Clinical Practice Guidelines for the management of locally advanced ...

Hormone refractory/castrate resistant disease with painful bone metastases
In a RCT (n=378) of pamidronate disodium (iv), Small et al 2003 31 did not find a significant overall
reduction in the number of SREs in the pamidronate arm (23%) compared with the placebo arm
(24%) after 27 weeks of treatment (p=1.00).
Four low-quality, underpowered RCTs examined the effects on response and progression of
bisphosphonates as an adjunct to chemotherapy. In an open phase 2 trial with 72 men, Figg et al
2005 32 compared alendronate plus ketoconazole with ketoconazole alone in hormone-independent
prostate cancer and found no difference in response rate ( p=1.00) or progression-free survival (p =
0.27). Eloma et al 1992 33 and Kylmala et al 1997 34 found that for those with six month (n=54) and 12
month (n=15) follow-up assessments, the addition of clodronate to estramustine did not significantly
reduce the incidence of progression. Similarly, Ernst et al 2003 35 , in a trial with 209 men, did not find
that clodronate given in addition to mitoxantrone and prednisone significantly improved symptomatic
progression-free survival. There was no specific reference made to SREs, however.
Prevention of bone metastases for patients with clinically organ-confined/non-metastatic prostate
cancer
A recent paper by Mason et al 2007 36 reports that in a randomised placebo-controlled trial with a
median follow up of ten years, men with locally advanced disease (most of whom received hormone
therapy or radiotherapy as primary treatment), did not receive any benefit in terms of decreased
incidence of symptomatic bone metastases or prostate cancer death when given sodium clodronate
orally at a dose of 2080mg per day for a maximum of five years (hazard ratio=1.31, 95% CI=0.84to
2.05).
Evidence summary Level References
Oral sodium clodronate resulted in a modest but not statistically
significant decrease in symptomatic skeletal-related events in
hormone-naïve metastatic bone prostate cancer.
Zoledronic acid (iv) 4mg three-weekly for 15 months significantly
reduced skeletal-related events in men with asymptomatic or mildly
symptomatic hormone refractory prostate cancer.
Pamidronate disodium (iv) 90mg three-weekly for 27 weeks did not
reduce skeletal-related events in men with symptomatic hormone
refractory prostate cancer.
II 28
II 29, 30
II 31
6.3.2 Bisphosphonates in the management of bone pain associated with
metastatic prostate cancer
Castrate-resistant prostate cancer with existing bone pain
Seven low-quality randomised trials (five were double blind) focus on the treatment of existing pain
of patients with painful bone metastases. Measurements of pain and pain outcomes varied. In three
studies men in both arms received anti-neoplastic therapy. Due to many confounding factors and
study limitations, no firm conclusions can be made regarding the ability of bisphosphonates to
manage existing bone pain related to prostate cancer.
The two larger and more informative studies are presented below:
Small et al 2003 31 examining two multi-centred randomised placebo controlled trials reported that
pamidronate disodium 90mg (iv) administered every three weeks for 27 weeks did not provide any
improved palliation of worst (p=0.89) or average (p=0.71) bone pain compared with placebo in men
Clinical practice guidelines for the management of locally advanced and metastatic prostate cancer
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