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© 2004 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, FRCS, Department of Surgery/Urology, Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame, Montréal, Quebec, Canada H2L 4M1 (e-mail: fred.saad{at}ssss.gouv.qc.ca)
Dr. Parker stated that in our trial (1) "zoledronic acid demonstrated statistically significant reductions in skeletal complications"; however, he questioned whether such reductions should be regarded as sufficient evidence to change clinical practice. First, he doubted the clinical significance of the statistically significant 0.47-point reduction we observed in the mean Brief Pain Inventory score (where 0 = no pain and 10 = worst pain) at 24 months among patients treated with zoledronic acid versus patients in the placebo group. Although this change in mean pain score may not appear great, certainly some patients experienced much larger decreases in pain scores. Moreover, the decreased incidence of radiation to bone among patients treated with zoledronic acid suggests that they experienced a decrease in severe bone pain. It is important to keep in mind that pain is a difficult clinical endpoint to assess and that this is the first randomized, placebo-controlled bisphosphonate trial in patients with prostate cancer to show a statistically significant and durable decrease in pain scores among patients treated with zoledronic acid compared with placebo. Neither intravenous pamidronate nor intravenous clodronate have demonstrated such a benefit (2,3).
Second, Dr. Parker stated that radiation therapy to bone "is also of debatable clinical significance" and suggested that radiation therapy should not be included in the composite endpoint as a skeletal-related event. He cited two randomized studies (3) of pamidronate in hormone-refractory prostate cancer as examples of studies that considered palliative radiotherapy to be part of routine care, not a skeletal complication. This statement is incorrect. Those studies (3) did include radiation to bone as a skeletal-related event and used a definition for skeletal-related events that was very similar to that used in our trial. Radiation to bone is an important indicator of the incidence of severe bone pain and has been shown to be associated with a statistically significant decrease in health-related quality of life (4). Therefore, it is appropriate to include palliative radiotherapy in the composite definition of a skeletal-related event.
Third, Dr. Parker stated that "zoledronic acid is not without adverse effects." However, if one considers the risk–benefit equation, the evidence supports the routine use of zoledronic acid in prostate cancer patients. The adverse events that occurred more frequently in the zoledronic acid group than in the placebo group were primarily mild-to-moderate flu-like symptoms, which occurred mainly after the first infusion and only rarely after later infusions. These adverse events would not be expected to affect quality of life to the same extent as skeletal complications. The skeletal-related events that are prevented by treatment with zoledronic acid, such as pathologic fractures and severe bone pain requiring palliative radiotherapy, are associated with clinically significant decrements in multiple domains of health-related quality of life (4). Fractures have also been shown to be an independent adverse predictor of survival in patients with prostate cancer (5). Pathologic fractures, in particular, can be devastating events in patients’ lives because they signal skeletal disease progression and can lead to substantial morbidity and mortality (6,7). Therefore, I submit that there is a sound clinical rationale for proactive treatment with zoledronic acid in patients with bone metastases from advanced prostate cancer and that the potential benefit of maintaining bone health outweighs the risks associated with intravenous bisphosphonate therapy.
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 Ernst DS, Tannock IF, Winquist EW, Venner PM, Reyno L, Moore MJ, et al. Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol 2003;21:3335–42.
3 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.
4 Weinfurt KP, Li Y, Castel LD, Timbie JW, Glendenning A, Schulman KA. The impact of skeletal-related events on health-related quality of life of patients with metastatic prostate cancer [abstract 662P]. Ann Oncol 2002;13(Suppl 5):180.
5 Oefelein MG, Ricchiuti V, Conrad W, Resnick MI. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol 2002;168:1005–7.[CrossRef][Web of Science][Medline]
6 Cereceda LE, Flechon A, Droz JP. Management of vertebral metastases in prostate cancer: a retrospective analysis in 119 patients. Clin Prostate Cancer 2003;2:34–40.[Medline]
7 Dijstra S, Wiggers T, van Geel BN, Boxma H. Impending and actual pathological fractures in patients with bone metastases of the long bones. A retrospective study of 233 surgically treated fractures. Eur J Surg 1994;160:535–42.[Medline]
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J Natl Cancer Inst 2004 96: 1480.
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