CORRESPONDENCE

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

Shi-Ming Tu, Sue-Hwa Lin, Christopher Logothetis

Affiliations of authors: S.-M. Tu, S.-H. Lin, C. Logothetis, Department of Genitourinary Medical Oncology; S.-H. Lin, Molecular Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.

Correspondence to: Shi-Ming Tu, MD, Department of Genitourinary Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 427, Houston, TX 77030 (e-mail: stu{at}mdanderson.org).

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 androgen-independent 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. 1Go). 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.



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Fig. 1. Updated Kaplan–Meier estimates of survival time for patients with androgen-independent prostate cancer and bone metastases who received induction chemotherapy followed by consolidation therapy consisting of doxorubicin and strontium-89 (A), of doxorubicin alone (B), or without consolidation therapy, i.e., not randomized (C) (5). Error bars are 95% confidence intervals, P<0.0001 by log-rank (Mantel–Cox) test. The numbers of surviving patients are shown below the graph.

 

REFERENCES

1 Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. A randomized, placebo-controlled trial of Zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458–68.[Abstract/Free Full Text]

2 Townsend MF, Sanders WH, Northway RO, Graham SDJ. Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate carcinoma. Cancer 1997;79:545–50.[CrossRef][ISI][Medline]

3 Daniell HW. Osteoporosis after orchiectomy for prostate cancer. J Urol 1997;157:439–44.[ISI][Medline]

4 Porter AT, McEwan AJ, Powe JE, Reid R, McGowan DG, Lukka H, et al. Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiation Oncology Biol Phys 1993;25:805–13.[ISI][Medline]

5 Tu S-M, Millikan RE, Mengistu B, Delpassand ES, Amato RJ, Pagliaro LC, et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomized phase II trial. Lancet 2001;357:336–41.[CrossRef][ISI][Medline]



             
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