1 Surveillance and Risk Assessment Division, Centre for Chronic Disease Prevention and Control, Population and Public Health Branch, Health Canada, Ottawa, Ontario, Canada.
2 OMNI Research Group, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
3 Clinical Epidemiology Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada.
Received for publication September 16, 2002; accepted for publication March 27, 2003.
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ABSTRACT |
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case-control studies; exercise; histology; lung neoplasms; recreation; smoking
Abbreviations: Abbreviations: IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; MET, metabolic equivalent; NECSS, National Enhanced Cancer Surveillance System.
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INTRODUCTION |
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Cigarette smoking is the most important risk factor for lung cancer, accounting for 8090 percent of lung cancers in the United States (3, 4). Occupational exposure, air pollution, and lifestyle factors may also play a role in the etiology of lung cancer. Physical activity improves ventilation and perfusion, which in turn may reduce both concentration of carcinogenic agents in the airways and duration of agent-airway interaction (2). Previous studies examining the association between physical activity and lung cancer risk have yielded inconsistent results (516). Seven of nine cohort studies (513) and one of three case-control studies (1416) found that increased occupational and leisure-time physical activity was associated with reduced risk of lung cancer. As a modifiable lifestyle factor, physical activity, if proven to protect against lung cancer, provides an opportunity to reduce the incidence of this fatal cancer.
Detailed data on individual risk factors collected through the Canadian National Enhanced Cancer Surveillance System (NECSS) provided us with a valuable opportunity to examine the relation between physical activity and lung cancer risk in Canada in a large population-based sample, permitting control for potential confounding factors and analysis of lung cancer risks by histologic subtypes. The large sample also enabled us to examine effect modification of cigarette smoking and body mass on assessment of the association between physical activity and lung cancer risk.
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MATERIALS AND METHODS |
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All cases included in NECSS had histologically confirmed primary lung cancer (code C34, as defined by the International Classification of Diseases for Oncology, Second Edition) (18) and were identified by the provincial cancer registries. Controls were identified through frequency matching with all 19 types of cancer cases to select population controls with similar age and gender distributions. The sampling strategies for control selection varied by province depending on database availability and quality. In Prince Edward Island, Nova Scotia, Manitoba, Saskatchewan, and British Columbia, provincial health insurance plans were used to derive a random sample of the provincial population stratified by age group and gender. More than 95 percent of Canadians are covered by these public plans, and persons are excluded only if covered through other federal plans. In Newfoundland and Alberta, random digit dialing was used to obtain a population sample.
Provincial cancer registries identified 4,858 incident lung cancer cases aged 2076 years in the seven provinces included in our study. Histologic types were based on the International Classification of Diseases for Oncology, Second Edition. Physician consent to contact the cases was obtained, and the registries sent a cover letter and questionnaire to the cases. Physicians refused consent for 371 (7.6 percent) cases, and 1,085 cases (22.3 percent) died before they could be sent questionnaires. Questionnaires were mailed to 3,402 cases; 94 of these questionnaires were returned because of a wrong address or an old address and the fact that no updated address could be found through publicly available sources. Of those sent questionnaires, 3,077 cases were contacted. Of the 3,402 eligible cases, completed questionnaires were received from 2,128 of them (62.6 percent).
Using the same protocol as that for the cases, we mailed questionnaires to the 5,107 potential controls without cancer who were selected in the seven provinces studied. For 81 of these people (1.6 percent), the questionnaires were returned because of a wrong address or an old address, and no updated address could be found by using publicly available sources. In all, 3,106 controls completed the questionnaires, representing 61.8 percent of those contacted and 60.8 percent of those ascertained.
Some variations in response rates occurred between provinces and between genders. The response rates for controls were 63.8 percent for females and 58.4 percent for males; for lung cancer cases, they were 62.8 percent for females and 62.3 percent for males. The response rates for the seven provinces varied from 56.0 percent to 69.5 percent for controls and from 57.9 percent to 73.7 percent for cases.
Data collection
The cancer registries identified most cases within 13 months of their diagnosis through pathology reports to minimize the loss of subjects because of severe illness and death. After physician consent was received, the registries sent these persons a cover letter and questionnaire to complete and return in a stamped, preaddressed envelope. If the questionnaire was not returned, a reminder postcard was sent out at 2 weeks, a second copy of the questionnaire was mailed at 4 weeks, and telephone contact was attempted after 6 weeks to offer the subject a telephone interview, if desired. Telephone follow-up was attempted when necessary for clarification and completeness.
The questionnaires collected information on subjects educational level, family income (average over the past 5 years), marital status, ethnic group, height, and weight. The questionnaires also included items on alcohol consumption, smoking history, employment history, history of occupational exposure to specific carcinogens, residential history, history of vitamin and mineral supplement use, and reproductive history. The diet component (a 60-item food frequency instrument) provided diet information from 2 years before the interview and general changes in the subjects diet compared with 20 years before. The design was based on two instruments that have been validated extensively: the National Cancer Institutes Block food frequency questionnaire (19) and the instrument used for the Nurses Health Study cohort (20); minor modification was made for the Canadian diet. Estimates of caloric and dietary fat intakes were calculated for each subject by substituting the number of kilojoules and grams of fat for each of the items in the diet questionnaire by using the Canadian Nutrient Guide (21).
