NEW YORKIn patients with androgen-independent prostate cancer, a pulsed
regimen of docetaxel (Taxotere) plus high-dose calcitriol is well tolerated
and results in disease response by a variety of standard measures, according
to results of a phase II trial.
"The combination is promising in androgen-independent prostate cancer as
measured by PSA response rate, measurable disease response rate, time to
progression, and overall survival," said investigator Tomasz M. Beer, MD,
assistant professor of medicine, Oregon Health & Science University.
With the possible exception of an increase in gastrointestinal side
effects, the toxicity profile was not different than what would be expected
with docetaxel alone; furthermore, the two agents do not appear to alter each
other’s pharmacokinetic profiles, said Dr. Beer, who presented the data at
the Mount Sinai School of Medicine Chemotherapy Foundation Symposium XX.
The findings are the latest to suggest a potential role in prostate cancer
for calcitriol, the biologically active form of vitamin D. Preclinically,
calcitriol has been shown to downregulate apoptosis inhibitors, induce cell
cycle arrest and differentiation, and inhibit proliferation of multiple
prostate cancer cell lines, including PC-3 and LNCaP.
In these cell lines, calcitriol at concentrations of 0.01 nM
(approximating endogenous calcitriol concentrations) did not significantly
inhibit growth. However, in concentrations of 1 nM and higher, there was a
significant and dose-dependent inhibition of both cell lines, said Dr. Beer,
describing results that came from his group’s laboratory but that are similar
to those reported by others.
These preclinical studies have also suggested synergy with several
cytotoxic agents, providing a rationale for the clinical trial of the
calcitriol/docetaxel combination. For example, Dr. Beer said, in PC-3 cells
incubated with either calcitriol or docetaxel, colony formation is about 60%
of what is seen in controls; in cells incubated with both agents, colony
formation is about 20% of control levels.
The major barrier to clinical application of these findings has been
hypercalcemia at calcitriol doses high enough to result in antitumor
activity. Development of high-dose calcitriol compounds that produce
transient high plasma levels of calcitriol when given weekly (high-dose pulse
administration or HDPA) has made such studies possible.