and a placebo arm hampered study enrollment.
Baseline characteristics were similar in both zoledronic acid treatment arms.
The proportion of patients with one or more SREs served as the primary endpoint. Secondary endpoints included time to first SRE and skeletal morbidity rate.
After 1 year of follow-up, SREs occurred in 22% of patients (n = 44) in the every-4-weeks group and 23.2% of patients (n = 47) in the every-12-weeks group. These results determined noninferiority as the proportional difference between groups of 1.2% had a 1-sided 97.5% CI bound (9.8%) that was less than 10% (noninferiority, P = .02).
The time to first SRE between treatment groups was not statistically significantly different (HR = 1.06; 95% CI, 0.7-1.6). The mean skeletal morbidity rate was 0.46 events per year in the every-4-weeks group and 0.5 events per year in the every-12-weeks group.
The safety profiles in both groups were comparable; at least one adverse event occurred in 95.5% of patients (n = 189) in the every-4-weeks group and 93.4% of patients (n = 189) in the every-12-weeks group.
“It’s more convenient to have one IV drip every 12 weeks than every 4 weeks,” Hortobagyi said. “Consequently, there’s lower cost. Another advantage is lower probability of long-term complications, such as osteonecrosis of the jaw, atypical long-bone fractures and renal dysfunction. Although these are relatively uncommon, they can be severe and disabling.”
These results support previous findings that showed after 1 year of bisphosphonate therapy, less frequent administration shows similar efficacy as monthly doses, Hortobagyi added.
“We have additional questions about optimal dose and schedule of administration of zoledronic acid that need to be addressed by future research,” Hortobagyi said.
Researchers noted that after discussions with the FDA, no changes are anticipated in the zoledronic acid label.
“These two studies give us confidence that these results are real and applicable today,” Hortobagyi said.
Multiple studies have shown a less intense schedule of zoledronic acid appears safe and maintains its efficacy in reducing the rate of SRE, Monica N. Fornier, MD, medical oncologist specializing in breast carcinoma at Memorial Sloan Kettering Cancer Center, wrote in an accompanying editorial.
“Based on these trials, clinicians treating patients with metastatic disease to bones with zoledronic acid should consider the 3-months dosing schedule, which has less effect on the quality of life of patients in the palliative setting of metastatic disease, reduced cost, and maintains efficacy,” Fornier wrote. – by Chuck Gormley
For more information:
Gabriel N. Hortobagyi, MD, FACP, can be reached at Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston TX 77030; email: ghortoba@mdanderson.org.
Disclosure: Hortobagyi reports consultant/advisory roles with Bayer, Celgene, Hoffman-La Roche, Lilly, Merck and Pfizer. Please see the full study for a list of all researchers’ relevant financial disclosures. Fornier reports no relevant financial disclosures.