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，已发现癌症死亡率与局部太阳UV-B辐射暴露之间的负相关，UV-B辐射是维生素D(VitD)的主要来源。饮食和血清研究还表明，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实验的有力支持。然而，没有一项随机临床试验使用维生素D干预足以将血清25OHD提高到最佳水平，并以癌症结果为目标。我们报道了一项以人群为基础的绝经后妇女样本中钙(Ca)和维生素D补充的双盲、安慰剂对照、随机试验。这项研究的第二个目标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效果。我们发现，维生素D3显著降低了60%的所有类型癌症的风险。这些发现需要通过一项以癌症发病率为主要结果的临床试验来证实。在这项应用中，我们建议测试在保持足够的钙摄入量的同时，将血清25OHD增加到最佳水平，是否可以在60岁以上的绝经后妇女的人群样本中降低癌症的发生率。具体目标是：1.从9个农村地区随机抽取60岁及以上独立生活的健康绝经后妇女人群；2.将2300名妇女纳入一项干预研究，将她们随机分配到两个治疗组中：1)维生素D3(2000IU/d)和钙(1200 mg/d)，或2)维生素D3安慰剂和钙安慰剂，并对每个受试者进行为期4年的跟踪；3.收集并储存每个受试者的白细胞，如果干预有效，检测遗传标记；4.确定补充维生素D3对所有类型癌症综合发病率的影响；5.在嵌套病例对照研究中确定在基线和第一年末收集的血清25OHD与4年以上癌症风险的关系；6.确定补充钙和维生素D3对特定癌症：乳腺癌、肺癌、结肠癌和骨髓瘤、白血病、淋巴瘤的发病率的影响。7.确定补充剂对其他疾病发病率的影响，特别是高血压、心血管疾病、骨关节炎、结肠腺瘤和糖尿病、上呼吸道感染和跌倒。在每次6个月的访问中，我们将评估：病史和社会史；不良事件；癌症诊断；是否坚持服用补充剂/安慰剂。每年测量身高、体重，分析血清25OHD。在基线和4年结束时，我们将评估饮食摄入量和体力活动。这项拟议的研究涉及NCI战略计划的目标，即“在2015年前消除癌症带来的痛苦和死亡。”它特别针对战略目标2，即“加快癌症预防工作的进展”。我们的营养干预研究的积极结果将导致一种廉价、安全的癌症预防方法。

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.