San Antonio – While treatment with the clodronate does not appear to affect disease-free survival among women with stages I-III breast cancer, the drug does appear to improve certain outcomes for women aged 50 years and older, according to the results of a phase III trial of more than 3,000 patients.
Disease-free survival (DFS) did not differ between women treated with clodronate and those given placebo (hazard ratio, 0.91; P = .27). However, women at least 50 years of age saw benefits in secondary protocol predefined end points, Dr. Alexander H.G. Paterson said at the San Antonio Breast Cancer Symposium.
"This is an easy treatment and it’s oral. It seems to have an effect in older women and low toxicity. We’ve now got four trials [pointing in] the same direction ... that is of a benefit in older patients," said Dr. Paterson, a professor in the departments of medicine and oncology at the University of Calgary in Canada.
In the double-blind, phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) B-34 clinical trial, patients with stage I-III breast cancer were randomized to receive oral clodronate 1,600 mg daily for 3 years or 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.
The groups were stratified by age (younger than 50 years or at least 50 years), number of positive nodes and estrogen receptor/progesterone receptor (ER/PR) status. The primary end point was disease-free survival, which was defined to include all recurrences, deaths, and second primary cancers. Secondary end points are the incidence of skeletal metastases, overall survival, recurrence-free interval, bone metastasis–free interval, and nonbone metastasis–free interval.
The researchers reported on 3,311 patients (1,656 on placebo and 1,655 on clodronate) with a median of 8 years in the study. Of note, almost two-thirds of patients (64%) were at least 50 years old at the time of enrollment. Three-quarters had pathologically-negative axillary nodes and almost a quarter (22%) had ER-negative or PR-negative breast cancer.
"Compliance was an issue. The drop in compliance really occurred in the first 6 months, when patients were also receiving intravenous chemotherapy," said Dr. Paterson. A total of 40% of patients did not complete 3 years of study therapy.
Patients on clodronate had a slightly lower rate of treatment failure at distant sites (5.4% vs. 6.6%). The researchers suspect that the disease-free survival benefit was attenuated due to the equivalent event rates for second primary cancers, contralateral cancers and local/regional relapses.
Overall toxicity was low and comparable for the two groups. There was one case of osteonecrosis of the jaw in the clodronate group.
However, clodronate showed benefit regarding distant metastases in all protocol predefined secondary end points. Hazard reductions ranged from 15% for overall survival to 26% for nonbone metastasis–free interval.
Dr. Paterson noted that secondary protocol predefined end point reductions were even greater among women at least 50 years of age. For these women, there was a 24% reduction in breast cancer recurrence–free interval (P = .05), a 39% reduction in bone metastasis–free interval (P = .024), and a 37% reduction in nonbone metastasis–free interval (P = .015). In addition, women 50 years and older had a 20% reduction in overall survival, though this was not statistically significant (P = 0.1).
"Similar beneficial results in older postmenopausal women are seen in other studies involving bisphosphonates," he said.
Bisphosponates are thought to inhibit the growth of bone metastases by inhibiting osteoclast function and subsequent bone turnover. However, the role of bisphosphonates in preventing or delaying the development of bone (or other) metastases in patients with early breast cancer remains unclear.
The trial received support from the National Cancer Institute and Bayer Schering Pharma Oy. Dr. Paterson disclosed that he is a consultant for GlaxoSmithKline, Amgen, Roche Diagnostics, and Nicomed.