Although some studies show benefits of physical activity or fitness in smokers in preventing cardiovascular disease mortality (10,23), there has been little research on the association of physical activity and smoking in relation to cancer mortality. Physical activity or cardiorespiratory fitness may provide protection against the risk of smoking-related cancer mortality. Exercise may reduce risk of lung cancer by enhancing immune function and reducing concentration of carcinogenic agents in the airways (13,28). Another plausible mechanism of protection from smoking-related carcinoma may include the effects of physical activity on leukocyte count and antioxidant defense and DNA repair systems. Better pulmonary function is inversely associated with leukocyte count, a specific marker of inflammation that contributes to carcinogenesis, and is positively associated with antioxidant defense and DNA repair systems that may inhibit tumor formation (7,8,11,20,31). However, there has been little research on the association of physical activity or fitness in relation to smoking-related cancer mortality. A few studies show an inverse association between physical activity and lung cancer events (13,28), or report no association between physical activity and pancreatic cancer events (13,27). Moreover, the relation of physical activity to nonsmoking-related cancer events needs more clarification. Although several prospective studies show good agreement for lower risk of colon cancer in active individuals, the association of activity to prostate and breast cancer needs further evaluation (1,4,9,12,13,15,19,22,26). We, therefore, examined the relation of cardiorespiratory fitness levels to smoking-related, nonsmoking-related, and total cancer mortality in men from the Aerobics Center Longitudinal Study. We also assessed the health effects of cardiorespiratory fitness in never, former, and current smokers in relation to smoking-related cancer mortality.
MATERIALS AND METHODS
Subjects and measurements.
Subjects were 25,892 men, ages 30–87 yr, who had a preventive medical evaluation between 1970 and 1994 at the Cooper Clinic in Dallas, Texas. All study participants were United States residents and had no personal history of myocardial infarction, stroke, or cancer at baseline.
The study protocol was reviewed and approved annually by the Institutional Review Board. All participants gave their informed written consent for the medical evaluation and registration in the follow-up study. The medical evaluation, performed after an overnight fast of at least 12 h, included a physical examination, anthropometry, electrocardiogram, blood chemistry analysis, blood pressure assessment, a maximal exercise treadmill test, self-report of health habits, and demographic characteristics. Additional details of examination procedures are published elsewhere (3).
Body weight and stature were measured with a standard physician’s scale and stadiometer. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared (kg·m−2) and was classified as underweight (<18.5 kg·m−2), normal weight (18.5 to <25 kg·m−2), overweight (25 to <30 kg·m−2), or obese (≥30 kg·m−2). Serum samples were analyzed by automated techniques in a laboratory that participates in the Centers for Disease Control and Prevention Lipid Standardization Program. Diabetes mellitus was defined as fasting plasma glucose levels ≥ 126 mg·dL−1 (7 mmol·L−1) or a history of physician-diagnosed diabetes mellitus.
Cardiorespiratory fitness was measured by a maximal treadmill exercise test using the Balke protocol (2). The treadmill speed was 88 m·min−1 for the first 25 min. The grade was 0% for the first minute, 2% the second minute, and increased 1% each minute until 25 min. After 25 min, the grade remained constant while the speed increased 5.4 m·min−1 until the subject reached exhaustion or was stopped by the supervising physician for medical reasons. All subjects achieved at least 85% of their age-predicted maximal heart rate (220 minus age in years) during the treadmill test. Total treadmill endurance time was used as an index of aerobic power, with time on treadmill with this protocol correlated highly (r = 0.92) with maximal oxygen uptake (V̇O2max) (25). Data are presented as maximal METs (metabolic equivalents) attained on the exercise test. METs are multiples of resting metabolic rate (RMR), which is taken as 3.5 mL of oxygen·kg−1·min−1. Men in the least-fit 20% of each age group were classified as low fit, the next 40% as moderately fit, and the remaining 40% as high fit (3).
