Phase III randomized trial of bisphosphonates as adjuvant therapy in breast cancer: S0307.

Abstract

BACKGROUND\nAdjuvant bisphosphonates, when given in a low estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early stage breast cancer.\n\n\nMETHODS\nPatients with stage I-III breast cancer were randomized to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival (OS) a secondary outcome. All statistical tests were two-sided.\n\n\nRESULTS\n6,097 patients enrolled. Median age was 52.7 years. Prior to randomization, 73.2% of patients indicated preference for oral versus intravenous formulation. DFS did not differ across arms in a log-rank test (p\u2009=\u20090.49). 5-year DFS was 88.3% (zoledronic acid, 95% CI 86.9%-89.6%), 87.6% (clodronate, 95% CI 86.1%-88.9%), and 87.4% (ibandronate, 95% CI 85.6%-88.9%). 5-year OS also did not differ between arms (log rank p\u2009=\u20090.50) and was 92.6% (zoledronic acid, 95% CI 91.4%-93.6%), 92.4% (clodronate 95% CI 91.2%-93.5%), and 92.9%% (ibandronate 95% CI 91.5%-94.1%). Bone as first site of recurrence did not differ between arms (P\u2009=\u20090.93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the Jaw (ONJ) was highest for zoledronic acid (1.26%), compared to clodronate (0.36%) and ibandronate (0.77%).\n\n\nCONCLUSIONS\nWe found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of ONJ with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the U.S. should be considered.