CORRESPONDENCE

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

Fred Saad
For the Zoledronic Acid Prostate Cancer Study Group

Correspondence to: Fred Saad, MD, FRCS, Uro-Oncology Clinic, Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame, 1560 Rue Sherbrooke East, Montreal, Quebec, Canada H2L 4M1 (e-mail: fredsaad{at}videotron.ca).

Tu et al. asked about the nature of clinical benefit of zoledronic acid and stated that only "pathological bone fracture" was statistically significantly improved. We noted, however, that the primary endpoint was the proportion of patients with any skeletal-related events (SREs), which has been accepted as the standard endpoint to determine clinical benefit of bisphosphonates in clinical studies. SRE is a composite endpoint consisting of not only fractures, but also of radiation therapy for bone pain or impending fractures, spinal cord compression, surgery, hypercalcemia, and in our study with prostate cancer, change of antineoplastic therapy for bone pain. Obviously, the study is powered to show difference in the primary endpoint, so we do not expect to show statistical significance in each individual type of SREs. In any case, we also analyzed the data excluding all non-symptomatic fractures as well as all fractures, and the primary endpoint remained statistically significant, indicating that the clinical benefit of zoledronic acid is beyond reduction of risk of fractures.

We concur with Dr. Tu that it is very difficult to distinguish between the effects of zoledronic acid on bone and on cancer cells because zoledronic acid was shown to have effects on both types of cells in preclinical studies. It is well understood that bone metastases occur as a result of the interaction between the tumor cells and the bone tissues that perpetuates a vicious cycle, which is interrupted by a bisphosphonate such as zoledronic acid. In addition, zoledronic acid has demonstrated antitumor and antiangiogenic properties in preclinical studies (1).

Dr. Tu also suggested that the efficacy of zoledronic acid may be interpreted as a result of anti-osteoporotic effect. However, the benefit of zoledronic acid remains even after fractures are excluded from the analysis, strongly arguing against the notion that the benefit of zoledronic acid is simply because of its anti-osteoporotic effects. Although it is not possible to differentiate what proportion of fractures result from osteoporosis or from bone metastases, it is more important to know that zoledronic acid has demonstrated efficacy in reducing the bone complications regardless of the underlying causes, thereby providing clinical significant benefit to patients.

The objective of bisphosphonate treatment in advanced cancer metastatic to bone is to improve the patients’ quality of life by reducing the number of bone complications that lead to morbidity and mortality. In hormone refractory prostate cancer, no agent has shown a survival benefit. Although Dr. Tu and colleagues have shown interesting findings on a regimen of chemotherapy in combination with strontium-89, these preliminary results need to be confirmed in the ongoing randomized phase III study.

REFERENCE

1 Green JR. Preclinical pharmacology of zoledronic acid. Semin Oncol 2002;29(6 Suppl 21):3–11.



             
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