Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study

ATBC队列后续研究自1994年以来一直存在。年龄在50岁到69岁之间的男性吸烟者是在1985年4月至1988年6月期间从芬兰西南部招募的。共有29,133名男性被随机分配到四个干预组中的一个：50毫克/天的α-生育酚(如dl-α-生育酚醋酸酯)；20毫克/天的β-胡萝卜素；α-生育酚和β-胡萝卜素；或安慰剂。在试验期间，他们被跟踪了5至8年，直到死亡，或1993年4月30日停止干预(中位数随访，6.1年)。干预后继续对终点进行随访。在通过基于人群的邮寄调查邀请参与和招募之后，该试验基于2x2析因设计将29,133名50-69岁的高加索人男性吸烟者随机分配到四个干预组中的一个：β-胡萝卜素(20毫克/天)、维生素E(50毫克/天，如dl-α-生育酚醋酸酯)，这两种药物都是药物，或者是安慰剂。在进入时，获得了医疗、饮食、吸烟和职业数据，以及体格测量、胸部X光和血清和脚趾甲样本。饮食是通过276项食物饮食问卷获得的，该问卷是为试验开发和验证的。为所有参与者收集、冷冻和储存基线血清，并测定维生素E、β-胡萝卜素、视黄醇、总胆固醇和高密度脂蛋白。随后在研究中收集了所有活跃参与者的随访血清和全血，并从选定的亚组中收集了额外的血清和红细胞样本。积极干预持续了5-8年，每年进行三次研究访问，在此期间，参与者被问及他们的健康和可能的主观副作用、胶囊依从性和自上次访问以来的吸烟习惯。试验结束时，每隔2-3年拍摄一次胸片。通过芬兰全国癌症登记处确定了所有发生的癌症，审查/摘录了医疗记录/病理幻灯片，并通过国家人口登记确定了死亡/潜在原因。ATBC队列随访研究的总体目标是在29,133名男性原始试验队列的基础上进行癌症病因学研究和干预后癌症监测。已经进行了队列分析、嵌套病例对照调查、遗传多态和其他分子参数分析，以及干预剂对相关生物标志物的生物学影响的研究，这些都是目前研究的重点。截至2012年，目前的累计确诊病例总数约为3900例肺癌、2700例前列腺癌、900例结直肠癌、800例膀胱癌、400-500例胃癌、胰腺癌和肾癌，以及450例头颈部癌症。ATBC研究中的癌症病因学研究已经从对补充的关注自然演变为几个集中反映我们的研究兴趣和研究资源可用性的领域，NCI和其他地方的高效研究人员数量不断增加。公共网站(http://atbcstudy.cancer.gov/))提供有关该项目的研究、数据、人员和资源的信息，包括启动合作的程序。高质量的研究数据、生物标本和正在进行的终点确定已被用于测试与前列腺癌(基于2500例)、肺癌(3500例)、结直肠癌(700例)、胰腺癌(400例)和其他癌症中具有潜在高归因风险的营养和其他因素相关的生化和遗传学假设。对前列腺癌、肺癌、肾癌、膀胱癌以及非霍奇金淋巴瘤和神经胶质瘤风险的研究已经完成。我们已经完成了对维生素D、E、A和硒状况的调查；类胡萝卜素和其他抗氧化剂；一碳代谢；能量平衡、胰岛素和生长因子；性类固醇；以及影响这些暴露的遗传变异。对营养表型，如血清维生素D状况的研究正在进行中。在受控维生素补充剂设计的背景下评估这些因素为我们提供了研究生物和生化相互作用的独特机会。ATBC研究的另一个重要方面是与癌症流行病学财团的外部研究人员的合作。其中包括：NCI乳腺癌和前列腺癌队列联盟(BPC3)、PanScan、饮食和癌症前瞻性研究汇集项目以及哈佛大学叶酸、单碳营养素、基因变异和结直肠癌专业中心。我们为这些强大的、高影响力的研究贡献科学专业知识、数据和队列资源，以及内部支持。

The ATBC Cohort Follow-up Study has been in place since 1994. Male smokers between the ages of 50 and 69 were recruited from southwestern Finland between April 1985 and June 1988. A total of 29,133 men were randomly assigned to one of four intervention groups: 50 mg/day alpha-tocopherol (as dl-alpha-tocopheryl acetate); 20 mg/day beta-carotene; both alpha-tocopherol and beta-carotene; or placebo. They were followed for five to eight years during the trial, until death, or 30 April 1993 when intervention was stopped (median follow-up, 6.1 years). Follow-up for endpoints was continued postintervention. Following invitation for participation and recruitment through a population-based postal survey, the trial randomly assigned 29,133 Caucasian 50-69 year old male smokers of 5 cigarettes daily to one of four intervention groups based on a 2x2 factorial design: beta-carotene (20 mg/day), vitamin E (50 mg/day, as dl-alpha-tocopheryl acetate), both agents, or placebo. At entry, medical, dietary, smoking, and occupational data were obtained, along with physical measurements, a chest x-ray, and serum and toenail samples. Diet was captured through a 276 food item dietary questionnaire that was developed and validated for the trial. Baseline serum was collected, frozen, and stored for all participants, and vitamin E, beta-carotene, retinol, and total and HDL cholesterol were determined. Follow-up serum and whole blood were collected for all active participants later in the study, as were additional serum and red blood cell samples from selected subsets. Active intervention continued for 5-8 years, with three