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ATBC Study – The Alpha-Tocopherol, Beta-Carotene Lung Cancer Prevention Study

The ATBC Study was a randomized, double-blind, placebo-controlled, 2x2 factorial design trial primarily testing the hypothesis that α-tocopherol and ß-carotene supplements reduce the incidence of lung and other cancers. From 1985 to 1988, 29 133 male smokers (at least 5 cigarettes per day) from the total male population aged 50 to 69 years of southwestern Finland (n=290,406) were recruited and randomized to 1 of 4 intervention regimens: α-tocopherol alone at 50 mg per day, ß-carotene alone at 20 mg per day, α-tocopherol plus ß-carotene, or placebo. Potential participants with a history of cancer or serious illness limiting long-term participation, those taking supplements of vitamin E, vitamin A, or ß-carotene in excess of predefined doses, and those being treated with anticoagulants were excluded. The trial ended in April 1993 but study participants continued to be followed through national registries to evaluate the long-term effects of the vitamins on cancer incidence, and overall mortality. The data is complete for cancer incidence and mortality through December 2011 (eighteen years beyond the end of the trial). The study was conducted in collaboration by THL and the U.S. National Cancer Institute.

http://atbcstudy.cancer.gov/

THL – The National Institute for Health and Welfare, NIH – U.S. National Institutes of Health
Principal Investigators:
Jarmo Virtamo (THL), firstname.lastname (at) thl.fi
Demetrius Albanes (NIH), daa (at) nih.gov
Contact persons:
Jarmo Virtamo (THL), firstname.lastname (at) thl.fi
Stephanie Weinstein (NIH), weinstes (at) mail.nih.gov

Key references:
http://atbcstudy.cancer.gov/pdfs/atbcaep41101994.pdf
http://atbcstudy.cancer.gov/pdfs/atbc33010291994.pdf

ATBC Study - Detailed Information:
Background
The ATBC Study was a randomized, double-blind, placebo-controlled, 2x2 factorial design trial primarily testing the hypothesis that α-tocopherol and ß-carotene supplements reduce the incidence of lung and other cancers. From 1985 to 1988, 29,133 male smokers (at least 5 cigarettes per day) from the total male population aged 50 to 69 years of southwestern Finland (N=290,406) were recruited and randomized to 1 of 4 intervention regimens: α-tocopherol alone at 50 mg per day, ß-carotene alone at 20 mg per day, α-tocopherol plus ß-carotene, or placebo. Potential participants with a history of cancer or serious illness limiting long-term participation, those taking supplements of vitamin E, vitamin A, or ß-carotene in excess of predefined doses, and those being treated with anticoagulants were excluded. All participants gave written informed consent, and the study was approved by the institutional review boards of the National Public Health Institute, Helsinki, Finland, and the National Cancer Institute, Bethesda, Md.

Study protocol
At baseline, the participants completed a questionnaire about their general background, smoking, and medical histories, including a question about physician-diagnosed diseases as cancer, diabetes, hypertension, stroke, coronary heart disease, myocardial infarction, valvular disease, arrhythmia, cardiac enlargement, and congestive heart failure. A trained study nurse reviewed the questionnaire for accuracy with the participant. The number of cigarettes smoked per day and the duration of smoking habit (in years) were noted. The men were given a detailed dietary history (including alcohol consumption) questionnaire, to be filled at home and returned 2 weeks later at the second baseline visit.
Participants made 3 follow-up visits per year. At each visit, the unused capsules were counted, and compliance was assessed. Overall average compliance, calculated by dividing the total number of unreturned capsules by the number of days active in the trial, was 93%, with no differences between the intervention groups. Only 4% demonstrated poor compliance (i.e., took <50% of the capsules), and practically all of them dropped out of the study during their first trial year. Compliance was correlated with serum levels of α-tocopherol and ß carotene.
The dropout rate, including deaths, was 30% (29.8% in the α-tocopherol group, 30.7% in the α-tocopherol and ß-carotene group, 31.0% in the ß-carotene group, and 30.3% in the placebo group). Twenty-one percent of the men stopped smoking (i.e., reported no smoking at 2 consecutive follow-up visits). The dropout rate and proportionof men who stopped smoking remained even across the 4 intervention groups throughout the follow-up. Also, the means of blood pressure and serum total cholesterol were identical in the trial groups during the follow-up.

Questionnaire and interview data
At baseline, the study individuals provided detailed information on demographic, medical, smoking-related, and occupational factors. In addition, they were interviewed for chest pain, claudication, and respiratory symptoms by a nurse. Food consumption over the previous 12 months was assessed at trial baseline using a validated self-administered dietary questionnaire. The food use questionnaire inquired about the usual frequency of consumption and portion sizes of 276 common food items/mixed dishes and beverages during the past year. A color picture booklet was provided to each participant to assist with portion size estimation. The detailed questionnaire allows examining hypotheses concerning new dietary factors.

Laboratory measurements and reserve sampling
Blood pressure and weight were measured at baseline and annually thereafter. Height was measured at baseline. A serum sample was obtained for measuring total cholesterol, HDL cholesterol, α-tocopherol, and ß-carotene at baseline and at 3 years. Serum α-tocopherol and ß-carotene levels were additionally followed up by continuous sampling. Sera were stored at -70°C. Serum total cholesterol was determined enzymatically (CHOD-PAP method, Boehringer Mannheim). α-tocopherol and ß-carotene levels were determined by high-performance liquid chromatography. Serum is still available for analyses for all the participants. Whole blood samples were collected from 20,400 participants at the end of the intervention in 1992–1993 and DNA has been extracted from over 2100 participants.

Registry links and data handling
Routinely: Hospital discharge register, Death Register, Cancer register, in collaboration with the Finnish Cancer Registry. Data is stored electronically.

Organization and specific comments
The ATBC data are exploited still in many ways, for example to follow up the long-term effects of alpha-tocopherol and beta-carotene supplementation on the incidence of cancer and cardiovascular disease, to study in a cohort design the risk factors for major chronic diseases, particularly those related to diet and to collaborate with various domestic and international organizations.

Major international collaborations are:
• The Harvard Cancer Pooling Project co-ordinated by the Harvard School of Public Health is a
collaborative project of 28 North American and European cohort studies with the goal of providing the best consensus between diet and cancer.
• The MORGAM project examines the gene-environment interactions for cardiovascular diseases.
• The Cohort Consortium is a partnership of 43 high-quality cohorts involving more than 4 million people formed by the U.S. National Cancer Institute to pool data and biospecimens including germline DNA, to conduct a wide range of cancer studies.