NEW YORK (Reuters Health) Dec 31 - Zoledronic acid is better than ibandronic acid for preventing skeletal events caused by bone metastases, according to new research.
However, both bisphosphonates have acceptable side-effect profiles, and ibandronic acid, which is taken orally, is more convenient and less complicated than zoledronic acid, which is given intravenously, the researchers said in a report online December 11 in The Lancet Oncology.
"All other things being equal, zoledronic acid should be the default option. For patients with difficult venous access, needle phobia or for whom monthly attendance for IV therapy is too inconvenient or expensive, oral ibandronic acid remains an option," said co-principal investigator Dr. Nick Murray of the Royal Adelaide Hospital in Adelaide, South Australia, by email to Reuters Health.
"Contrary to our expectations, daily oral ibandronic acid (ibandronate) is not as good as four weekly IV zoledronic acid (zoledronate) treatments," he said. "Zoledronic acid is likely to be the most effective bisphosphonate drug for the treatment of bone metastases from breast cancer."
Dr. Murray, his co-principal investigator, Dr. Peter Barrett-Lee of Cardiff University, and their colleagues conducted the open-label phase III non-inferiority ZICE trial in 99 hospitals in the UK.
Patients with at least one breast cancer metastasis to bone and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 were eligible. Among the exclusion criteria were central nervous system metastases; dental problems; active peptic ulcers; and renal or liver function impairment. (More information about the trial is available here: http://clinicaltrials.gov/show/NCT00326820.)
The original participants were diagnosed with multiple bone metastases within three months before randomization. But about a year and a half into the study, the researchers began to include patients with one metastasis, to account for all patients who would in the real world be treated with bisphosphonates.
The overall median age was 61 years, nearly all participants were female, and between 68% and 69% were postmenopausal.
For 96 weeks, patients received either IV zoledronic acid, 4 mg every 3 to 4 weeks, or oral ibandronic acid, 50 mg daily.
Renal toxicity developed in 32% of patients on zoledronic acid and 24% of patients on ibandronic acid (p=0·001), although rates of fatigue, nausea or vomiting, increased bone pain, jaw osteonecrosis, joint pain, infection, and overall survival were similar in both groups.
In the primary per-protocol analysis, annual rates of skeletal-related events per person-year were 0.499 (95% CI 0·454-0·549) with ibandronic acid and 0.435 (0·393-0·480) with zoledronic acid; the rate ratio for skeletal-related events was 1·148 (95% CI 0·967-1·362).
The intention-to-treat analysis supported the primary per-protocol results, with rates of skeletal-related events per person-year of 0.507 in the ibandronic acid group and 0.425 in the zoledronic acid group. The rate ratio of ibandronic acid vs zoledronic acid was 1.190 (95% CI 1.012-1·400; p=0·035).
Because the upper CI exceeded predetermined margin of inferiority, the researchers couldn't say that ibandronic acid is not inferior to zoledronic acid to prevent skeletal-related events in patients with breast cancer with bone metastases.
"Like many others, I had assumed the two treatments were likely to be similarly effective. The finding that they are not has implications for daily clinical practice and illustrates the important role of randomized clinical trials in defining appropriate therapy selection," he said.
"In many countries, denosumab is becoming the treatment of choice for the management of bone metastases from breast cancer; however, zoledronic acid remains a reasonable alternative," Dr. Murray said in an email.
In an editorial, Dr. Luis Costa of the Hospital de Santa Maria of the Instituto de Medicina Molecular of the University of Lisbon, Portugal, asks if it's still acceptable to use oral ibandronic acid to prevent skeletal-related events in breast cancer now that other treatments are available.
"Denosumab, a fully human monoclonal IgG2 antibody monoclonal against RANKL (Receptor activator of nuclear factor kappa-B ligand), is now licensed to treat patients with breast cancer with bone metastases," he points out.
"Denosumab was better than zoledronic acid in delaying and preventing skeletal-related events with a favorable toxic effect profile. However, the answer to the question of whether oral ibandronic acid is still acceptable continues to be yes, if convenience is a major factor for a patient," he said.
The study was supported by Roche Products Ltd, which markets ibandronate as Bonivia, and by the UK's National Institute for Health Research Cancer Network.
SOURCE: http://bit.ly/1alAurx
Lancet Oncology 2013.
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