study visits annually during which participants were asked about their health and possible subjective side effects, capsule compliance, and smoking habits since the last visit. Chest films were taken at 2-3 year intervals and at the end of the trial. All incident cancers were identified through the nationwide Finnish Cancer Registry, medical records/pathology slides were reviewed / abstracted, and deaths/underlying causes were identified through the National Population Register. The ATBC Cohort Follow-up Study has had the overall aim of conducting cancer etiologic research and post-intervention cancer surveillance based on the original trial cohort of 29,133 men. Cohort analyses, nested case-control investigations, analyses of genetic polymorphisms and other molecular parameters, and studies of the biological effects of the intervention agents on relevant biomarkers have been conducted and are the focus of ongoing research. Current cumulative totals of diagnosed cases through 2012 include approximately 3,900 lung, 2,700 prostate, 900 colorectal, 800 bladder, 400-500 each for stomach, pancreas, and kidney cancers, and 450 head and neck. Cancer etiologic research in the ATBC Study has evolved naturally from the focus on supplementation into several areas of concentration that reflect both our research interests and the availability of study resources to a continually growing number of highly productive investigators both at NCI and elsewhere. A public website (http://atbcstudy.cancer.gov/) provides information regarding the project's research, data, personnel, and resources, including procedures for initiating collaborations. The high-quality study data, biological specimens, and ongoing endpoint ascertainment have been applied to testing biochemical and genetic hypotheses related to nutritional and other factors having potentially high attributable risks in prostate (based on 2,500 cases), lung (3,500 cases), colorectal (700 cases), pancreatic (400 cases) and other cancers. GWAS studies of risk for prostate, lung, renal, and bladder cancers, as well as NHL and glioma are completed. We have completed investigations of vitamins D, E, A and selenium status; carotenoids and other antioxidants; one-carbon metabolism; energy balance, insulin, and growth factors; sex steroids; and genetic variants impacting these exposures. GWAS studies of nutrition phenotypes such as serum vitamin D status are being conducted. Evaluation of these factors within the context of the controlled vitamin supplementation design has afforded us unique opportunities to investigate biological and biochemical interactions.Another important dimension of the ATBC Study has been collaborations with extramural researchers in cancer epidemiological consortia. These include: the NCI Breast and Prostate Cancer Cohort Consortium (BPC3), PanScan, the Pooling Project of Prospective Studies of Diet and Cancer, and the Harvard Specialized Center on Folate, One-Carbon Nutrients, Gene Variants and Colorectal Cancer. We contribute scientific expertise, data and cohort resources, and intramural support to these powerful, high-impact studies.