Cigarette smoking habit and alcohol intake were assessed with self-report on a medical history questionnaire. Smoking status was classified as never smoker, former smoker, or current smoker based on responses to questions at the baseline examination: “Do you currently use tobacco?” and “Have you used any of the following (cigarettes, cigars, pipe, etc.) in the past but do not use them now?” Current and former smokers also were asked to provide information on how long they had smoked and on the number of cigarettes they smoked per day, but there were much missing data on this variable. Current smokers were further classified as smoking <20, 20 to <40, and ≥ 40 cigarettes per day. Alcohol consumption was classified as none, light (<15 units·wk−1), moderate (15 to ≤ 30 units·wk−1), and heavy (≥31 units·wk−1). One unit of alcohol intake was defined as a bottle/can of beer (12 oz), a glass of wine (5 oz), or 1.5 oz of hard liquor.
Ascertainment of mortality.
Participants were followed for mortality from the baseline examination to the date of death or to December 31, 1994. We identified deaths among study subjects from the National Death Index, and obtained official death certificates from the departments of vital records of the various states. A nosologist determined the underlying cause of death according to the International Classification of Diseases, Ninth Revision, with cancer defined as codes 140 to 239. Smoking-related cancers (codes 141–149, 150, 157, 161, 162, 188, and 189) included cancers of lung, trachea, bronchus, oral cavity, larynx, esophagus, pancreas, bladder, and kidney (6). Nonsmoking-related cancers included cancers of colon, rectal, digestive, pleura, bone/connective tissue, skin, breast, prostate, brain/nervous system, thyroid, myeloma, lymphoma, leukemia, and unspecified (codes 151, 152, 155, 156, 158, 159, 163, 170–176, 185, 191–193, 200–208, 239).
We used proportional hazards regression to examine the relation of cardiorespiratory fitness levels to smoking-related, nonsmoking-related, and total cancer mortality, respectively (5). Relative risks (RRs) and 95% confidence intervals (CIs) were estimated after adjustment for age and examination year, and also after further adjustment for smoking habits (never, former, or current [<20, 20 to <40, or ≥ 40 cigarettes·d−1]), alcohol intake (none, light, moderate, or heavy), body mass index (BMI; <18.5, 18.5 to <25, 25 to <30, and ≥30 kg·m−2), and diabetes mellitus (yes/no). Low-fit men were the reference category. Inspection of empirical cumulative hazard plots [−ln−ln (survival function) versus time t by cardiorespiratory fitness levels (low, moderate, and high)] indicated that the proportional hazards assumption was justified. We also examined the associations among cardiorespiratory fitness, smoking habits, and smoking-related cancer mortality. Trends across fitness levels were tested by treating fitness categories as an ordinal scale. Population attributable risks (PAR), P e x (RR − 1)/1 + P e x (RR − 1), were also estimated for low cardiorespiratory fitness and current smokers, where P e is the proportion of the exposed population and relative risk (RR) is adjusted RR for the exposure (14). All statistical analyses were performed using Statistical Analysis Systems software (SAS Institute, Cary, NC).
During an average of 10 yr of follow-up (259,124 man-yr), we observed 335 cancer (133 from smoking-related cancer, 202 from nonsmoking-related cancer) deaths. Table 1 provides baseline descriptive characteristics of all men by cardiorespiratory fitness levels. In general, high-fit men had a lower prevalence of physical inactivity, type 2 diabetes, and current smoking habit.
