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Extended bisphosphonate treatment fails to improve breast cancer survival
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SAN ANTONIO — Extending adjuvant zoledronate treatment from 2 years to 5 years failed to prolong DFS and OS among patients with high-risk early-stage breast cancer, according to results of the phase 3 SUCCESS A trial presented at the San Antonio Breast Cancer Symposium.
“Bisphosphonates prevent the loss of bone density and have been shown to reduce skeletal-related events in patients with cancer,” Wolfgang Janni, MD, PhD, of University of Ulm in Germany, said during his presentation. “According to a recent meta-analysis, adjuvant bisphosphonate treatment in patients with early breast cancer leads to improved breast cancer survival and a reduced rate of breast cancer recurrences in the bone, especially in postmenopausal patients.”
Thus, many international guidelines recommend adjuvant bisphosphonates to be offered as part of adjuvant systemic treatment among postmenopausal women. However, an analysis of duration of bisphosphonate treatment is lacking.
Thus, Janni and colleagues evaluated 2 years compared with 5 years of bisphosphonate treatment among 3,421 of 3,754 patients in the SUCCESS A trial who received at least one dose of zoledronate.
Researchers had randomly assigned patients in that trial to adjuvant chemotherapy with three cycles of 5-FU, epirubicin and cyclophosphamide followed by either three cycles of docetaxel or three cycles of gemcitabine-docetaxel.
Following chemotherapy, researchers randomly assigned patients to zoledronate treatment for 2 years (4 mg IV every 3 months) or 5 years (4 mg IV every 3 months for 2 years, 4 mg IV every 6 months for the following 3 years).
Researchers used adapted DFS and adapted OS — with survival times measured as of 2 years after the start of adjuvant treatment — to analyze outcomes. Median observation time was 2.95 years for DFS and 3 years for OS.
After excluding patients lost to follow-up, researchers analyzed data from 2,987 patients assigned 5 years (n = 1,540) or 2 years (n = 1,447) of zoledronate treatment.
Patients assigned 5 years of treatment did not demonstrate improved DFS (HR = 0.97; 95% CI, 0.75-1.25) or OS (HR = 0.98; 95% CI, 0.67-1.42).
Subgroup analysis by menopausal status also revealed no difference for premenopausal women (DFS, HR = 1.21; 95% CI, 0.81-1.81; OS, HR = 0.93; 95% CI, 0.57-1.53) or postmenopausal women (DFS, HR = 0.85; 95% CI, 0.62-1.16; OS, HR = 0.96; 95% CI, 0.67-1.39).
“Please be aware of the limited number of patients in these two subgroups,” Janni said.
The incidence of bone recurrence as first distant recurrence as of 2 years after the start of adjuvant treatment also did not differ between the two arms.
Adverse events of any grade (46.2% vs. 27.2%) and grade 3 or grade 4 (7.6% vs. 5.1%) occurred more frequently in the 5-year arm. The most frequent adverse event was bone pain, occurring among 8.3% who received extended treatment and 3.7% who did not receive extended treatment.
Researchers also measured circulating tumor cells (CTCs) in patients treated.
“Previous publications have shown that CTCs are present in approximately 20% of patients with primary disease and 60% of patients with advanced breast cancer,” Janni said. “Level-one data previously demonstrated that CTCs are an independent prognostic marker of metastatic and primary breast cancer, both at the time of diagnosis and long-term follow-up.”
However, results of this analysis failed to show a difference in the CTCs detected in patients treated for 5 or 2 years. A comparable proportion of patients treated with extended vs. nonextended treatment had CTCs present 5 years after adjuvant chemotherapy (10.5% vs. 7.2%).
“Given the demonstrated prognostic relevance of CTCs, this result is in line with the negative survival analysis results in this study,” Janni said.
The study should be interpreted with caution due to several limitations, Janni added. These include a limited observation time, a higher number of patients lost to follow-up in the 2-year arm, and the low number of events.
“At this early time point, our study showed no difference in DFS or OS between 5 years and 2 years of adjuvant zoledronate treatment following neoadjuvant chemotherapy in high-risk early breast cancer, irrespective of menopausal status,” Janni said. “Five years of adjuvant zoledronate treatment should not be considered currently in these patients in the absence of decreased bone density.” – by Alexandra Todak
Reference:
Janni W, et al. Abstract GS1-06. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2017; San Antonio.
Disclosures: The researchers report no relevant financial disclosures.
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Aditya Bardia, MBBS, MPH
There has been a lot of interest in the use of bisphosphonates for ER-positive breast cancer in the adjuvant setting. The initial bisphosphonate study was positive with zoledronic acid, but then subsequently a similar study was negative. So, it’s been an open question whether we should use bisphosphonates.
Recently ASCO updated its guidelines, which recommend that bisphosphonates should be considered in patients with early breast cancer.
This study looked at 2 vs. 5 years and essentially did not see any difference. The study did not look at 2 years vs. 5 years vs. no bisphosphonates. Based on this study, I think the recommendation would still be to use bisphosphonates for appropriate patients, but 2 years is probably sufficient. You do not necessarily need 5 years.
However, there could be a difference with longer follow-up because, for ER-positive disease, recurrences don’t necessarily occur in the first 5 years. Recurrences can occur after the first 5 years, even up to 20 years later. With any ER-positive study, the duration of follow-up is always an important question.
If you look at this broadly, I think we give bisphosphonates more than they are needed. If you look in the metastatic setting, the recommendation was to use bisphosphonates every month. But, researchers then did a study looking at monthly vs. every 3 months, and the outcomes were the same.
These data also are consistent that bisphosphonates are helpful, but we don’t need to use them for a long period of time. This is very different than endocrine therapy, which we do recommend for 5 years, or even up to 10 years. It’s a very different class of agent, and we probably don’t need it for an extended period of time.
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