Novel treatment regimens for
androgen-independent
prostate cancer (
AIPC) are needed because currently available approaches have not been shown to improve survival.
Docetaxel provides a good foundation for new therapeutic combinations because of its promising single-agent activity against
prostate cancer and its favorable tolerability profile, particularly when administered weekly. In both tissue culture and animal models of
prostate cancer,
calcitriol (the biologically active form of
vitamin D) enhanced the activity of
docetaxel,
paclitaxel, and
platinum compounds. These effects were particularly notable at supraphysiologic
calcitriol concentrations. Weekly
calcitriol dosing is associated with minimal toxicity and permits substantial dose escalation over the daily schedule. A weekly
calcitriol dose of 0.5 microg/kg produces plasma
calcitriol levels 25-fold higher than the physiologic range. In a preclinical study at the Oregon Health Sciences University,
calcitriol 5 micromol/L plus
docetaxel 0.15 nmol/L was at least additive in inhibiting PC-3 colony formation. A phase II study is evaluating weekly administration of 0.5 microg/kg
calcitriol orally on day 1 followed by 36 mg/m(2)
docetaxel intravenously on day 2 in patients with
AIPC (repeated for 6 consecutive weeks of each 8-week cycle). At the time of a preliminary analysis, 11 patients had been enrolled and were actively being treated. All 5 patients who had completed 8 weeks of
calcitriol/
docetaxel treatment achieved
prostate-specific antigen (PSA) reductions of > or =50%. Two of these patients had confirmatory assessments, both meeting the formal PSA response criteria. Treatment has been well tolerated, with 1 patient experiencing a self-limited grade 3 toxicity and no patients experiencing grade 4 or 5 toxicities.