Table 2 shows the RRs of smoking-related, nonsmoking-related, and total cancer mortality by cardiorespiratory fitness levels in men. There was an inverse association between cardiorespiratory fitness levels and smoking-related cancer mortality (P < 0.001 for trend). Proportional hazards regression analyses, adjusted for age and examination year, showed that high-fit men had 66% (P < 0.001) and moderate-fit men 43% (P = 0.001) lower risk of smoking-related cancer mortality when compared with low-fit men. This relation remained after further adjustment for smoking habits, alcohol intake, body mass index, and diabetes mellitus (P < 0.001 for trend). There was also an inverse association between cardiorespiratory fitness levels and nonsmoking-related cancer mortality (P = 0.001 for trend). After adjustment for multiple risk factors, high-fit men had 46% (P = 0.001) and moderate-fit men had 34% (P = 0.01) lower risk of nonsmoking-related cancer mortality when compared with low-fit men, respectively. We also found similar results for overall cancer mortality. After adjustment for all risk factors, cardiorespiratory fitness levels were inversely associated with total cancer mortality (P < 0.001 for trend). High-fit men had 55% (P < 0.001) and moderate-fit men 38% (P < 0.01) lower risk of overall cancer mortality when compared with low-fit men, respectively.
Although there was no significant interaction of cardiorespiratory fitness levels with smoking categories, we examined the interrelations among cardiorespiratory fitness, smoking habits, and smoking-related cancer mortality. Figure 1 shows that, after adjustment for multiple risk factors, high-fit never-smokers had the lowest smoking-related cancer mortality, whereas low-fit current smokers had the highest smoking-related cancer mortality. Mortality rates were progressively lower across low, moderate, and high fitness groups in current (P = 0.04 for trend) and former (P = 0.06 for trend) smokers, and somewhat weaker for never smokers (P = 0.14 for trend).
Table 3 presents estimates of PAR for low cardiorespiratory fitness and current smoking in men. Smoking-related cancer mortality in this population might have been reduced by 13% if they had been fit (moderate or high fitness levels), and might have been reduced by 25% if they had not been cigarette smokers.
We investigated the health effects of cardiorespiratory fitness in relation to smoking-related, nonsmoking-related, and total cancer mortality in 25,892 men, ages 30–87 yr. Our major finding was that men with moderate or high levels of cardiorespiratory fitness had low risk of smoking-related cancer mortality when compared with low fit men. This association persisted in former and current smokers.
This is the first prospective study to evaluate the relation of cardiorespiratory fitness to smoking-related cancer mortality. Our findings are consistent with Harvard alumni and Norwegian studies in which there was an inverse association between physical activity and lung cancer incidence or mortality (13,28). However, the relation of physical activity or fitness in relation to other smoking-related cancer incidence or mortality remains less clear. A few studies show no relation between physical activity and pancreatic cancer mortality in men (13,27). In our study, lung, pancreas, kidney, and esophagus were frequent smoking-related cancers, whereas colon, prostate, and leukemia were frequent nonsmoking-related cancers. Our data indicate that moderate and high levels of cardiorespiratory fitness may provide some protection against the risk of smoking-related cancer mortality. We observed this inverse association with or without adjustment for cigarette smoking. Cigarette smoking was a significant risk factor for smoking-related (P < 0.001) but not for nonsmoking-related (P = 0.27) cancer mortality, whereas cardiorespiratory fitness was an independent risk factor for both smoking-related (P < 0.001) and nonsmoking-related (P < 0.001) cancer mortality.
Our data also show that there is an inverse association between cardiorespiratory fitness and nonsmoking-related cancer mortality. In general, a recent meta-analysis and other systematic reviews document that active individuals had low risk of colon, prostate, and breast cancers when compared with sedentary individuals (4,19,22,26), although the findings are sometimes inconsistent, especially for prostate and breast cancers (1,9,12,13,15). For example, the Nurses’ Health study shows an inverse association between physical activity and colon cancer incidence (18), whereas the Harvard alumni and Physicians’ health studies show no relation between physical activity and colon cancer incidence or mortality (12,13). Moreover, there was no association between physical activity and prostate cancer incidence or mortality in the U.S. physicians, Harvard alumni, and Health professionals follow-up studies (9,13,15), although the Aerobics Center Longitudinal Study shows an inverse association between cardiorespiratory activity or fitness and incident prostate cancer (21). The reason for these discrepancies is unknown but may be due to inconsistent physical activity assessment by different cohort studies or imprecise measurement of self-reported physical activity within populations. Further studies are needed to determine whether the objective marker of cardiorespiratory fitness is associated with site-specific cancer incidence or mortality.
