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Zoledronic Acid: Less Frequent Dosing May Be Just as Good

October 2012, Vol 5, No 7

In women with metastatic breast cancer, less frequent dosing of zoledronic acid (ZA) may be as protective as the standard monthly infusion, according to 2 studies presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO).

The Italian ZOOM trial was a phase 3 prospective randomized study of 425 women with stage IV breast cancer and bone metastases. After 1 year of standard ZA treatment (4 mg every 4 weeks), patients were randomized to continue with monthly infusions or to receive ZA every 3 months (4 mg every 12 weeks).

The study concluded that an every-12-week infusion was not inferior to the standard monthly infusion. The mean skeletal morbidity rate (number of skeletal-related events per patient per year) was 0.26 and 0.22, respectively, which indicated statistical noninferiority of the less frequent dosing schedule. Toxicities were also similar between the arms, reported Dino Amadori, MD, of the Istituto Scientifico Romagnolo in Meldola, Italy.

Bone Turnover Remains Suppressed After a Single Dose
A Canadian study looked at 1 turnover following a single dose of ZA and found that after a single 4-mg dose, bone turnover remained suppressed at 12 weeks in 73% of patients.

The study involved 26 patients with metastatic breast cancer to the bone and no prior ZA treatment. Patients received a single dose of ZA, and biomarkers of bone turnover (serum carboxy-terminal collagen crosslinks [CTX]) were collected every 2 weeks subsequently. Patients remained on study if their biomarkers remained suppressed but came off study as soon as they escaped from suppression (rise >50% of baseline).

At 12 weeks, 73% of patients had continued suppression of bone turnover by serum CTX. The patients who escaped suppression did so at a median of 8 weeks after the first infusion.

“Biomarkers of bone turnover have been found to correlate with the risk of developing a skeletal-related event, and with response to bisphosphonate therapy,” noted Christine E. Simmons, MD, of the University of Toronto.

The magnitude of suppression of serum CTX at week 4 was significantly greater in those who had continued suppression compared with those who escaped suppression before 12 weeks (75% vs 58%; P = .02). The absolute baseline value of CTX was significantly lower in patients who maintained suppression (507 ng/L vs 745 ng/L; P = .04). Quality-of-life scores and pain medication use did not change appreciably during this period.

“Our study suggests that ZA does not need to be given at conventional dosing frequency in the majority of patients, and can be withheld without increased morbidity or effect on quality of life,” Simmons said. “We think that baseline serum CTX (<600 ng/L) and magnitude of suppression of CTX (>70%) may predict for those who can wait 12 weeks between doses.”

Studies Address an Important Issue
Teresa Gilewski, MD, of Memorial Sloan-Kettering Cancer Center, New York, who discussed the findings at the Best of ASCO meeting in Boston, Massachusetts, said the studies address an important issue that has implications for patient convenience and cost of care. While confirmation is needed, she said, it is possible that some patients may fare as well with less frequent infusions.

ASCO guidelines state that bone-modifying agents should be continued until the patient’s performance status substantially declines; however, the optimal schedule and duration of ZA have not been widely established. Gilewski questioned whether some patients may be doing well enough—having significant reductions in the volume of bone destruction—that long-term ZA treatment may be unnecessary.

“The biggest strength of the Italian study is that it raises an incredibly important clinical question, in terms of patient compliance and economic issues,” she said. While the study did not assess the extent of bone destruction, she believes that such data might help guide the dosing interval. “In patients with a lot of destruction, we may be less likely to change the infusion schedule, compared to patients with just 1 or 2 sites. But if patients are doing well, we may be more willing to consider the change,” Gilewski said.

Currently, however, she said the data are preliminary and should not yet be clinically applied. Studies are under way that may validate the findings.

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