Affiliations of authors: L. Djoussé, Y. Zhang, M. Hood, R. C. Ellison (Section of Preventive Medicine and Epidemiology), B. E. Kreger (Section of General Internal Medicine), Evans Department of Medicine, Boston University School of Medicine, Boston, MA; J. F. Dorgan, Fox Chase Cancer Center, Philadelphia, PA; A. Schatzkin, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; R. B. DAgostino, D. L. Copenhafer, Department of Mathematics, Boston University, Boston.
Correspondence to: Luc Djoussé, M.D., D.Sc., Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Rm. B-612, 715 Albany St., Boston, MA 02118 (e-mail: ldjousse{at}bu.edu).
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ABSTRACT |
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INTRODUCTION |
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SUBJECTS AND METHODS |
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The Framingham Study is a population-based cohort study started in 1948 in Framingham, Massachusetts. The original cohort included 5209 participants, 2862 years of age at the first examination. Survivors have been examined every 2 years since then. In 1971, 5124 children of the original cohort and their spouses were invited to participate in a prospective study, referred to as the Framingham Offspring Study. Since 1971, participants in the offspring cohort were reexamined 8 years after the first examination and every 4 years thereafter. During each clinic visit, participants of these two studies undergo a series of tests and examinations, including a detailed medical history, a physician-administered physical examination, and an assessment of blood parameters and cardiac and lung function. Noninvasive cardiovascular tests and series of laboratory tests are also obtained. Detailed descriptions of the Framingham Study have been published previously (11,12). Written informed consent was obtained from study participants, and the study protocol was approved by the Institutional Review Board of Boston Medical Center. This study included 4265 participants from the original cohort and 4973 subjects from the offspring cohort.
Ascertainment of Lung Cancer
As described previously (13), cases of lung cancer were identified through self-report at clinic visits to the Framingham Study, by surveillance of hospitalizations at the only local hospital in Framingham, and by searching the National Death Index. For each suspected case of lung cancer, histopathologic reports were requested from the source of diagnosis (hospital and physicians offices) and were reviewed along with the subjects chart to determine the date of diagnosis and the classification according to the International Classification of Diseases in Oncology [topography code 162 (14)]. Based on histopathology, lung cancers were further grouped into the following three major categories: squamous cell carcinoma, adenocarcinoma, and other types. For multiple occurrences of lung cancer, only the first diagnosis was considered for these analyses.
Alcohol Consumption
Information on alcohol consumption has been collected repeatedly from both the original and offspring cohorts. At two early examinations (examinations 2 and 7) of the original cohort, subjects were asked how many 2-ounce cocktails, 8-ounce glasses of beer, and 4-ounce glasses of wine they consumed in a month. At subsequent examinations (examinations 1215 and 1723) of the original cohort and at all examinations (examinations 16) of the offspring cohort, subjects were asked about the number of 1.5-ounce cocktails, 12-ounce glasses (or cans) of beer, and 5-ounce glasses of wine they consumed in a week. Total alcohol consumption (g/day) was computed by multiplying the average content of alcohol in beer, wine, and mixed drinks times the number of drinks consumed. Because there was a secular change in the alcohol content of liquor commonly consumed (from 100 proof to 80 proof) and the type of wine generally consumed (from fortified to table wine), as well as a change in the average serving sizes of drinks, we used two different conversion formulas to calculate the total ethanol content according to when the data were collected. For examinations 2 and 7 of the original cohort, the total ethanol content (g/day) was calculated as ([1.0 x the number of cocktails per month] + [0.4 x the number of beers per month] + [0.67 x the number of glasses of wine per month]) x 28.35/30; the latter term represents 28.35 g of alcohol per fluid ounce divided by 30 days in a month. For all later examinations in the original cohort and all examinations in the offspring cohort, the ethanol intake per day was estimated as ([0.57 x the number of cocktails per week] + [0.44 x the number of beers per week] + [0.40 x the number of glasses of wine per week]) x 28.35/7; the latter term represents 28.35 g of alcohol per fluid ounce divided by 7 days in a week.
