NEW YORKIn patients with androgen-independent prostate cancer, a pulsed regimen of docetaxel(Drug information on docetaxel) (Taxotere) plus high-dose calcitriol(Drug information on 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.