A Phase II study of high-dose tamoxifen in patients with hormone- refractory prostate cancer

Raymond C. Bergan*, Eddie Reed, Charles E. Myers, Donna Headlee, Otis Brawley, Hea Kyoung Cho, W. Douglas Figg, Anne Tompkins, W. Marston Linehan, David Kohler, Seth M. Steinberg, Mikhail V. Blagosklonny

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

95 Scopus citations


Micromolar concentrations of tamoxifen inhibit the activity of protein kinase C and were recently shown to inhibit prostate cancer cell growth in preclinical studies. Because micromolar concentrations can be attained with high-dose therapy, the clinical activity of high-dose tamoxifen was evaluated in patients with metastatic adenocarcinoma of the prostate. Between December 1993 and February 1997, 30 patients with hormone-refractory metastatic adenocarcinoma of the prostate were continuously administered tamoxifen at 160 mg/m2/day. Therapy was continued until disease progression. All study patients had failed prior treatment with combined androgen blockade, had castrate levels of testosterone, and were heavily pretreated, having received a median of three prior regimens. The average steady-state plasma concentration of tamoxifen was 2.96 ± 1.32 μM (mean ± SD). Grade 3 neurotoxicity was observed in 29% of patients and was rapidly reversible and readily managed with dose modification. Otherwise, grade 3 toxicities were rare. One partial response (80% decline in prostate-specific antigen) was observed (3.3%), whereas disease stabilization was observed in six patients (20%), for a combined partial response/stable disease response rate of 23%. Median time to progression was 2.1 months, and median survival time was 10.5 months. High-dose tamoxifen therapy was well tolerated and associated with micromolar concentrations of tamoxifen in human plasma, and it demonstrated activity, albeit limited, in a heavily pretreated patient cohort with hormone-refractory prostate cancer. These findings suggest that further investigation of the role of protein kinase C modulation in prostate cancer is warranted.

Original languageEnglish
Pages (from-to)2366-2373
Number of pages8
JournalClinical Cancer Research
Issue number9
StatePublished - Sep 1999
Externally publishedYes


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