A Phase II Study of High-Dose Tamoxifen in Patients with Hormone-refractory Prostate Cancer

• Published in: Clinical cancer research 1999-09, Vol.5 (9), p.2366-2373
• Main Authors: BERGAN, R. C, REED, E, STEINBERG, S. M, BLAGOSKLONNY, M. V, MYERS, C. E, HEADLEE, D, BRAWLEY, O, CHO, H.-K, FIGG, W. D, TOMPKINS, A, LINEHAN, W. M, KOHLER, D
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - blood; Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents, Hormonal - adverse effects; Antineoplastic Agents, Hormonal - blood; Antineoplastic Agents, Hormonal - pharmacokinetics; Antineoplastic Agents, Hormonal - therapeutic use; Biological and medical sciences; Chemotherapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Humans; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Prostatic Neoplasms - blood; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Quality of Life; Survival Analysis; Tamoxifen - adverse effects; Tamoxifen - blood; Tamoxifen - pharmacokinetics; Tamoxifen - therapeutic use
• ISSN: 1078-0432; 1557-3265

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/m 2 /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 μ m (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.