Passive smoking exposure was assessed by obtaining a lifetime occupational history and residential history. Subjects were asked the address, first and last year of residence, and number of regular smokers usually living in the subjects home for each Canadian residence in which the subject had lived for at least 1 year. The questionnaire on occupational history collected data on job title, years of employment, and number of regular smokers in the immediate work area for each job held for at least 1 year.
Assessment of physical activity
The questionnaires collected information on recreational physical activity 2 years before the interview. The frequency and duration of activities were assessed by recording the session frequency, season of participation, and average time per session for each of 12 of the most common types of moderate and strenuous leisure-time physical activities in Canada. The assessment was based on average frequency and duration of recreational physical activity participated in over the past years. Individual activities included walking for exercise, jogging or running, gardening or yard work, home exercise or exercise classes, golf, racquet sports, bowling or curling, swimming or water exercises, skiing or skating, bicycling, social dancing, and other strenuous exercise. The intensity of the activity was estimated by assigning a specific metabolic equivalent (MET) value to each reported activity. The MET values used here were abstracted from the Compendium of Physical Activities (22). A MET is defined as the ratio of the associated metabolic rate for a specific activity to the resting metabolic rate (23). One MET is the average seated resting energy cost for an adult and is set at 3.5 ml/kg per minute of oxygen. For this analysis, we estimated the average MET-hours per week spent engaging in recreational physical activities. We categorized levels of recreational physical activity as moderate (MET 3 to
6), vigorous (MET >6), and total (moderate plus vigorous) (1). The variables used in the analysis were the sum of each category of moderate, vigorous, and total (moderate plus vigorous) physical activities.
Statistical analysis
We calculated odds ratios and corresponding 95 percent confidence intervals by using the unconditional logistic regression model with the SAS software package (version 8; SAS Institute, Inc., Cary, North Carolina). Variables were categorized into quartiles based on the frequency distribution of the variables among controls. Potential confounding variables considered in the initial regression models were gender, age, province of residence, educational level, family income adequacy, marital status, ethnic group, smoking status (never smoked, ex-smoker, current smoker), pack-years of smoking, alcohol consumption, body mass index, total calorie intake, total dietary fat intake, vegetable intake, passive smoking, and occupational exposure. In the initial model, we conducted a full assessment of potential confounders by using a stepwise selection procedure. A p value of 0.10 was used for entry into and removal from the model. We retained variables in the final models that have previously been considered biologically important, even though they did not reach a statistically significant level in the initial assessment. We adjusted all models for age (10-year groups) and province of residence because age is strongly associated with cancer risk, the method for identifying cases and controls varied by province, and cases and controls were not directly matched. The final multivariate models were also adjusted for smoking status (never smoked, ex-smoker, current smoker); pack-years of smoking (0, 110, 1120, 2130, >30); total years of residential and occupational exposure to passive smoking (quartiles); occupational exposure to asbestos, coal tar, soot, pitch, creosote, and asphalt (yes, no); educational level (>12, 1012, 9 years); alcohol consumption (servings/week, continuous); caloric intake (kJ/week, quartiles); vegetable consumption (servings/week, quartiles); and body mass index (weight (kg)/height (m)2, quartiles).
Although the interaction term of gender and physical activity was not statistically significant in the regression model, some differences concerning the association between physical activity and lung cancer risk by gender may exist; therefore, we conducted the analyses for males and females separately in addition to the analyses for all subjects. We examined possible effect modification by smoking status and pack-years of smoking. We also analyzed effect modification by body mass index because body mass index is related to level of insulin-like growth factors (IGFs) and their binding protein (IGFBP)-3, which might be one of the possible mechanisms accounting for the association between physical activity and lung cancer risk. In addition, we performed stratified analyses by histologic types of lung cancer. We conducted tests for trend for all models of categorized data by treating the different categories as a single ordinal variable.
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RESULTS |
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Table 1 compares the distribution of characteristics of lung cancer cases and controls. Compared with controls, lung cancer cases were older; were less educated; had a lower family income; were more often occupationally exposed to asbestos, coal tar, soot, pitch, creosote, and asphalt; were more often current smokers and less often ex-smokers and never smokers; reported more pack-years of smoking and more cigarettes smoked per day; started smoking at a younger age; were exposed to more years of residential and/or occupational passive smoking; drank more alcohol; and had higher intakes of total calories and dietary fat. The cases also reported lower levels of moderate, vigorous, and total recreational physical activity compared with controls. The average body mass index and vegetable consumption for cases and controls were similar. Variables retained in the model in which the stepwise regression method was used included gender, age, province of residence, smoking status, pack-years of smoking, alcohol consumption, occupational exposure, calorie intake, body mass index, and vegetable intake. The tests for interaction for gender, smoking status, pack-years of smoking, and body mass index with total physical activity were not statistically significant.
