Re: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma (multiple letters) [3]

Indications:Bone metastases and androgen-independent prostate cancer.

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TypeofStudy:Letters to the editor.

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FreeText:Comment on the randomized, placebo-controlled trial of Zometa in patients with hormone-refractory metastatic prostate carcinoma and reply. The comment indicated that the clinical benefit of Zometa in the treatment of bone metastases and androgen-independent prostate cancer 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 Zometa (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. The comments suggest that improved understanding of the role of bone cells such as osteoclasts and osteoblasts and their response to Zometa in the context of prostate cancer bone metastases will form the basis of future studies. Given the absence of any detectable antitumor activity, the results from the clinical trial are more suggestive of an effect of Zometa on osteoporosis rather than on the tumor. In reply, author of the clinical trial of Zometa noted 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 with prostate cancer, change of antineoplastic therapy for bone pain. The study is powered to show difference in the primary endpoint, so statistical significance in each individual type of SREs is not expected. In any case, the analyzed data excluded all non-symptomatic fractures as well as all fractures, and the primary endpoint remained statistically significant, indicating that the clinical benefit of Zometa is beyond reduction of risk of fractures. The author concurs with the comment that it is very difficult to distinguish between the effects of Zometa on bone and on cancer cells because Zometa 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 Zometa. In addition, the author cited a study that demonstrated the antitumor and antiangiogenic properties of Zometa in preclinical studies. On the comment that the efficacy of Zometa may be interpreted as a result of anti-osteoporotic effect, the author notes that the benefit of Zometa remains even after fractures are excluded from the analysis, which strongly argues against the notion that the benefit of Zometa is simply that of 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 Zometa 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 author's comments 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.