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）的时代已经导致了对前列腺癌（PCa）的诊断。 低度前列腺癌的检出率增加，而低度前列腺癌的转移扩散或死亡风险很小。 此外，这些男性现在可能会暴露于过度治疗的发病率，而很少或根本没有益处。 癌症特异性存活率。因此，主动监测（AS）已发展成为一种推荐的管理策略， 患有低度疾病的男性，提供仔细监测的个体化方法的益处 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合格性标准的变化，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的更高的决策冲突， 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，在一项研究中， AS男性是一个积极性高、渴望积极生活方式的亚群 改变，以进一步降低PCa进展的风险-提供机会， 化学预防使用5-α-还原酶抑制剂的化学预防策略显著降低了 前列腺癌的发展风险。然而，它们的使用也与高- 严重限制了它们的临床应用。目前，缺乏研究， 系统地检查了AS男性的化学预防剂。绿色茶儿茶素 影响致癌作用的几个标志，包括前列腺癌，具有可接受的安全性 这使得它们成为PCa化学预防的有吸引力的候选者。几种流行病学，体外， 我们的团队和其他人完成的临床前和早期试验表明，GTC是有效的 通过多种机制的PCa致癌抑制剂，在组织和血浆中生物可利用， 几种中间生物标志物涉及PCa进展，并且在这些剂量下没有毒性。基于 根据现有的证据，我们假设经活检证实的前列腺癌患者， 符合AS的标准，接受GTC 800 mg EGCG/天（与安慰剂相比）24个月， 临床进展率显著降低。我们将使用一个严格的 II期随机临床试验的实验设计，以评价安全性、有效性和 GTC调节临床进展和相关生物标志物的潜在机制 与前列腺癌AS患者的前列腺癌进展相关。这项研究的积极结果将至关重要 为III期临床试验的开发提供信息，并最终提供二级化学预防策略 在AS男性中，目前没有降低进展为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.