Re: A Randomized, Placebo- Controlled Trial of Zoledronic Acid in Patients with Hormone- Refractory Metastatic Prostate Carcinoma

The article by Saad et al. (1) indicated clinical benefit for the use of zoledronic acid in the treatment of bone metastases and androgen-independent prostate cancer. However, the precise nature and biologic implication of the clinical benefit deserves further scrutiny. The endpoint used to determine clinical benefit was “skeletal-related events.” However, only “pathologic bone fracture” was statistically significantly improved in patients who received zoledronic acid (4 mg). Other events, such as nonvertebral fractures, radiation therapy to bone, surgery to bone, spinal cord compressions, and change in antineoplastic treatments were not statistically significantly altered. Thus, although the findings demonstrated benefit to patients treated with androgen ablation, they did not provide any indication whether this benefit resulted from a direct effect on the bone and/or the cancer. From our perspective, it would be useful to distinguish the effect of zoledronic acid on the bone (i.e., osteoporosis) from an effect on the cancer (2,3). Distinguishing between the two effects will be difficult given the complexities of the stromal–epithelial interactions after prostate cancer metastasizes to the bone. However, a rational development of therapy requires further understanding of this interaction. Improved understanding of the role of bone cells such as osteoclasts and osteoblasts and their response to zoledronic acid in the context of prostate cancer bone metastases will form the basis of future studies. Given the absence of any detectable antitumor activity, we interpret the results from Saad et al. (1) to be more suggestive of an effect of zoledronic acid on osteoporosis rather than on the tumor. The final arbiter of clinical benefit is increased survival time. Unfortunately, treating only the osteoclastic or the osteoblastic components (with zoledronic acid and strontium-89, respectively) of bone metastases has not provided any survival advantage for patients with androgen-independent prostate cancer (1,4). Although there are no phase III data indicating a survival advantage, we have reported encouraging results from an initial study of bone-targeted therapy in advanced prostate cancer (5). The patients in our study (5) were selected by their initial response to chemotherapy and thus the results might not be applicable to all patients with androgenindependent prostate cancer and bone metastases. An updated survival time of the three categories of patients reported continues to demonstrate a longer survival time for those patients who received combination treatment involving induction chemotherapy and consolidation strontium-89 that targeted both the tumor and osteoblastic components (5) (Fig. 1). A confirmatory randomized phase III trial (MDA-3410) using this strategy is currently open for patient accrual at the Community Clinical Oncology Program (CCOP) and the Cancer Treatment Support Unit (CTSU) of the National Cancer Institute.