Wednesday, January 26, 2005

Failed Chemoprevention Study Provides Vital Information about Asbestos and Cancer

BrooklynDodger observes that some studies funded for suspect motives produce results pivotal for public health. For example, the pharma funded clinical trial of VIOXX use against colon polyps [done to increase marketing] revealed, or at least cemented understanding of the dangers overmarketing of COX-2 inhibitors posed to cardiac health. It also may have started a new paradigm about COX's and clotting.

Similarly, the results below are derived from a chemoprevention trial of whether Vitamin A - an antioxidant - protected against future effects of past asbestos [and cigarette smoke] exposure. Among other critics, BrooklynDodger complained that NCI was dumping huge resources into a project that diverted effort from identifying and abating exposure to occupational and environmental carcinogen exposure.

The investigators had enrolled over 4,000 asbestos workers [and a larger number of smokers], screened them at baseline and followed them for over a decade. Recruitment must have been a huge task. Double digit millions must have been spent on this project. In order to measure the impact of the intervention, the investigators had to develop previously unavailable information about the natural history of asbestos and lung cancer.

Previously, the main news from this project was that the chemoprevention study was terminated because Vitamin A increased the risk of lung cancer. BrooklynDodger confesses a certain schadenfreud on hearing that news. Nevertheless, the investigators continued painstaking analysis of results, which they have now published.

The study confirmed excessive rates of lung cancer among men with radiographic asbestosis, but also among workers with no evidence of asbestosis. Among workers with no evidence of asbestosis at baseline, men with more than 40 years' exposure in high-risk trades had a risk approximately fivefold higher than men with 5*10 years. Pleural plaques on the baseline x-ray and abnormal baseline lung function tests were strong independent predictors of subsequent lung cancer.

These results come at a time when asbestos compensation legislation is before the Congress. Frankly, this paper was submitted in February and accepted in August of last year, and might have informed the debate to this point.

The news is a little grim for formerly exposed asbestos workers - even those who exit their trade with a clean x-ray are at increased risk. More thoughts on the implications will follow.

American Journal of Epidemiology 2005 161(3):260-270;

Predictors of Lung Cancer among Asbestos-exposed Men in the ß-Carotene and Retinol Efficacy Trial

Mark R. Cullen1 , Matt J. Barnett2, John R. Balmes3, Brenda Cartmel1, Carrie A. Redlich1, Carl A. Brodkin4, Scott Barnhart4, Linda Rosenstock5, Gary E. Goodman2,6, Sam P. Hammar7, Mark D. Thornquist2 and Gilbert S. Omenn8,9
1 Occupational and Environmental Medicine Program and the Cancer Center, Yale University School of Medicine, New Haven, CT.
2 Fred Hutchinson Cancer Research Center, Seattle, WA.
3 Department of Medicine, University of California School of Medicine, San Francisco, CA.
4 Harborview Medical Center, Seattle, WA.
5 School of Public Health, University of California, Los Angeles, Los Angeles, CA.
6 Swedish Medical Center Cancer Institute, Seattle, WA.
7 Pathology Associates of Kitsap County/Diagnostic Specialties Laboratory, Bremerton, WA.
8 Departments of Internal Medicine and Human Genetics, University of Michigan Medical School, Ann Arbor, MI.
9 Department of Public Health, University of Michigan School of Public Health, Ann Arbor, MI

Despite numerous published studies, debate continues regarding the risk of developing lung cancer among men exposed occupationally to asbestos, particularly those without radiographic or functional evidence of asbestosis. The ß-Carotene and Retinol Efficacy Trial (CARET), a study of vitamin supplementation for chemoprevention of lung cancer, has followed 4,060 heavily exposed US men for 9*17 years. Lung cancer incidence for 1989*2002 was analyzed using a stratified proportional hazards model. The study confirmed excessive rates of lung cancer among men with radiographic asbestosis. Comparison of study arms revealed a strong, unanticipated synergy between radiographic profusion category and the active intervention. In the large subgroup of men with normal lung parenchyma on chest radiograph at baseline, there was evidence of exposure-related lung cancer risk: Men with more than 40 years' exposure in high-risk trades had a risk approximately fivefold higher than men with 5*10 years, after adjustment for covariates. The effect in these men was independent of study intervention arm, but pleural plaques on the baseline radiograph and abnormal baseline flow rate were strong independent predictors of subsequent lung cancer. Residual confounding by subclinical asbestosis, exposure to unmeasured lung carcinogens, or differences in smoking are unlikely to explain these observations better than a carcinogenic effect of asbestos per se.

Key Words: asbestos; asbestosis; beta carotene; clinical trial [publication type]; lung neoplasms; occupational exposure; vitamin A

Copyright © 2005 Johns Hopkins Bloomberg School of Public Health.

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