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DISCUSSION |
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The inverse association between physical activity and lung cancer risk observed in our study is consistent with findings from the majority of previous studies (614), although some found no association (5, 15, 16) and one reported a positive association (10). The latter study (10) and another that found no association (16) were both hospital-based case-control studies, and they used only occupational title collected in conjunction with cancer incidence reporting to produce a surrogate measure of physical activity.
The greater reduction in lung cancer risk for certain histologic subtypes associated with total recreational physical activity for men is similar to the finding from a prospective study of 81,516 men and women by Thune and Lund (8), which found that the association was strongest for small cell carcinoma and less marked for adenocarcinoma, with no association for squamous cell carcinoma in men. The Thune and Lund study considered only squamous cell carcinoma, small cell carcinoma, and adenocarcinoma in men because of the small numbers for other subtypes. However, another prospective cohort study by Colbert et al. (5) of 27,087 male smokers did not find a risk reduction for squamous cell carcinoma, small cell carcinoma, or adenocarcinoma lung cancer. To our knowledge, no previous study has examined the association of lung cancer with physical activity by histologic subtype for women.
There are several hypothesizes underlying biologic mechanisms related to the association between physical activity and lung cancer risk. The first is that increased levels of physical activity increase pulmonary ventilation and perfusion (2426), which in turn reduces both concentration of carcinogenic agents in the airways and duration of agent-airway interaction as well as the subsequent risk of lung cancer (2729). Thune and Lund (8) suggested that increased pulmonary function may be more important in relation to small cell and adenocarcinoma subtypes because they are more often located in the periphery of the lung and increased pulmonary function influences particle deposition; this hypothesis may explain some of the difference in risk reduction associated with physical activity by histologic subtypes for men, but it cannot explain the difference for women. The second hypothesis is that exercise may affect lung cancer risk through its effects on IGFs and their binding proteins (IGFBPs) (30). IGF is down-regulated by increased production of its binding protein (IGFBP-3). Increased levels of physical activity have been shown to increase IGFBPs and decrease IGFs, whereas excess body mass index leads to reductions in IGFBPs (2). Experimental data have demonstrated that IGFs stimulate both small-cell and non-small-cell growth and inhibit cellular apoptosis (31, 32); IGFBP-3 inhibits the growth of non-small-cell lung cancer (33). High levels of circulating IGF-I were associated with an increased risk and high levels of IGFBP-3 with a decreased risk of lung cancer in two case-control studies (34, 35) and one prospective study (36).
The third hypothesis is that exercise may improve immunosurveillance by enhancing immune function (3742). The final possibility is that exercise may improve antioxidant defense systems by up-regulating both the activities of free scavenger enzymes and antioxidant levels to counteract the oxidative damage caused by cigarette smoking (30, 4348). These mechanisms may work separately or in combination to reduce lung cancer risk.
Most of the previous studies assessed men only or men and women together. Because of our large sample, we were able to examine the association between physical activity and lung cancer risk for men and women separately. To our knowledge, this is only the second study to examine the association separately for each gender. Furthermore, we measured and assessed a wide range of potential confounders, thereby overcoming some of the limitations of previous studies. Ours used a standard method of measuring physical activity, examining all parameters (frequency, intensity, and duration). The large sample size also enabled us to evaluate the association stratified by some potential effect modifiers such as smoking and body mass index. The ability to assess effect modification helps to shed light on the underlying mechanism. For example, the finding that physical activity had a much higher protective effect against lung cancer for smokers suggests that increased pulmonary ventilation may attenuate the effect of cigarette smoking in inducing lung cancer. On the other hand, the finding of no protection from physical activity against lung cancer for the obese suggests that obesity may somewhat offset the effect of physical activity.
Limitations of the present study should not be overlooked. One inherent problem in all case-control studies is recall bias. Although cases may have recalled relevant behaviors in more detail than controls did, physical activity is not widely accepted as having much influence on lung cancer risk. Some degree of recall bias concerning other risk factors might have existed, especially past cigarette smoking up to several decades ago. Misclassification of exposure was a possibility and was likely to be nondifferential. Another limitation is that we were not able to collect information about occupational activity or household activity or about lifetime physical activity; therefore, we could not assess the effect of total lifetime physical activity on the risk of lung cancer. In addition, because 22.3 percent of eligible lung cancer cases had died before they could be recruited for the present study, our results may be generalizable only to either less aggressive lung cancer tumors or to healthier subjects able to be diagnosed earlier or respond better to treatment.
In summary, our study suggests that recreational physical activity is associated with a reduced risk of lung cancer in both men and women, which was attributed to both moderate and vigorous activity. The risk reduction was more noticeable for smokers and for subjects with low (<25 kg/m2) and medium (25<30 kg/m2) body mass indexes. Because physical activity is a modifiable lifestyle factor, our study findings have implications for preventing lung cancer.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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