title: A Phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer.
abstract: 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 microM (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.
authors.affiliation: Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Bergan
authors.forename: E
authors.initials: E
authors.lastname: Reed
authors.forename: C E
authors.initials: CE
authors.lastname: Myers
authors.forename: D
authors.initials: D
authors.lastname: Headlee
authors.forename: O
authors.initials: O
authors.lastname: Brawley
authors.forename: H K
authors.initials: HK
authors.lastname: Cho
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: A
authors.initials: A
authors.lastname: Tompkins
authors.forename: W M
authors.initials: WM
authors.lastname: Linehan
authors.forename: D
authors.initials: D
authors.lastname: Kohler
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: M V
authors.initials: MV
authors.lastname: Blagosklonny
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D011788:Quality of Life; D016019:Survival Analysis; D013629:Tamoxifen / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen