Vitamin D3 Supplementation for Low-Risk Prostate Cancer: A Randomized Trial

描述（由申请人提供）： 前列腺癌是男性中最常见的恶性肿瘤，2011年造成33，000多人死亡。然而，大多数前列腺癌的生长和进展速度相对较慢，是无毒药物或营养干预的理想候选者，可以降低临床相关疾病的发生率，延迟癌症进展，并将恶性过程转变为慢性，可管理的疾病。这项拨款申请的中心假设是，维生素D3补充剂将使被诊断为早期低风险前列腺癌的退伍军人受试者受益，他们选择通过积极监测来管理他们的疾病。具体来说，我们假设每天服用4000国际单位（IU）维生素D3的退伍军人（干预组）与服用安慰剂的退伍军人受试者（对照组）相比，在重复活检时，阳性核心数量和Gleason评分将有所改善，并且接受明确治疗（乳房切除术或放射治疗）的可能性降低。为了验证这一假设，我们提出了以下具体目标：1）确定维生素D3（每天4,000 IU，至少一年）是否会导致显著的 与服用安慰剂的退伍军人受试者相比，服用维生素D3的退伍军人受试者在重复活检时的病理状态改善。该假设将通过随机临床试验进行检验，该试验将入组136例退伍军人受试者（每组68例受试者），诊断为低风险前列腺癌（Gleason评分d 6，PSA d10，临床分期T1 C或T2 a）。将通过Gleason评分的变化和前列腺穿刺活检标本中阳性核心的数量在基线和研究结束之间测量病理状态。将进行研究前和研究后活检，作为主动监测的标准医疗护理的一部分。2)确定与安慰剂相比，补充维生素D3是否会导致在重复活检结果后接受确定性治疗（乳腺切除术或放射治疗）的退伍军人受试者数量显著减少。3)分析基线和研究结束时血清胆钙化醇、25（OH）D、1，25（OH）2D和前列腺特异性抗原（PSA）水平的变化，并估计这些指标变化与病理结局之间的相关性。4)比较治疗前和治疗后活检组织标本中与前列腺癌进展具有统计学相关性的分子生物标志物的表达。将处理石蜡包埋切片，以通过免疫组织化学技术评估以下生物标志物的表达：维生素D受体（VDR）、p21、肿瘤生长因子β（TGF β）、环氧合酶2（考克斯- 2）和NF κ B。所有这些蛋白质产物都影响前列腺癌进展中的生长控制和慢性炎症，并且特别受到维生素D状态的影响。 补充维生素D3不仅可以为主动监测提供一个受欢迎的补充，而且还可以帮助我们避免对那些对干预策略有反应的受试者过度治疗低风险疾病，这种干预策略具有极高的成本效益，易于实施。与此同时，补充维生素D3将帮助我们识别那些受潜在侵袭性疾病影响的患者（无应答者），并应考虑确定性治疗。

DESCRIPTION (provided by applicant): Prostate cancer is the most prevalent malignancy in men, responsible for more than 33,000 deaths in 2011. However, most prostate cancers have a relatively slow rate of growth and progression and are ideal candidates for non-toxic pharmacological or nutritional interventions that could reduce the incidence of clinically relevant disease, delay cancer progression, and modify a malignant process into a chronic, manageable disease. The central hypothesis of this grant application is that vitamin D3 supplementation will benefit Veteran subjects diagnosed with early-stage, low-risk prostate cancer, who elect to have their disease managed through active surveillance. Specifically, we hypothesize that Veterans who take 4000 international units (IU) of vitamin D3 per day (intervention group) will show an improvement in the number of positive cores and in Gleason score at repeat biopsy, and a decreased likelihood of undergoing definitive treatment (prostatectomy or radiation therapy), compared to Veteran subjects taking placebo (control group). To test this hypothesis, we propose the following Specific Aims: 1) To determine whether vitamin D3 (4,000 IU per day for at least one year) will result in a significant improvement of the pathology status at repeat biopsy in Veteran subjects taking vitamin D3, compared to Veteran subjects taking placebo. This hypothesis will be tested through a randomized clinical trial, which will enroll 136 Veteran subjects (68 participants per arm), diagnosed with low-risk prostate cancer (Gleason score d6, PSA d10, clinical stage T1C or T2a). The pathology status will be measured by the change in Gleason score and the number of positive cores in prostate needle biopsy specimens between baseline and the end of the study. Pre- and post-study biopsies will be performed as part of the standard medical care for active surveillance. 2) To determine whether vitamin D3 supplementation, compared to placebo, will result in a significant decrease in the number of Veteran subjects who will undergo definitive treatment (prostatectomy or radiation therapy), following the outcome of repeat biopsy. 3) To analyze changes in the serum levels of cholecalciferol, 25(OH)D, 1,25(OH)2D, and prostate-specific antigen (PSA) at baseline and at the end of the study, and to estimate the associations between changes in these measures and pathology outcomes. 4) To compare the expression of molecular biomarkers, which are prognostically relevant to prostate cancer progression, in pre- and post-treatment biopsy tissue specimens. Paraffin- embedded sections will be processed to assess by immunohistochemical techniques the expression of the following biomarkers: vitamin D receptor (VDR), p21, tumor growth factor beta (TGFbeta), cyclooxygenase 2 (COX- 2), and NFkappaB. All of these protein products impact growth control and chronic inflammation in prostate cancer progression and are specifically affected by vitamin D status. Vitamin D3 supplementation may not only provide a welcome addition to active surveillance, but also help us avoid over treating low-risk disease in subjects who respond to an intervention strategy that is extremely cost-effective and easy to implement. At the same time, Vitamin D3 supplementation would help us identify those patients (non-responders) who are affected by potentially aggressive disease and should consider definitive treatment.