CORRESPONDENCE

Re: Long-Term Efficacy of Zoledronic Acid for the Prevention of Skeletal Complications in Patients With Metastatic Hormone-Refractory Prostate Cancer

Christopher C. Parker

Correspondence to: Christopher C. Parker, BA, MRCP, MD, FRCR, Academic Unit of Radiotherapy and Oncology, Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, U.K. (e-mail: Chris.Parker{at}icr.ac.uk)

I was interested to read the updated results of the Zoledronic Acid Prostate Cancer Study Group’s randomized placebo-controlled trial in men with bone metastases from hormone-refractory prostate cancer (HRPC) (1). This was a positive trial, in the sense that zoledronic acid demonstrated statistically significant reductions in skeletal complications. However, there are several reasons why I question whether the reported reduction in skeletal complications, particularly in the absence of any impact on either overall survival or quality of life, should be regarded as sufficient evidence to change clinical practice.

First, statistical significance does not equal clinical significance. Saad et al. (1) reported that zoledronic acid had a statistically significant effect on pain control at 24 months, in that patients who received 4 mg of zoledronic acid had a smaller increase in their Brief Pain Inventory (BPI) scores than patients who received placebo (0.58 versus 1.05; P = .024). Given that BPI is measured on an 11-point scale (ranging from 0 to 10), the clinical significance of a difference of 0.47 points (95% confidence interval = 0.06 to 0.88 points) is doubtful.

Second, not all skeletal complications are created equal. Some skeletal complications, such as spinal cord compression, can be devastating, whereas others, such as asymptomatic fractures, are of little or no relevance to the patient. The authors acknowledge this point by presenting data for the effect of zoledronic acid on skeletal complications excluding asymptomatic fractures. However, radiation therapy to bone, which is the single most common "skeletal complication," is also of debatable clinical significance. For example, two randomized studies of pamidronate in HRPC considered palliative radiotherapy as part of routine care, not as a skeletal complication (2). It would be interesting to know the magnitude of the benefit of zoledronic acid on skeletal complications when both asymptomatic fractures and radiation to bone are excluded. In their original analysis of the trial data, Saad et al. (3) reported that 29.3% of patients in the placebo group received radiation to bone within 15 months of randomization, compared with 22.9% of those in 4-mg zoledronic acid group and 24.0% of those in the 8/4-mg zoledronic acid group. Whether or not radiation to bone is classified as a skeletal complication, I question the utility of regular intravenous infusions every 3 weeks for up to 15 months in order to reduce the need for a single fraction of radiation by approximately 6%.

Third, zoledronic acid is not without adverse effects. Saad et al. (2) reported that, compared with patients receiving placebo, those receiving 4 mg of zoledronic acid had increased risks of fatigue (32.7% versus 25.5%), anemia (26.6% versus 17.8%), myalgia (24.8% versus 17.8%), fever (20.1% versus 13.0%), edema (19.2% versus 13.0%), and weight loss (16.8% versus 12.5%). In considering the clinical role of zoledronic acid in patients with HRPC, it is important to take into account the balance between the risks of adverse effects and the potential benefits of reducing skeletal events. The lack of any published quality-of-life data from the Saad et al. study is an important omission. In the absence of such data, and given the range of adverse effects listed above, one could speculate that zoledronic acid might have a detrimental, rather than a beneficial, effect on the quality of life of men with HRPC.

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.[Abstract/Free Full Text]

2 Small EJ, Smith MR, Seaman JJ, Petrone S, Kowalski MO. Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 2003;21:4277–84.[Abstract/Free Full Text]

3 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]



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