<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1
2359855&dopt=Abstract>

A randomized, placebo-controlled trial of zoledronic acid in patients with
hormone-refractory metastatic prostate carcinoma.

   * Saad F,
   * Gleason DM,
   * Murray R,
   * Tchekmedyian S,
   * Venner P,
   * Lacombe L,
   * Chin JL,
   * Vinholes JJ,
   * Goas JA,
   * Chen B;
   * Zoledronic Acid Prostate Cancer Study Group.

Uro-Oncology Clinic, Centre Hospitalier de l'Universite de Montreal,
Hopital Notre-Dame, Montreal, Quebec, Canada. fred.saad@ssss.gouv.qc.ca

BACKGROUND: Bone metastases are a common cause of morbidity in patients
with prostate carcinoma. We studied the effect of a new bisphosphonate,
zoledronic acid, which blocks bone destruction, on skeletal complications
in prostate cancer patients with bone metastases.

METHODS: Patients with hormone-refractory prostate cancer and a history of
bone metastases were randomly assigned to a double-blind treatment regimen
of intravenous zoledronic acid at 4 mg (N = 214), zoledronic acid at 8 mg
(subsequently reduced to 4 mg; 8/4) (N = 221), or placebo (N = 208) every
3 weeks for 15 months. Proportions of patients with skeletal-related
events, time to the first skeletal-related event, skeletal morbidity rate,
pain and analgesic scores, disease progression, and safety were assessed.
All statistical tests were two-sided.

RESULTS: Approximately 38% of patients who received zoledronic acid at 4
mg, 28% who received zoledronic acid at 8/4 mg, and 31% who received
placebo completed the study. A greater proportion of patients who received
placebo had skeletal-related events than those who received zoledronic
acid at 4 mg (44.2% versus 33.2%; difference = -11.0%, 95% confidence
interval [CI] = -20.3% to -1.8%; P =.021) or those who received zoledronic
acid at 8/4 mg (38.5%; difference versus placebo = -5.8%, 95% CI = -15.1%
to 3.6%; P =.222).

Median time to first skeletal-related event was 321 days for patients who
received placebo, was not reached for patients who received zoledronic
acid at 4 mg (P =.011 versus placebo), and was 363 days for those who
received zoledronic acid at 8/4 mg (P =.491 versus placebo). Compared with
urinary markers in patients who received placebo, urinary markers of bone
resorption were statistically significantly decreased in patients who
received zoledronic acid at either dose (P =.001). Pain and analgesic
scores increased more in patients who received placebo than in patients
who received zoledronic acid, but there were no differences in disease
progression, performance status, or quality-of-life scores among the
groups. Zoledronic acid at 4 mg given as a 15-minute infusion was well
tolerated, but the 8-mg dose was associated with renal function
deterioration.

CONCLUSION: Zoledronic acid at 4 mg reduced skeletal-related events in
prostate cancer patients with bone metastases.

PMID: 12359855 [PubMed - indexed for MEDLINE]

<http://www.cancer.gov/clinicaltrials/results/bone-complications-0602/print?page=
&keyword=>

Zoledronic Acid Reduces Bone Complications of Advanced Prostate Cancer

Excerpts

Patients with advanced prostate cancer have a high risk of developing bone
complications such as fractures, spinal cord compression, and bone pain.
In a study published in the October 2, 2002, issue of the Journal of the
National Cancer Institute (see the journal abstract), patients with
prostate cancer that had spread to the bones had fewer fractures and other
bone complications when they took a new drug, zoledronic acid (also called
zolendronate or Zometa®) than when they took a placebo (a dummy
substance).

However, the reduction in bone complications did not delay disease
progression, lengthen survival, or improve quality of life for the men
treated with zoledronic acid compared with those who received a placebo.

In an accompanying editorial, Christina Canil, M.D., and Ian Tannock,
M.D., both of the University of Toronto in Ontario, Canada, write that
“Zoledronic acid is a reasonable option for patients who do not respond to
alternative therapies and who are at high risk for bone fractures or
spinal cord compression, but currently zoledronic acid cannot be
recommended as a standard therapy….”

Average survival and time to disease progression were not significantly
different in the three groups. Patients’ assessments of their quality of
life, including pain, also did not differ significantly. Flu-like symptoms
(fatigue, anemia, joint pain, fever, and swelling in the legs) were
slightly more common among men in the two groups treated with zoledronic
acid than in those who received a placebo.

It is puzzling that patients who started the study on a higher dose of
zoledronic acid did less well than those on the lower dose, says NCI’s
Dahut. “There is no obvious explanation why patients who received 8
milligrams of the study drug should have more bone complications than
those who received 4 milligrams.”

Zoledronic acid is a new drug in a class known as bisphosphonates. Other
bisphosphonate drugs are used to treat cancer that has spread to the bones
in patients with breast cancer and multiple myeloma. Zoledronic acid was
approved by the U.S. Food and Drug Administration in February 2002 for the
prevention of bone complications in prostate cancer.

Preliminary data from this study were presented in May 2002 at the
American Urological Association annual meeting. A brief follow-up report
was published in the June 2, 2004, [see below] issue of the Journal of the
National Cancer Institute (see the journal abstract), providing 24 months
of data.

___________________________________________________
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra
ct&list_uids=15173273>

J Natl Cancer Inst. 2004 Jun 2;96(11):879-82.

Long-term efficacy of zoledronic acid for the prevention of skeletal
complications in patients with metastatic hormone-refractory prostate
cancer.

Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin
JL, Vinholes JJ, Goas JA, Zheng M; Zoledronic Acid Prostate Cancer Study
Group.

Centre Hospitalier de l'Universite de Montreal, Hopital Notre-Dame,
Montreal, Quebec, Canada. fred.saad@ssss.gouv.qc.ca

In a placebo-controlled randomized clinical trial, zoledronic acid (4 mg
via a 15-minute infusion every 3 weeks for 15 months) reduced the
incidence of skeletal-related events (SREs) in men with hormone-refractory
metastatic prostate cancer.

Among 122 patients who completed a total of 24 months on study, fewer
patients in the 4-mg zoledronic acid group than in the placebo group had
at least one SRE (38% versus 49%, difference = -11.0%, 95% confidence
interval [CI] = -20.2% to -1.3%; P =.028), and the annual incidence of
SREs was 0.77 for the 4-mg zoledronic acid group versus 1.47 for the
placebo group (P=.005). T

he median time to the first SRE was 488 days for the 4-mg zoledronic acid
group versus 321 days for the placebo group (P =.009). Compared with
placebo, 4 mg of zoledronic acid reduced the ongoing risk of SREs by 36%
(risk ratio = 0.64, 95% CI = 0.485 to 0.845; P =.002).

Patients in the 4-mg zoledronic acid group had a lower incidence of SREs
than did patients in the placebo group, regardless of whether they had an
SRE prior to entry in the study. Long-term treatment with 4 mg of
zoledronic acid is safe and provides sustained clinical benefits for men
with metastatic hormone-refractory prostate cancer.

PMID: 15173273 [PubMed - indexed for MEDLINE]