Adjuvant bisphosphonate therapy: the future

Bisphosphonates are established as a useful component in the treatment of skeletal metastases in breast cancer and multiple myeloma, and may prove to be useful in other cancers that metastasize to bone. Recent attention has focused on possible preventive effects of bisphosphonates, in the adjuvant therapy of patients with operable breast cancer, either by disrupting the interactions between micrometastatic tumor cells and the bone microenvironment or by direct actions on tumor cells. Three adjuvant trials of the oral bisphosphonate clodronate have been completed, but the results have been conflicting. A reduction in bone and visceral metastases and increased survival with adjuvant clodronate was seen in one study of 302 patients with breast cancer. Another open-label study (299 patients) has shown increased visceral metastases and decreased survival, while an interim analysis of a third, larger, placebo-controlled study (1,079 patients) showed a beneficial effect on bone metastases, but no effect on visceral metastases or survival. The final analysis of this trial is expected in 2001. The evidence has been sufficiently encouraging that further randomized trials are planned or in progress with clodronate and other bisphosphonates including intravenous pamidronate, zoledronate, and oral ibandronate. Careful trial design and selection of patients at high risk for bone recurrence are important for studies to detect adjuvant effects. Convenience and cost are likely to be important considerations for the long-term adjuvant use of bisphosphonates. Oral formulations and the introduction of highly potent bisphosphonates may offer advantages, and require clinical assessment.