A recently presented study revealed that the bisphosphonate clodronate had a low incidence of adverse events and toxicity among patients with breast cancer and may modestly reduce the incidence of distant metastases in postmenopausal women.
Three previous trials of oral clodronate have given mixed results. The largest trial (placebo-controlled) and a smaller open-label trial suggested that oral clodronate benefits patients by prolonging bone metastases-free survival and overall survival. However, a third open-label study failed to show any benefit with an apparent detrimental effect on survival. In the B-34 prospective, randomized, double-blind, phase III clinical trial professor A. Paterson, MD (University of Calgary, Canada) and colleagues randomly assigned 3,323 patients with stage I, II or III breast cancer patients to receive three years of clodronate or an oral placebo three times a day. In addition, the patients also underwent surgery (lumpectomies or mastectomies) and received radiation therapy and chemotherapy or hormonal therapy.
During the 2011 CTRC-AACR San Antonio Breast Cancer Symposium, Paterson presented data on the 3,311 patients (99.6%) with follow-up information. Slightly more than 75% of the patients had pathologically negative axillary nodes, 64% were 50 years or older at entry and 22% had estrogen receptor negative (ER-) or progesterone receptor negative (PgR-) breast cancer. The median follow-up for patients who were still alive was 7.6 years.
Two hundred and eighty-six patients in the clodronate group experienced disease events, compared to 312 in the placebo group. As such, the relative reduction of events in the clodronate group compared to the placebo treated patients was 9%. “This reduction was smaller than had been hoped for and was not statistically significant,” Paterson said. Furthermore, researchers observed a 16% relative reduction in mortality in the clodronate group. They also observed relative reductions of 23% and 26% in the clodronate group for the occurrence of 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,” Paterson said.
A subgroup analysis of the data further showed that clodronate might perform better in patients aged 50 years or older when diagnosed with breast cancer and in women with ER/PgR-positive nodes. Clodronate was generally well tolerated, and the toxicities observed were mainly due to concomitant systemic chemotherapy, according to the researchers.
In conclusion, this was the largest study to assess clodronate in a placebo-controlled manner. At this point, clinical indications are not absolute, but a tolerable agent that has a known beneficial effect on osteopenia with a small reduction in distant disease recurrence may be of interest to some patients and clinicians.