In our study, men with moderate and high levels of cardiorespiratory fitness had low risk of smoking-related cancer mortality in former and current smokers. In fact, former smokers are at higher risk of cancer mortality when compared with never-smokers and require a range from 10 to 20 yr before returning the similar RRs of lung, tobacco-related, or total cancer as individuals who had never smoked (16,32). Some biopsy studies also document molecular damages in the bronchial epithelium in former smokers who had stopped smoking for 1–48 yr (17,29). Our data show that former smokers had a lower risk of smoking-related cancer mortality in moderate and high levels of cardiorespiratory fitness. These data suggest that cardiorespiratory fitness may enhance longevity after smoking cessation. We also observed a lower risk of cancer mortality in high-fit current smokers when compared with low-fit current smokers. Moderate and high cardiorespiratory fitness may provide health benefits in current smokers with modest possible protection from fitness.
It is plausible that increased pulmonary function may reduce smoking-related cancer mortality. Better pulmonary function is associated with better immune and antioxidant defense systems that may inhibit smoking-related tumor formation (11,24,30). In fact, aerobic exercise increases natural killer cells and cytotoxic activity of T cells (24,30), and enhances activities of glutathione peroxidase, superoxide dismutase, and catalase (11) that may degrade carcinogenesis from oxidative stress. Another possible mechanism is the inverse association between pulmonary function and leukocyte count (20,31), in which an elevated leukocyte count contributes to carcinogenesis (8,31). Furthermore, high pulmonary function may also positively influence DNA repair systems, although the mechanism is unknown (7).
Mechanisms for physical activity to decrease nonsmoking-related cancers such as colon and prostate cancer have been previously reported (4,19,22). It is possible that improvements in physical activity may decrease prostate cancer risk by decreasing testosterone levels, a risk marker for prostate cancer (22). It is also possible that high levels of physical activity may decrease colon cancer by reducing gastrointestinal transit time, thereby reducing colonic exposure to carcinogens in the fecal stream (4). Larger studies are needed to determine whether physical activity or fitness is related to other specific smoking-related cancers, including pancreas, bladder, and kidney.
A limitation of our study is that we did not measure cancer incidence; thus, the causal relation of cardiorespiratory fitness to cancer events may be limited. For instance, fitness may improve survival from cancer rather than prevent or delay its occurrence. It also could be that people prone to cancer are less capable of exercising or becoming fit. Another limitation of the present study is that we were not able to adjust for diet or other potential confounding variables, such as passive smoking. A strength of this study is that it represents the largest published cohort study of objectively measured cardiorespiratory fitness to smoking-related, nonsmoking-related, and total cancer mortality. In addition, our study population is homogeneous on race, education, and occupation, which reduces the likelihood of confounding by these important sociodemographic characteristics.
In conclusion, we found that men with moderate or high levels of cardiorespiratory fitness had reduced risk of cancer mortality when compared with low fit men.
We thank the physicians and technicians of the Cooper Clinic for collecting the data for this study, Dr. Kenneth H. Cooper, M.D., for initiating the Aerobics Center Longitudinal Study, Carolyn E. Barlow, M.S., for data management support, and Melba S. Morrow, M.A., for editorial assistance. We thank Aaron Folsom, M.D., for his valuable comments. We are grateful for the guidance of the Scientific Advisory Board of The Cooper Institute.
This study was supported in part by U.S. Public Health Service research grant AG06945 from the National Institute on Aging, Bethesda, MD.
Address for correspondence: Dr. Steven N. Blair, The Cooper Institute, 12330 Preston Road, Dallas, TX 75230; E-mail [email protected] cooperinst.org.
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