Phase II, Randomized, Placebo-Controlled Trial of Neoadjuvant Celecoxib in Men With Clinically Localized Prostate Cancer: Evaluation of Drug-Specific Biomarkers
Phase II, Randomized, Placebo-Controlled Trial of Neoadjuvant Celecoxib in Men With Clinically Localized Prostate Cancer: Evaluation of Drug-Specific Biomarkers
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DOI：
10.1200/jco.2009.21.9410
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发表时间：
2009-10-20
影响因子：
45.3
通讯作者：
Carducci, Michael A.
中科院分区：
文献类型：
--
作者：
Antonarakis, Emmanuel S.;Heath, Elisabeth I.;Carducci, Michael A.
目的环氧合酶-2（考克斯-2）是一个潜在的预防包括前列腺癌在内的多种恶性肿瘤的药理学靶点。患者和方法患有局限性前列腺癌且Gleason总和>= 7、前列腺特异性抗原（PSA）>= 15 ng/mL、临床分期T2 b或更高的患者，或任何联合用药，包膜穿透风险大于45%，在膀胱切除术前随机分配至塞来昔布400 mg口服，每日2次或安慰剂组，持续4 - 6周。主要终点是两组前列腺前列腺素水平的差异。次要终点是考克斯-1和-2表达的差异;氧化的DNA碱基;增殖、凋亡和血管生成的标志物。还测量了组织塞来昔布浓度。三级终点是药物的安全性和compliance.Results73例患者同意，64例被随机分配，并列入意向治疗分析。任何主要或次要结局均无治疗差异。多变量回归分析显示，肿瘤组织中考克斯-2的表达显著低于良性前列腺组织（P = 0.01），而增殖标记物Ki-67的表达显著高于良性前列腺组织（P <0.0001）。在接受治疗的患者的前列腺组织中，塞来昔布是可测量的，表明塞来昔布达到了其目标。塞来昔布是安全的，只导致1级toxics.ConclusionTreatment与4至6周的塞来昔布没有影响中间生物标志物的前列腺癌发生，尽管实现可测量的组织水平。我们警告在其他研究中不要使用塞来昔布400 mg每日两次作为前列腺癌的预防剂。
PurposeCyclooxygenase-2 (COX-2) is a potential pharmacologic target for the prevention of various malignancies, including prostate cancer. We conducted a randomized, double-blind trial to examine the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy.Patients and MethodsPatients with localized prostate cancer and Gleason sum >= 7, prostate-specific antigen (PSA) >= 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy. The primary end point was the difference in prostatic prostaglandin levels between the two groups. Secondary end points were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. Tertiary end points were drug safety and compliance.ResultsSeventy-three patients consented, and 64 were randomly assigned and included in the intention-to-treat analysis. There were no treatment differences in any of the primary or secondary outcomes. Multivariable regression revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67 (P < .0001). Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities.ConclusionTreatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies.