Clinical Trial of Vitamin D3 to Reduce Cancer Risk in Postmenopausal Women

描述（由申请人提供）： 在乳腺癌、结肠癌、直肠癌、卵巢癌、前列腺癌、胃癌和许多其他癌症中，发现癌症死亡率与区域太阳紫外线-B辐射照射（维生素D的主要来源）之间呈负相关。饮食和血清研究也表明，维生素D是结肠腺瘤和许多癌症的危险因素。维生素D的抗癌作用得到了体外和动物研究的有力支持。然而，没有随机临床试验使用维生素D干预足以提高血清25 OHD到最佳水平，并针对癌症的结果。我们报告了一项在基于人群的绝经后妇女样本中进行的双盲、安慰剂对照、随机试验，研究钙（Ca）和维生素D补充剂。该研究的次要目的是确定单独使用钙和钙加维生素D3在降低所有类型癌症风险方面的功效。我们发现维生素D3可以显著降低60%的所有类型癌症的风险。这些发现需要通过以癌症发病率为主要结局的临床试验来证实。在本申请中，我们建议测试是否增加血清25 OHD到最佳水平，同时保持足够的钙摄入量，降低癌症的发病率在人口为基础的样本绝经后妇女60岁以上。具体目标是：1.随机抽取9个农村县60岁及以上健康独立生活的绝经后妇女;将2300名妇女纳入干预研究，将她们随机分配到2个治疗组之一：1）维生素D3（2000 IU/d）和钙（1200 mg/d），或2）维生素D3安慰剂和钙安慰剂，并对每位受试者进行4年随访; 3.收集并储存每个受试者的白色血细胞，以便在发现干预有效时测试遗传标记; 4.确定补充维生素D3对所有类型癌症合并发病率的影响; 5.在巢式病例对照研究中确定在基线和第1年结束时收集的血清25 OHD与4年内癌症风险的相关性; 6.确定补充钙和维生素D3对特定癌症发病率的影响：乳腺癌，肺癌，结肠癌和骨髓瘤，白血病，淋巴瘤。7.确定补充剂对其他疾病发生率的影响，特别是高血压、心血管疾病、骨关节炎、结肠腺瘤和糖尿病、上呼吸道感染和福尔斯。在每次6个月访视时，我们将评估：病史和社会史;不良事件;癌症诊断;以及对补充剂/安慰剂的依从性。每年，我们将获得身高和体重，并分析血清25 OHD。在基线和4年结束时，我们将评估饮食摄入和体力活动。这项拟议的研究涉及NCI战略计划的目标，即“到2015年消除癌症造成的痛苦和死亡。它具体涉及战略目标2，即“加快癌症预防的进展”。“我们的营养干预研究的积极结果将导致一种廉价，安全的预防癌症的方法。公共卫生相关性：该项目的目的是确定在严格的临床试验中，维生素D3和钙补充剂是否可以降低所有类型癌症的风险。积极的发现将为卫生政策的改变提供支持，以促进人口中的最佳维生素D水平。

DESCRIPTION (provided by applicant): An inverse correlation between cancer mortality rates and regional solar UV-B radiation exposure, a major source of vitamin D (vit D), has been found for cancers of the breast, colon, rectum, ovary, prostate, stomach, and numerous other cancers. Dietary and serum studies also demonstrate that vit D is a risk factor in colonic adenomas and for numerous cancers. The anticancer effect of vit D is strongly supported by in vitro and animal studies. However, no randomized clinical trials have used a vit D intervention sufficient to raise serum 25OHD to optimum levels and have targeted a cancer outcome. We reported a double-blind, placebo-controlled, randomized trial of calcium (Ca) and vit D supplementation in a population-based sample of postmenopausal women. A secondary objective of that study was to determine the efficacy of Ca alone and of Ca plus vit D3 in reducing risk of cancer of all types. We found that vit D3 significantly reduced the risk of all-types cancer by 60%. These findings need to be confirmed with a clinical trial designed with incidence of cancer as the primary outcome. In this application we propose to test whether increasing serum 25OHD to optimal levels, while maintaining adequate Ca intake, reduces the incidence of cancer in a population-based sample of postmenopausal women 60+ years of age. The Specific Aims are to: 1. Sample randomly the population of healthy independently-living postmenopausal women 60 years and older from 9 rural counties; 2. Enroll 2300 women into an intervention study, assign them randomly to 1 of 2 treatment groups: 1) vit D3 (2000 IU/d) and Ca (1200 mg/d), or 2) vit D3 placebo and Ca placebo, and to follow each subject for 4 years; 3. Collect and store white blood cells from every subject to test for genetic markers should the intervention be found effective; 4. Determine the effect of supplementation with vit D3 on incidence of all types of cancer combined; 5. Determine in a nested-case control study the association of serum 25OHD collected at baseline and the end of year 1 with risk of cancer over 4 years; 6. Determine the effect of supplementation with calcium and vit D3 on incidence of specific cancers: breast, lung, colon and myeloma, leukemia, lymphoma. 7. Determine the effect of supplementation on incidence of other disorders, specifically hypertension, cardiovascular disease, osteoarthritis, colonic adenomas and diabetes, upper respiratory infections and falls. At each 6-mo visit, we will assess: medical and social history; adverse events; cancer diagnoses; and adherence to supplement/placebo. Annually, we will obtain height and weight and analyze serum 25OHD. At baseline and end of 4 yrs, we will assess dietary intake and physical activity. The proposed study addresses the goal of NCI's Strategic Plan to "eliminate the suffering and death due to cancer by 2015." It specifically addresses Strategic Objective 2, to "accelerate progress in cancer prevention." Positive findings from our nutritional intervention study will result in an inexpensive, safe method of preventing cancer. PUBLIC HEALTH RELEVANCE: Project Narrative The purpose of this project is to determine whether, in a rigorous clinical trial, vitamin D3 and calcium supplementation decreases risk of all types of cancer. Positive findings will provide support for health policy changes to promote optimal vitamin D levels in the population.