The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a large scale, randomized controlled trial to determine whether certain screening tests will reduce the number of deaths from these cancers. PLCO is a multi-institutional clinical trial being conducted at ten sites, geographically and demographically disparate, around the U.S. This controlled trial is a Phase III trial conducting human subjects research. PLCO enrolled 154,942 male and female participants. The PLCO participants are comparable to the general United States population. Life style, dietary and risk factor information was collected from participants. The intervention arm received for lung cancer, posterior-anterior (PA) chest x-ray annually for four screens (except never smokers who received three annual screens), flexible sigmoidoscopy (FSG) at enrollment and again at the fourth or sixth annual screening interval depending on time of enrollment to screen for colorectal cancer. For prostate cancer, men received six annual prostate screens with prostate-specific antigen (PSA) and four digital rectal exams (DRE). Women were screened for ovarian cancer with CA-125 antigen for six annual screens and with transvaginal ultrasound (TVU) for four annual screens. The usual care (control) arm received regular health care from their primary care provider. Whole blood, sequential serum samples and one plasma sample were collected from the intervention arm. Aliquots from these samples are stored in the PLCO Biorepository through collaboration with the Division of Cancer Epidemiology and Genetics (DCEG). The usual care arm provided buccal cell DNA samples which are also stored in the PLCO Biorepository. The PLCO Biorepository currently has over 2.9 million specimens that can be used for etiologic and early marker studies. PLCO is collecting colo-rectal, ovarian, prostate and lung tumor tissue from those participants who have developed cancer. Tissue microarrays are then constructed. STUDY DESIGN: The PLCO is a two-armed, randomized trial in which more than 38,000 men were screened for lung, colorectal, and prostate cancers and approximately 39,000 women were screened for lung, colorectal, and ovarian cancers. Equal numbers of men and women participating as controls continue their usual medical care practices. The eligible age range at entry was 55-74 years. Both screened and control participants are to be followed for at least 13 years from randomization for cancer and death ascertainment to determine if the screening regimen results in reduced disease-specific mortality. Baseline information including demographic characteristics, known risk factors for the cancers under study, and screening history were collected from all participants. In addition, participants completed dietary, food frequency questionnaires and subsequently a risk factor questionnaire that supplements the baseline data provided at the time they enrolled. Blood samples collected at each screening visit were processed into separate components and stored for future molecular analyses. Control participants provided Buccal cell DNA. Participants in both the intervention and control arms completed a dietary questionnaire. All participants also provide annual health status information. Special efforts made to enhance the recruitment of minorities occurred at several screening locations. One site in Detroit, MI focused efforts on increasing the participation of African Americans. A site in Denver, CO hired Spanish speaking staff to enhance the number of Hispanic Americans enrolled in PLCO. BIOREPOSITORY: The PLCO Biorepository contains approximately 2.9 million biologic specimens collected during the six screening years. These samples include serum, plasma and buffy coat and DNA samples. These specimens are an invaluable resource for cancer research. Some of the characteristics that make the PLCO biospecimens uniquely valuable include: Large sample size allows statistical power Specimens are collected prospectively, before cancer diagnosis Serial specimens are collected at each of the 6 annual screenings Detailed background and clinical data are available The PLCO Etiology and Early Marker Studies (EEMS) component is an integral part of the PLCO Trial. The PLCO EEMS has two main focuses: etiologic studies that investigate the environmental, biochemical and genetic risk factors for cancer; and early detection studies that aim to develop reproducible, diagnostics-ready biomarkers of early disease. The PLCO EEMS directly addresses the following strategic priorities of the National Cancer Institute: Understand the causes and mechanisms of cancer Improve early detection and diagnosis National Lung Screening Trial II. II. Abstract: The National Lung Screening Trial (NLST), launched in September 2002, continues to be a critically important component of the NCI goal to eliminate death and suffering from lung cancer. Unfortunately, lung cancer remains the leading cause of cancer death. To date, randomized controlled trials of screening modalities such as chest x-ray and sputum cytology have not demonstrated any impact on lung cancer mortality. Therefore, without effective screening or substantive improvements in effective therapies little progress has been made in lowering lung cancer mortality. Promisingly, technological advances, specifically, the advent of low-dose techniques with rapid, computerized helical computed tomography, have allowed detection of smaller lung nodules. Other potential early detection strategies such as serum, plasma and sputum biomarkers are currently preliminary, and require substantial refinement and validation before examination in a randomized, controlled trial for lung cancer screening. The NLST will determine whether the most promising current strategy for early detection, low-dose helical CT (LDCT) lowers lung cancer mortality. The NLST was designed to detect a 20% or greater reduction in lung cancer mortality with the use of LDCT over chest X-ray (CXR), should such a benefit exist. The trial built upon the PLCO Cancer Screening Trial, which is studying the usefulness of CXR screening compared with community care. Published findings from the Mayo Clinic CT cohort study provide a cautionary note about screening with spiral CT. The researchers compared findings from the historic Mayo Lung Project (intense CXR screening) with findings from a subset of their CT participants who were comparable to the former study's participants in terms of lung cancer risk factors and showed no difference in lung cancer mortality rates. NLST is a well-powered, randomized controlled clinical trial able to assess lung cancer mortality with ample statistical power. NLST began in September 2002 and randomized over 53,000 heavy and/or long-term smokers to low-dose, helical computed tomography (CT) or chest X-ray (CXR). Participants received an initial and two subsequent screening exams. Participants who receive a positive or suspicious screening result are notified and referred to their primary care practitioner to determine appropriate follow up procedures. Screening occurs on sophisticated state-of-the-art equipment in radiology departments with highly qualified staff specifically trained and certified in NLST procedures. The helical CT equipment reflects that currently in use in academic practices across the United States. GE, Siemens, Philips and Toshiba are the CT manufacturers represented. They represent all the manufacturers of this specialty equipment in the world. Importantly, a minimum four-panel detector is required and equipment upgrades to 8, 16 and 64 panel detectors occur as the institutions make capital investments. An intensive quality assurance program has been developed to ensure adherence to harmonized, image acquisition parameters, image quality and dose-minimization parameters. The concept of low-dose helical CT is to optimize image acquisition with the lowest dose possible and take advantage of the contrast provided by lung aeration. Radiation dose is carefully monitored and controlled for all equipment at all sites. Recent evidence announced by the National Academy of Sciences indicates the prudence of minimizing radiation exposure, as doses in the 10 100 mSv range have been associated with an elevated risk of cancer death in atomic bomb survivors. The low dose screen administered is consonant with a low radiation risk in the 55 74 year old smokers in the NLST. Participants will be contacted annually to determine current health status. Follow up includes ascertainment of adverse medical outcomes, cancer incidence, cause of death, and mortality impact.