NSABP Protocol B-34—Disappointing findings were reported from B-34, a prospective, randomized, double-blind, phase III clinical trial of oral clodronate in patients with stage I, II, or III breast cancer (SABC 2011 abstract S2-3). The largest placebo-controlled study to date of an oral bisphosphonate in patients with early breast cancer, the trial failed to meet its primary end point of disease-free survival (DFS), reported Alexander H.G. Paterson, MD, professor in the departments of medicine and oncology at the University of Calgary, Alberta, Canada.
Secondary end points were incidence of skeletal metastases, overall survival (OS), relapse-free survival, incidence of non-skeletal metastases, and incidence of skeletal morbid events.
Slightly more than 75% percent of 3311 patients evaluated had pathologically negative axillary nodes, 64% percent were older than 50 years at entry, and 22% had estrogen receptor (ER)-negative or progesterone(Drug information on progesterone) receptor (PR)-negative breast cancer.
Patients were randomly assigned to receive oral clodronate 1600mg daily for 3 years compared to placebo given alone or in addition to adjuvant chemotherapy or hormone therapy. Patients also underwent surgery (lumpectomies or mastectomies) and received radiation therapy and chemotherapy or hormonal therapy. Median follow-up for patients who were still alive was 7.6 years.
There were 598 patients who experienced disease events, defined as any cancer (either recurrent breast cancer or a new primary) or death (cancer related or otherwise): 286 in the clodronate group and 312 in the placebo group. The relative reduction of events in the clodronate group was about 9% compared with the placebo group.
"This reduction was smaller than had been hoped for and was not statistically significant," said Dr. Patterson. A relative reduction in mortality of 16% was observed in the clodronate group, as well as reductions of 23% and 26% in skeletal and nonskeletal metastases, respectively.
"Although clodronate appeared more favorable for all endpoints, only the comparisons of the distant metastasis-free interval and nonskeletal metastasis-free interval were statistically significant and favorable for the clodronate patients," said Dr. Paterson.
Results also suggested that clodronate might perform better in patients who are 50 years or older when diagnosed with breast cancer, and in women with ER/PR-positive nodes. Clodronate was generally tolerable, and the toxicities observed were considered by the investigators mainly due to concomitant systemic chemotherapy.
GAIN Trial—Results from the prospective, multicenter, controlled, non-blinded, randomized phase 3 German Adjuvant Intergroup Node Positive (GAIN) study demonstrated no improvement in DFS among patients with breast cancer who were treated with dose-dense chemotherapy and the oral bisphosphonate ibandronate (2011 SABC abstract S2-4). Findings were reported by Volker Möbus, PhD, head of the department of obstetrics and gynecology at Klinikum Frankfurt Höchst GmbH, Frankfurt.
Investigators randomly assigned 3,023 patients with primary breast cancer to 2 different chemotherapy regimens and then further assigned them to 50 mg daily of oral ibandronate or observation. After a median follow-up of 38.7 months, "we found no significant difference between groups in the primary end point" of DFS, said Dr Möbus.
He described the results as "disappointing" compared to other studies of bisphosphonates in breast cancer patients. "So far, clinical trials of adjuvant bisphosphonates in early breast cancer have shown variable results, independent from their application (oral compared with intravenous)," he explained. "In the AZURE trial, 95% of patients received chemotherapy and only postmenopausal patients showed an improvement in the zoledronic acid(Drug information on zoledronic acid) group. "In our [GAIN] trial, all patients received dose-dense chemotherapy, and unfortunately, we could not show a benefit in any subgroup. We speculate that the high efficacy of dose-dense chemotherapy erases the potential effect of bisphosphonates, which is shown in patients with endocrine treatment only."
"There were four presentations on bisphosphonate therapy, and unfortunately, one is more puzzled than ever," commented Harold J. Burstein, MD, PhD, assistant professor of medicine at Harvard Medical School and medical oncologist in the Breast Oncology Center at Dana-Farber Cancer Institute, Boston. "The two largest studies showed no compelling gains; the two smaller studies suggested more benefit. It will take more analyses to help us understand whether or how to use these drugs to prevent breast cancer recurrence."