Zanardi Silvia, Puntoni Matteo, Maffezzini Massimo, Bandelloni Roberto, Mori Marco, Argusti Alessandra, Campodonico Fabio, Turbino Laura, Branchi Daniela, Montironi Rodolfo, Decensi Andrea
Medical Oncology Unit, Galliera Hospital, Genova, Italy.
Cancer Prev Res (Phila). 2009 Apr;2(4):377-84. doi: 10.1158/1940-6207.CAPR-08-0205. Epub 2009 Mar 31.
Men with elevated prostate-specific antigen (PSA) and negative prostate biopsies are at risk for prostate cancer. The antiandrogen bicalutamide has a prolonged half-life, thus potentially allowing an intermittent administration to retain activity while reducing toxicity. We conducted a phase I-II trial of weekly bicalutamide in men with PSA >4 ng/mL and negative biopsies.
Eighty subjects were nonrandomly assigned to a three-arm trial to either bicalutamide 50 mg/wk (n = 26) or 100 mg/wk (n = 28) or no treatment (n = 26) for 6 months. Blood samples were obtained at 0, 3, and 6 months, and prostate biopsies were repeated after 6 months. The outcome measures were 6-month changes of tissue Ki-67 (primary end point), high-grade prostatic intraepithelial neoplasia (HG-PIN), proliferative inflammatory atrophy, circulating PSA, and sex hormones.
Ki-67 expression was higher in HG-PIN than in normal tissue (10% versus 3%; P < 0.01) but was not modulated by bicalutamide in normal luminal cells. A trend toward an improvement of HG-PIN status was found in treated subjects (26% improved, 60% had no change, 15% worsened) as compared with the no-treatment arm (4% improved, 83% had no change, 13% worsened; P = 0.07). Proliferative inflammatory atrophy prevalence was not reduced by bicalutamide. Bicalutamide reduced PSA by 50% in both arms and raised testosterone and estradiol levels. Asymptomatic breast swelling was noted in 40% of the treated cases.
A weekly administration of bicalutamide seems to be reasonably safe and shows an encouraging signal of activity on HG-PIN prevalence, supporting further studies of this schedule in men at high risk despite the negative primary end-point findings on Ki-67.
前列腺特异性抗原（PSA）升高但前列腺活检结果为阴性的男性存在患前列腺癌的风险。抗雄激素药物比卡鲁胺半衰期较长，因此有可能采用间歇性给药，在保持活性的同时降低毒性。我们对PSA>4 ng/mL且活检结果为阴性的男性进行了比卡鲁胺每周给药的I-II期试验。
80名受试者被非随机分配至三组试验，分别接受每周50 mg比卡鲁胺（n = 26）或100 mg比卡鲁胺（n = 28）治疗，或不接受治疗（n = 26），为期6个月。在0、3和6个月时采集血样，并在6个月后重复进行前列腺活检。观察指标为组织Ki-67的6个月变化（主要终点）、高级别前列腺上皮内瘤变（HG-PIN）、增殖性炎性萎缩、循环PSA和性激素。
HG-PIN中Ki-67表达高于正常组织（10%对3%；P < 0.01），但在正常管腔细胞中不受比卡鲁胺调节。与未治疗组相比，治疗组HG-PIN状态有改善趋势（26%改善，60%无变化，15%恶化）（4%改善，83%无变化，13%恶化；P = 0.07）。比卡鲁胺未降低增殖性炎性萎缩的患病率。比卡鲁胺在两组中均使PSA降低50%，并提高了睾酮和雌二醇水平。40%的治疗病例出现无症状乳腺肿胀。
每周给药比卡鲁胺似乎相当安全，并且在HG-PIN患病率方面显示出令人鼓舞的活性信号，尽管Ki-67的主要终点结果为阴性，但仍支持对该给药方案在高危男性中进行进一步研究。
