Phase II Clinical trial of GTC in Men on Active Surveillance

摘要： 使用血清前列腺特异性抗原(PSA)筛查前列腺癌(PCA)的时代已经导致了 增加对转移扩散或死亡风险很小的低级别前列腺癌的检测。 此外，这些人现在可能暴露在过度治疗的病症中，而很少或根本没有受益。 癌症特有的存活率。因此，主动监视(AS)已演变为一种推荐的管理策略 患有低级别疾病的男性，提供了仔细监测的个性化方法的好处 疾病进展，足以允许及时的治疗干预。然而，对不足的担忧- 分级，AS资格标准的变化，患者报告的焦虑，抑郁，对可能的 疾病的进展以及关于选择AS的更高决策冲突，AS上的男性一直如此 据报道，最终选择治疗，肿瘤特征没有任何重大变化。另一方面， AS上的男性是一个亚群体，他们非常有动力，渴望创造积极的生活方式 进一步降低其PCA进展风险的变化-为 化学预防。使用5-α还原酶抑制剂的化学预防策略显著减少了 前列腺癌进展的风险。然而，它们的使用也与高血糖的检测增加有关。 严重限制了它们的临床应用。目前，很少有研究表明， 系统地检查AS男性的化学预防药物。绿茶儿茶素(GTC) 以可接受的安全性影响癌症发生的几个特征，包括前列腺癌的发生 个人资料，使它们成为PCA化学预防的有吸引力的候选者。几个流行病学的，体外的， 我们团队和其他人完成的临床前和早期试验表明，GTC是有效的 通过多种机制抑制前列腺癌的发生，在组织和血浆中生物可用，减少 几个中间生物标志物与前列腺癌进展有关，在这些剂量下没有毒性。基于 根据现有的证据，我们假设，接受活检的男性被证实患有前列腺癌 符合AS标准的患者，每天服用GTC 800毫克EGCG(与安慰剂相比)，持续24个月，将 临床进展率显著降低。我们将使用严格的 试验设计为II期随机临床试验，以评估其安全性、有效性和 GTC调控临床进展的可能机制及相关生物标志物 与男性前列腺癌的进展有关，与前列腺癌有关。这项研究的积极结果将是至关重要的 为第三阶段临床试验的发展提供信息，并最终提供二次化学预防的战略 对于患有AS的男性来说，目前还没有降低进展到PCa风险的选择。

Abstract: The era of screening for prostate cancer (PCa) using serum prostate specific antigen (PSA) has led to an increase in the detection of low-grade prostate cancers that pose little risk of either metastatic spread or death. Additionally, these men may be now exposed to morbidities of over treatment with little or no benefit of cancer-specific survival. Active surveillance (AS) has thus evolved as a recommended management strategy for men with low grade disease, providing the benefit of an individualized approach of carefully monitoring disease progression, sufficient to permit timely therapeutic intervention. However, concerns about under- grading, variations in criteria for AS eligibility, patient reported anxiety, depression, doubts about the possible progression of the disease as well as higher decisional conflict regarding selection of AS, men on AS have been reported to ultimately opt for treatment without any major change in tumor characteristics. On the other hand, men on AS are a subgroup, who are highly motivated and eager to make positive lifestyle changes to further reduce their risk of PCa progression- providing an opportunity for chemoprevention. Chemoprevention strategies with 5-alpha-reductase inhibitors significantly reduced the risk of prostate cancer progression. However their use was also associated with increased detection of high- grade disease, severely limiting their clinical adoption. Currently, there is a paucity of research that systematically examines agents for chemoprevention in men on AS. Green tea catechins (GTC) influence several hallmarks of carcinogenesis, including prostate carcinogenesis, with an acceptable safety profile, making them attractive candidates for PCa chemoprevention. Several epidemiological, in vitro, preclinical and early phase trials completed by our team and others have shown that the GTC are potent inhibitors of PCa carcinogenesis through multiple mechanisms, bioavailable in tissue and plasma, reduces several intermediate biomarkers implicated in PCa progression and without toxicities at these doses. Based on the available evidence, we hypothesize that men with biopsy proven adenocarcinoma of the prostate who meet the criteria for AS, who receive GTC at a dose of 800 mg EGCG per day (vs. placebo) for 24 months, will have a significantly decreased rate of clinical progression. We will test this hypothesis using a rigorous experimental design in a phase II, randomized clinical trial to evaluate the safety, effectiveness and potential mechanism by which GTC modulates clinical progression and the related biological biomarkers relevant to PCa progression in men on AS for PCa. Positive results from this study will be critical to inform development a phase III clinical trial and ultimately provide a strategy for secondary chemoprevention in men on AS, for whom, currently, there are no options for reducing risk of progression to PCa.