"Based on our results, I would argue against an extension of adjuvant zoledronate treatment beyond two years with 4 mg every three months (as used in our study) or three years with 4 mg every six months (per ESMO guidelines; https://bit.ly/2TiO9CU) in the absence of signs of decreased bone density," Dr. Thomas Friedl of University Hospital Ulm in Germany told Reuters Health by email.
"However, it is clear that the issue of optimal adjuvant bisphosphonate treatment duration in breast cancer patients is not yet solved," he added. "We need more large randomized clinical trials evaluating the efficacy of adjuvant bisphosphonate in terms of metastasis prevention to address important questions regarding doses, dosing intervals and durations, possibly with longer follow-up to account for late recurrences in patients with hormone receptor-positive disease."
As reported in JAMA Oncology, the multicenter phase 3 open-label trial (SUCCESS A) in Germany enrolled patients with either node-positive or high-risk node-negative primary invasive breast cancer from 2005-2007 (last patient out, 2014).
Data on 2,987 patients (median age 53) were available for analysis. Patients were first randomized to adjuvant chemotherapy with three cycles of fluorouracil, epirubicin, and cyclophosphamide followed by three cycles of docetaxel with or without gemcitabine.
After chemotherapy, they underwent a second randomization of five years of zoledronate (4 mg intravenously every three months for two years, followed by 4 mg intravenously every six months for three years) or two years of zoledronate (4 mg intravenously every three months for two years).
No significant differences between patients who received zoledronate for 5 years vs. 2 years were found in disease-free survival (hazard ratio, 0.97), overall survival (HR, 0.98), and distant disease-free survival (HR, 0.87).
Adverse events were more frequent in the 5-year (46.2%) versus 2-year (27.2%) arm; this was particularly true for the skeletal-related events bone pain (5 years, 8.3% vs. 2 years, 3.7%) and arthralgia (5 years, 5.1% vs 2 years, 3.1%).
Dr. Friedl said clinicians should "carefully consider if adjuvant zoledronate treatment has to be extended beyond two or three years. Patients should be closely monitored regarding their bone health and signs of decreasing bone density before extending zoledronate treatment, and special attention should be given to zoledronate-related adverse events such as hypocalcemia, bone pain, arthralgia and osteonecrosis of the jaw."
Dr. Eitan Amir of Princess Margaret Cancer Center and the University of Toronto, coauthor of a related editorial, commented in an email to Reuters Health, "When added to historical therapy, adjuvant bisphosphonates are associated with a significant, but modest reduction in bone recurrence. The optimal duration of adjuvant bisphosphonate therapy is unknown."
"While methodological limitations may have impacted on the observed outcomes in SUCCESS A," he said, "it is unlikely that a substantial difference would have been observed even in the absence of these limitations."
"In light of the modest outcomes of bisphosphonates compared to no bone-targeted therapy in historical trials and the substantially improved outcomes observed in modern trials in early breast cancer, an important question needs to be answered," he said. "In a contemporary breast cancer setting what, if any, is the benefit from any adjuvant bisphosphonates?"
This study was funded in part by AstraZeneca, Chugai, Menarini Silicon Biosystems (formerly Veridex), Lilly, Novartis, and Sanofi-Aventis. Dr. Friedl and many coauthors have received fees from one or more of these companies.
SOURCE: https://bit.ly/3hi2wiS and https://bit.ly/3y8GaY2 JAMA Oncology, online June 24, 2021.
By Marilynn Larkin
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