Carlson, Robert H.
CHICAGO—Studies that show how to achieve the same treatment outcomes but put less burden on the patient are obviously very important to patient quality of life. One such study, described here at the American Society of Clinical Oncology Annual Meeting, shows that zoledronic acid administered once every 12 weeks instead of the standard once every four weeks does not compromise efficacy among women with breast cancer and bone metastases (Abstract LBA9500^).
Besides offering convenience, the less-frequent schedule had fewer adverse events leading to dose reduction, fewer cases of osteonecrosis of the jaw, and less impairment of renal function, reported Gabriel N. Hortobagyi, MD, Professor, Chair, and Program Director in the Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer, speaking in the Patient and Survivor Care oral abstract session.
“The less frequent treatments are just as effective for such patients, and the longer schedule reduces the inconvenience and cost of treatments.”
The prospective, randomized, double-blind, multicenter, Phase III OPTIMIZE-2 study, supported by Novartis, included 403 patients (median age of 59) who had already been receiving zoledronic acid for one year on the once-monthly schedule, starting at diagnosis of bone metastases. Patients on the less-frequent schedule received placebo between zoledronic acid to maintain the blind, and the primary study endpoint was non-inferiority of the less-frequent schedule.
Hortobagyi said that initially there was a placebo arm, to be administered every four weeks, but that was dropped after it became clear that it was a major obstacle to accrual.
Skeletal-related events were defined as fractures of the long bones and vertebrae, spinal cord compressions, and interventions precipitated by bone metastases. The skeletal event rates were comparable between the two arms of the study—22.0 percent over one year in the monthly arm versus 23.2 percent in the every-three-months arm.
Other efficacy measures such as time to first skeletal event and bone turnover markers were also similar between the two arms, Hortobagyi reported. And there were no differences in pain levels and use of pain medications between the two treatment schedules.
Similarly, no obvious differences in the overall safety profile and in kidney side effects were noted between the two zoledronic acid treatment regimens.
Among patients on the once-monthly schedule there were two cases (1.0%) of osteonecrosis of the jaw and none in the less-frequent schedule.
GABRIEL N. HORTOBAGY...Image Tools
Regarding the efficacy data, though, Hortobagyi said that due to some design limitations and statistical concerns, such as the relatively modest size of the trial and the assumptions that go into a non-inferiority trial, those results should be interpreted with caution.
More Time to be with Families
The moderator of an ASCO news conference highlighting studies that showed improved patient care and quality of life, Patricia Ganz, MD, Professor in the UCLA Schools of Medicine and Public Health and Director of the Jonsson Comprehensive Cancer Center's Division of Cancer Prevention and Control Research, commented: “This is a very high-quality randomized trial that tells us that women living with advanced metastatic breast cancer with bone metastases do not necessarily have to come in every four weeks to get this treatment —They can safely come in every 12 weeks.”
What this means for the patients, she said, is that they have more time to spend with family and friends rather than visiting the doctor's office, less toxicity in terms of having something infused into the vein, and less cost. “This is really part of the value equation,” Ganz said. “Sometimes we have to add to treatment and sometimes we take away to add value to the patient care.”
‘Practical Study, Huge Difference in Patients' Lives’
Asked for her opinion for this article, Angela DeMichele, MD, Associate Professor of Medicine and Epidemiology, Co-Leader of the Breast Cancer Program, and Director of Clinical Trials at the University of Pennsylvania, said, “This is a practical study that will make a huge difference in patients' lives. These are patients trying to get on with their lives, they have jobs, things to do, and kids to take care of, and it really is asking a lot for them to come in every month.
“So often we want to use scientific evidence to guide what we do, but we're bound by how the study is designed, and that's not necessarily the only way therapies will work.”
She said she will put the results into practice immediately for her patients who are or will be on zoledronic acid. She noted that she prescribes zoledronic acid for some of her breast cancer patients and denosumab for others, with side effects and convenience among the reasons for choosing one over the other.
“Knowing a patient could come in less frequently might make one drug more appealing than the other,” she said.
“These are the practical considerations we talk about with patients: ‘Here is what we know, here is what we don't know, and what's going to fit best into your life without compromising patients care.’?”
DeMichele said she is looking forward to seeing more follow-up data on denosumab, noting that so far the main patient complaint about zoledronic acid is bony pain for a few days after the infusion, more so than for denosumab, and that dosing zoledronic acid less frequently would certainly make treatment more comfortable for patients.
Tom Smith: Discussing Drug Costs, and Alternatives
Physicians have an obligation to share comparative cost information with their patients, particularly when two drugs have similar efficacy but much different costs. So said Thomas J. Smith, MD, Professor of Palliative Medicine and Professor of Oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, speaking at the ASCO Annual Meeting in a session on Patient and Survivor Care.
“We should be able to explain to patients that there are small differences in efficacy, usually accompanied by huge differences in cost.”
Among the abstracts he discussed were the Phase III OPTIMIZE-2 study reported by Dr. Hortobagyi, and a Phase III study comparing denosumab with zoledronic acid in patients with metastatic bone disease (Abstract 9501).
“Make no bones about it; this is an important study,” Smith said with a straight face about the Hortobagyi study. Non-inferiority for the two zoledronic acid dosing schedules was also the conclusion reached by the European ZOOM trial, Smiths noted, citing: Amadori D et al: Lancet Oncology 2013;14:663 - 670.
The savings are obvious, and huge, he said. “Generic zoledronic acid costs $300 for 5 mg, and if you add to that professional fees, infusional fee, lab work, parking, time off from work, a quick back-of-the-envelope calculation shows that the once-monthly schedule costs about $7,000 per year, versus $2,500 for every three months.”
In the denosumab-versus-zoledronic acid study, the superiority of denosumab was clear cut and across every subgroup—“convincing even a skeptic like me,” Smith said. The hazard ratio for time to first on-study skeletal-related event ranged from 0.75 to 0.86 depending on the subgroup.
The cost of denosumab is about $1,900 versus about $300 for zoledronic acid, he said.
“The real question is whether the absolute difference in skeletal-related events worth thousands of dollars per month,” he said. “Or, should we be spending those dollars instead on treatment?”
© 2014 by Lippincott Williams & Wilkins, Inc.