Lung cancer mortality after 16 years in MRFIT participants in intervention and usual-care groups. Multiple Risk Factor Intervention Trial.

PURPOSE: The Multiple Risk Factor Intervention Trial (MRFIT), a randomized clinical trial for the primary prevention of coronary heart disease, enrolled 12,866 men (including 8194 cigarette smokers) aged 35-57 years at 22 clinical centers across the United States. Participants were randomized either to special intervention (SI), which included an intensive smoking cessation program, or to usual care (UC). After 16 years of follow-up, lung cancer mortality rates were higher in the SI than in the UC group. Since rates of smoking cessation in SI were higher than those for UC for the 6 years of the trial, and since risk of lung cancer mortality is known to decline with smoking cessation, these results were unexpected. The purpose of the present study was to investigate hypotheses that could explain the higher observed lung cancer mortality rates in the SI as compared with the UC group. METHODS: Analytic methods were employed to determine whether SI and UC participants differed either in baseline characteristics or in characteristics that changed during the trial and to determine whether these differences could explain the higher rates of lung cancer mortality among SI as compared to UC participants. Rates of mortality from coronary heart (CHD) were examined to explore the possibility that prevention of CHD death may have contributed to greater mortality due to lung cancer in the SI group. RESULTS: From randomization through December 1990, 135 SI and 117 UC participants died from lung cancer. The relative difference between the SI and U groups adjusted for age and number of cigarettes smoked per day, was 1.17 (95% CI:0.92-1.51). The greatest difference between the SI and UC groups in lung cancer mortality rates occurred among the heaviest smokers at baseline who did not achieve sustained smoking cessation by year 2. In this group the rates of death from CHD were approximately the same among the SI and UC subjects. No differences in baseline characteristics were found between SI and UC smokers who did not achieve sustained cessation by year 2, and there were no differences in follow-up characteristics between the two study groups that could explain the difference in lung cancer mortality. CONCLUSIONS: None of the hypotheses proposed to explain the unexpected higher rates of lung cancer mortality among SI as compared with UC subjects were sustained by the data. Thus we conclude that the difference observed is due to chance, and that a longer period of sustained smoking cessation plus follow-up is necessary to detect a reduction in lung cancer mortality as a result of smoking cessation intervention in a randomized clinical trial.

Brief description of the Multiple Risk Factor Intervention Trial.

The Multiple Risk Factor Intervention Trial (MRFIT) was one of the coronary heart disease prevention trials recommended to the National Heart and Lung Institute in 1971 as an alternative to a national single-factor dietary trial, which was judged to be infeasible. MRFIT was a randomized, primary prevention trial, conducted at 22 US clinical centers from 1973 to 1982 to test whether lowering elevated serum cholesterol and diastolic blood pressure and ceasing cigarette smoking would reduce coronary heart disease mortality. Men 35-57 y of age (n = 12,866) with one or more of these risk factors were randomly assigned to the special intervention (SI) or usual care (UC) group and followed for 6-8 y. UC men were given information on risk factors, referred to their usual sources of care, and reexamined annually. SI participants received group and individual counseling on a fat-modified diet, a stepped-care drug treatment program for diastolic hypertension (after an initial attempt at blood pressure control by weight reduction, if indicated), and, for cigarette smokers, counseling aimed at cessation. SI men had risk factor assessments every 4 mo and annual examinations that were generally identical to those given to UC men and that always included measurement of blood cholesterol concentration. A listing of variables measured at each visit along with the design and major mortality results of MRFIT are included in this chapter.

Recruitment of participants in the Lung Health Study, I: Description of methods.

The recruitment experience is described for a large multicenter clinical trial, the Lung Health Study, which required the screening of more than 73,000 male and female smokers aged 35-60. This paper summarizes the plans, methods, and recruiting experience of the 10 participating clinical centers. Recruitment proposals were prepared by each clinical center as part of the contract application process. Recruitment directors and staff were appointed whose primary responsibility was recruitment. Only one clinical center retained its original plan throughout; most clinical centers achieved their recruitment goals by supplementing their originally proposed strategies with one or more methods. The most frequently used methods were worksite, public site, mass mail, telephone, media, and referral strategies. The most significant contributions to the success of the recruitment process were the willingness and initiative of the clinical centers' staff to explore alternative techniques that would take advantage of local circumstances and their ability to incorporate as many workable recruitment methods as necessary to achieve the goal.

Relationship between carotenoids and cancer. The Multiple Risk Factor Intervention Trial (MRFIT) Study.

We evaluated the baseline serum levels of beta carotene, total carotenoids, vitamin A and E, and retinol-binding protein among 156 initially healthy men who participated in the Multiple Risk Factor Intervention Trial (MRFIT) and who subsequently died of cancer and 311 controls individually matched for age, smoking status, randomization group, date of randomization, and clinical center. Both total carotenoids and beta carotene levels were lower in the 66 lung cancer cases than in their matched controls. For all cancer deaths combined, there were no significant differences in total carotenoids or beta carotene between cases and controls. The relationship between lower serum carotenoid levels and lung cancer persisted after adjusting for the number of cigarettes, alcohol intake, serum thiocyanate levels, and cholesterol levels in the blood. Serum levels of retinol, alpha tocopherol, and retinol-binding protein were not related to any cancer site. The results of this study provide further evidence for a possible protective effect of beta carotene against lung cancer among cigarette smokers.

Overall and coronary heart disease mortality rates in relation to major risk factors in 325,348 men screened for the MRFIT. Multiple Risk Factor Intervention Trial.

The influence of risk factors on CHD and all-cause mortality rates in 35- to 57-year-old men is examined by means of data on 325,348 white men who were screened for the MRFIT. This large data set permits an unusually detailed analysis of factors associated with the 6968 deaths, including 2426 ascribed to CHD, that were detected in the Social Security Administration data set during 6 years of follow-up. Simple cross classification of the data confirms the independent effect of serum cholesterol concentration, diastolic blood pressure, and cigarette smoking as risk factors for CHD and all-cause mortality rates. A distinct escalation of risk is noted for combinations of these risk factors. The strength of the association of each of the risk factors with CHD and all-cause mortality rates diminished with increasing age, although the number of excess deaths attributable to the risk factors increased because of the higher death rates in older men. Comparison of these findings with those observed in the five populations studied in the Pooling Project revealed an overall similarity in the risk relationships. It is estimated that elimination of these risk factors has the potential for reducing the CHD mortality rate by two thirds in 35- to 45-year old men, and by one half in 46- to 57-year-old men.