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Longer-interval zoledronic acid dosing noninferior to standard dosing for bone metastases
A 12-week treatment interval of zoledronic acid for bone metastases from breast cancer, prostate cancer or multiple myeloma did not increase the number of skeletal events over 2 years compared with standard dosing every 4 weeks, according to results of a noninferior open-label clinical trial.
“For patients, the longer dosing interval of zoledronic acid may mean fewer trips to their hematologist’s or oncologist’s office, fewer IV infusions, and lower cost without loss of efficacy,” Andrew L. Himelstein, MD, FACP, of Helen F. Graham Cancer Center & Research Institute at Christiana Care Health System, told HemOnc Today.
Bone involvement is a common clinical problem among patients with metastatic cancer. Currently, the standard dosing interval for zoledronic acid — an aminobisphosphonate administered intravenously to treat various bone diseases — reduces the risks for fractures and bone pain among these patients, according to Himelstein.
Because there is not a current optimal dosing interval, Himelstein and colleagues randomly assigned 1,822 patients (median age, 65 years) with metastatic breast cancer (n = 855), metastatic prostate cancer (n = 689) or multiple myeloma (n = 278) with at least one bone involvement site to a regimen of zoledronic acid every 4 weeks (n = 911) or every 12 weeks (n = 911) for 2 years.
The proportion of patients having at least one skeletal-related event — defined as clinical fracture, spinal cord compression, radiation to bone or surgery involving bone — at 2 years served as the study’s primary endpoint. Secondary endpoints included the proportion of patients with at least one skeletal-related event by disease type, pain, incidence of osteonecrosis of the jaw, kidney infection, skeletal morbidity rate and suppression of bone turnover.
All 1,822 patients were included in intention-to-treat (ITT) and sensitivity analyses (median follow-up, 425 days). The stratified ITT Cochran-Mantel-Haenszel test was used under the assumption that dropouts experienced at least one skeletal-related event. Prespecified sensitivity analysis used the assumption that dropouts without at least one skeletal-related event at the time of drop out did not have at least one skeletal-related event.
Researchers established a 7% absolute difference as the noninferiority threshold between the two dosing schedules.
Overall, 795 patients completed the study at 2 years.
ITT analysis showed 260 patients who received zoledronic acid every 4 weeks and 253 patients who received zoledronic acid every 12 weeks experienced at least one skeletal event within 2 years (risk difference, –0.3%; P < .001 for noninferiority). Sensitivity analysis also demonstrated noninferiority (risk difference, 1%; P < .001).
“Our study showed no increase in the risk of skeletal-related events ... or in the risk for side effects when zoledronic acid was given every 12 weeks instead of every 4 weeks for 2 years in patients with bone metastases from breast cancer, prostate cancer or multiple myeloma,” Himelstein said.
In addition, pain scores, performance status scores and the incidence of jaw osteonecrosis and kidney dysfunction were not significantly different between the groups. The researchers noted that although jaw osteonecrosis occurred more in the 12-week group compared with the 4-week group (2% vs. 1%; P = .08), the overall incidence of jaw osteonecrosis was lower than the 7% incidence reported in earlier studies of zoledronic acid, possibly due to a shorter duration of treatment (24 months vs. 37 to 48 months).
Bone turnover (elevated C-terminal telopeptide levels) was greater in patients who received zoledronic acid every 12 weeks, despite skeletal morbidity rates being numerically identical, according to the research.
“We feel that clinicians can now consider giving zoledronic acid every 12 weeks to their patients with breast cancer, prostate cancer or multiple myeloma who have bone involvement,” Himelstein said. – by Melinda Stevens
For more information:
Andrew L. Himelstein , MD, can be reached at Helen F. Graham Cancer Center & Research Institute, 4701 Ogletown-Stanton Rd., Ste 3400, Newark, DE 19713; email: ahimelstein@cbg.org.
Disclosures: Himelstein reports no relevant financial disclosures. One researcher reports owning stock in Gilead Sciences, Regeneron Pharmaceuticals and UnitedHealth Group. Another researcher reports owning stock in Pfizer.