© 2005 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Long-Term Efficacy of Zoledronic Acid for the Prevention of Skeletal Complications in Patients with Metastatic Hormone-Refractory Prostate Cancer
Correspondence to: Fred Saad, MD, Director of Urologic Oncology, Professor of Surgery Department of Surgery/Urology, Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame, 1560 Rue Sherbrooke East, Montréal, PQ, Canada H2L 4M1 (e-mail: fred.saad{at}ssss.gouv.qc.ca)
Dr. Tanvetyanon raised concerns about the long-term safety of zoledronic acid for the treatment of bone metastases in patients with hormone-refractory prostate cancer. These concerns must be viewed from the perspective of this patient population, in which the median survival is 15 to 18 months. This 24-month randomized, placebo-controlled, double-blind study offers the most stringent and objective assessment of the efficacy and safety of zoledronic acid in prostate cancer. In this trial, there was no statistically significant difference between the renal safety profiles of 4 mg of zoledronic acid (via 15-minute infusion every 3 weeks for 2 years) and the placebo (hazard ratio for time to first increase in serum creatinine concentration = 1.137; P = .752) (1). Dr. Tanvetyanon cites a case study of a multiple myeloma patient who developed renal failure and glomerular disease after 40 months of pamidronate treatment. However, this case is not relevant to our trial and thus should not affect the conclusions from our trial. Similarly, reported cases of osteopetrosis are not relevant to our trial because they occurred after pamidronate was administered at doses much higher than those approved for clinical use. We have no evidence to support the speculation that the high doses of zoledronic acid used in our study cause osteopetrosis. Osteonecrosis of the jaw (ONJ), a poorly defined clinical entity with multiple risk factors (2), has recently been reported in cancer patients treated with bisphosphonates (3); however, it is unclear whether there is a causal relationship between bisphosphonate use and ONJ.
With regard to the continuing benefit of long-term zoledronic acid treatment, the trial suggested by Dr. Tanvetyanon is not feasible because there would be ethical concerns if treatment were stopped after 15 months. We cannot eliminate the possibility that the amount of zoledronic acid that accumulates in bone after 15 months of treatment is sufficient to provide sustained long-term benefit. However, the extent to which zoledronic acid may accumulate or provide continued benefit if treatment was stopped is unknown given that prostate cancer patients with bone metastases have high rates of bone turnover and are at continuous risk for skeletal complications, which can occur multiple times during the course of this chronic disease. Results of a multiple events analysis demonstrated that zoledronic acid reduced the overall risk of one or more events by approximately 40% (1). An exploratory analysis of the extension phase of the trial (1) and a second-event analysis (4) have provided data that suggest that zoledronic acid provides continued benefits. Therefore, consistent with guidelines from the American Society of Clinical Oncology for bisphosphonate use in breast cancer (5), the use of bisphosphonates should be continued as long as they are tolerated. Although this treatment approach may be costly, a pharmacoeconomic analysis has shown that approximately 50% of the total cost of treating advanced prostate cancer can be attributed to skeletal complications (6).
Finally, with regard to the effects on pain observed in this trial, zoledronic acid is the only bisphosphonate to demonstrate statistically significant and sustained reductions in pain compared with placebo in patients with prostate cancer in a randomized double-blind study. The statistically significant reduction in mean pain scores in the zoledronic acid group compared with the placebo group is considered clinically meaningful, particularly given that many patients did not have pain at baseline. In addition, zoledronic acid statistically significantly reduced the need for radiotherapy, which was used mainly for pain control (7).
The clinical benefits of zoledronic acid were clearly demonstrated in this trial. Patients with bone metastases from prostate cancer should be treated with zoledronic acid for an adequate period, although it is not clear if that period should be 24 months or longer.
REFERENCES
1 Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879–82.
2 Tarassoff P, Csermak K. Avascular necrosis of the jaws: risk factors in metastatic cancer patients. J Oral Maxillofac Surg 2003;61:1238–9.[Medline]
3 Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527–34.[CrossRef][Web of Science][Medline]
4 Saad F, Gleason DM, Murray R, Tchekmedyian NSS, Venner P, Lacombe L, et al. Continuing benefit of zoledronic acid for the prevention of skeletal complications in men with advanced prostate cancer [abstract]. Proc Am Soc Clin Oncol. 2004;23:399.
5 Hillner BE, Ingle JN, Chlebowski RT, Gralow J, Yee GC, Janjan NA, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. Published erratum in: J Clin Oncol. 2004;22:1351. J Clin Oncol 2003;21:4042–57.
6 Groot MT, Boeken Kruger CG, Pelger RC, Uyl-de Groot CA. Costs of prostate cancer, metastatic to the bone, in The Netherlands. Eur Urol 2003;43: 226–32.[CrossRef][Web of Science][Medline]
7 Major PP, Cook RJ, Chen BL, Zheng M. Zoledronic acid reduces the need for radiation to bone in patients with breast or prostate cancer metastatic to bone: a survival-adjusted cumulative incidence analysis [abstract]. Proc Am Soc Clin Oncol. 2004;23:739.
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J Natl Cancer Inst 2005 97: 70.
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