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

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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