Published: 27 June 2005
There is level 1 evidence that Zoledronate at 4 mg IV administered every 3 weeks for 12-24 months reduces skeletal related events (SREs) in men with hormone resistant prostate cancer and bone metastases. SREs were defined as a pathological fracture, radiation therapy to bone, surgery to bone, or a change in chemotherapy to treat bone pain. Zoledronate produces an 8% absolute reduction (from 44-36%) in SREs at 15 months. The annual incidence of SREs was 0.77 for the 4-mg zoledronic acid group versus 1.47 for the placebo group. This translates into a number need to treat of 12 patients to prevent 1 skeletal related event. This is not associated with any definitive demonstration of survival benefit, pain or quality of life improvement. Repeated intravenous administrations of Zoledronate can have adverse effects and its use must be balanced by the benefit. A request for BCCA funding for Zoledronic Acid was not successful, however, Zoledronate is available for use under the palliative drug benefit program, which is designed to provide support within the last 6 months of life.
Background information on bisphosphonates in prostate cancer
In the context of androgen deprivation therapy osteoporosis may be found or develop. Bisphosphonates have a significant role to play in the treatment of established osteoporosis. Although bisphosphonates (and other products) will benefit bone density in patients without osteoporosis, it is not clear that there will be any reduction in fractures - the key endpoint in prevention. Medical interventions, on the other hand, may have complications and costs. For more detail please see Osteoporosis Screening Guidelines.
In view of practice trends and requests, the BC Cancer Agency (BCCA) Genitourinary (GU) Tumour Group has reviewed the evidence of the role of bisphosphonates in hormone refractory prostate cancer. We agree with the Ontario guidelines (Berry et al) in regards to the cited references and most of their conclusions. The BCCA GU Tumour Group does not agree with the conclusions of Berry et al on the use of clodronate for metastatic bone pain in prostate cancer patients.
Although evidence supports the use of bisphosphonates in pain relief (9000 patients from 51 randomized trials), the effect is small (about 0.5 in a 10 point pain scale) and delayed by about 12 weeks (Wong 2004). At present there is insufficient evidence to support their first line use for bone pain. When analysis is focused on evidence in the context of metastatic prostate cancer the effects are minimal and only a trend on subset analysis of a clodronate trial. In view of the benefits from analgesics, co-analgesics, radiotherapy (including strontium), chemotherapy and on occasion surgical intervention, the role of bisphosphonates for pain relief should be considered as an adjunct to these approaches where pain control proves difficult.
References:
Genitourinary Cancer Disease Site Group. Berry S, Waldron T, Winquist E, Lukka H. The use of bisphosphonates in men with hormone-refractory prostate cancer [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2005 Jan 10. 34 p. (Practice guideline report; no. 3-14). [43 references]
Wong R, Shukla VK, Mensinkai S, Wiffen P. An assessment of bisphosphonate drugs to manage pain secondary to bone metastases [Technology overview no 14]. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 2004.
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.[comment]. Journal of the National Cancer Institute 2002;94(19):1458-68.
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(11):879-882.
