Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up.

Clodronate is the first oral bisphosphonate shown to improve overall survival and reduce the occurrence of bone metastases when used as an adjunctive therapy in women with primary breast cancer. In this study, a significant reduction in mortality was demonstrated at a median follow-up of 103 months.

In patients with breast cancer, the most common site for distant metastasis is bone {1}. The resulting metastatic bone disease can cause bone pain, fractures, and spinal cord compression. Bisphosphonates are used to reduce the risk of patients experiencing a skeletal-related event and to alleviate bone pain, thereby improving quality of life. A large amount of preclinical evidence suggests that bisphosphonates may also have direct effects against tumors. These include inhibition of tumor cell adhesion to bone, tumor growth, angiogenesis and induction of apoptotic effects on cancer cells {2-4}. These findings have raised considerable interest in studying bisphosphonates earlier in the course of breast cancer, in the adjuvant setting. Clodronate is an oral bisphosphonate that accumulates on bone surfaces where it inhibits osteoclast activity. In a large-scale, randomized, placebo-controlled trial of 1069 patients with stages I–III breast cancer who received clodronate 1600mg or placebo daily for 2 years, adjuvant clodronate treatment reduced the risk of death by 23% at 5 years (p=0.048) and reduced the risk of bone metastases by 31% over the same time period (p=0.043) {5}. This article by Diel et al. reports the long-term follow-up data from the same study, now with a median of 8.5 years of follow-up. 302 patients with primary breast cancer classified as stage T1-T4 and histologically classified as N0-N2 were randomly assigned to receive either clodronate 1600mg/day for 2 years (treatment group) or placebo (control group). All patients in both groups received standard surgical treatment and customary adjuvant endocrine therapy or chemotherapy +/- radiotherapy. The primary endpoints included the incidence and number of new bone and visceral metastases, as well as the length of time to their appearance and overall survival (OS). Although the differences in the incidence of bony and visceral metastases and the duration of disease-free survival were no longer significant by this time, the significant improvement in OS was maintained in the clodronate group, with death occurring in 20.4% of clodronate-treated patients and 40.7% of controls (p=0.049). Oral clodronate is the first and only oral bisphosphonate reported to significantly reduce the occurrence of bone metastases and significantly prolong survival in women with primary breast cancer, although the optimal duration of treatment remains to be defined. Numerous studies of adjuvant bisphosphonate treatment in patients with breast cancer are recruiting patients or have completed patient recruitment and await data analysis. In our opinion, further positive studies are necessary for a change in clinical practice.

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