Other Variables
Information on smoking was collected at each examination with standardized questionnaires administered by the examining physician. Each subject was asked if he or she smoked cigarettes. If the answer was yes, the average number of cigarettes smoked per day was recorded. Current nonsmokers were asked if they had ever smoked in the past; a positive answer was used to classify former smokers. To calculate pack-years of smoking, the average number of cigarettes smoked per day was divided by 20 and then multiplied by the number of years of cigarette smoking.
Information on education was self-reported.
Statistical Analysis
Of the 5209 subjects in the original cohort, we excluded 944 subjects because of missing data on smoking pack-years from 534 subjects or smoking status from 50 subjects or alcohol intake from 360 subjects. Of the 5124 subjects in the offspring cohort, 151 subjects were excluded because of missing data on smoking pack-years (from 42 subjects) or alcohol intake (from 109 subjects). All analyses were conducted initially within each cohort separately and combined after observing that the findings were similar in the original and the offspring cohorts.
We used the risk sets method (15) to control for confounding by smoking, age, sex, and year of birth. For each case patient with lung cancer, all subjects who were free of lung cancer at the time of the case patients diagnosis and who met the matching criteria (matched to the case patient by age [±2 years], pack-years of cigarette smoking [±2 pack-years], sex, year of birth [±2 years], and smoking status [never, former, and current smokers]) were used as control subjects. The median number of control subjects per case patient was 3 (range = 1156). For case patients who were former smokers, control subjects were also matched on the number of years since the case patient quit smoking (±2 years). Each case patient and all of his or her matching control subjects constituted a risk set. Control subjects could be included in more than one risk set, and case patients could be included in risk sets as control subjects for case patients with earlier lung cancer diagnoses.
Alcohol consumption was categorized as follows: 0, 0.112, 12.124, and greater than 24 g/day (one "drink" is about 12 g of alcohol). Because alcohol data were not collected at every examination in the cohort study, for each risk set, total alcohol intake for each subject was computed as a weighted average of reported alcohol intake from examination 2 until the examination preceding the case patients diagnosis, with weights proportional to the time interval between reports of alcohol consumption. Within a risk set, pack-years of cigarette smoking were averaged across examinations from the first until the last examination preceding the diagnosis of lung cancer in the case patient. Person-years of follow-up were calculated from baseline until 1) the first occurrence of lung cancer, 2) loss to follow-up, or 3) the end of the study period. Crude incidence rates were computed by dividing the number of case patients with lung cancer by the number of person-years of follow-up in the corresponding alcohol category.
We used conditional logistic regression models to estimate the adjusted relative risk of lung cancer adjusting for age, year of birth, sex, pack-years of smoking, and smoking status. In this regression analysis, each risk set was treated as a stratum. We modeled alcohol intake as a series of indicator variables. We also evaluated education as a proxy to assess the effect of socioeconomic status on the association between alcohol consumption and lung cancer. Subjects were categorized as having less than a high school education, being a high-school graduate, or having some college and higher, and indicator variables were included in the regression models. However, additional adjustment for education in the conditional logistic regression model did not change the results, and so education was not included in the final model. We also used an unrestricted quadratic spline to assess a doseresponse relationship between alcohol intake and the risk of lung cancer. Knots were set at 6, 12, and 24 g of alcohol per day.
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RESULTS |
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Baseline characteristics of the 9238 subjects who were eligible to be included in the analysis are presented in Table 1. In the original cohort, the 194 subjects who became case patients smoked more cigarettes and consumed more alcohol than did the control subjects. Case patients were more likely to be male, heavy smokers, and less educated, and were slightly younger than control subjects. Similar to the original cohort, case patients in the offspring cohort smoked more, consumed more alcohol, and were less educated than control subjects (Table 1
). However, unlike the original cohort, offspring case patients were about 5 years older than control subjects.
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DISCUSSION |
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Although moderate alcohol consumption has been inversely related to cardiovascular (16), all-cause (17), and cancer (17) mortality in some studies, data on the association between moderate alcohol consumption and risk of lung cancer in a community-based population have been inconsistent. Our findings are consistent with those studies that did not find an increased risk of lung cancer with alcohol consumption (1,2,1821). Results from a meta-analysis indicated the lack of an association between alcohol consumption and lung cancer at lower levels of alcohol consumption (less than 2000 g/month) after adjustment for smoking and an increased risk of lung cancer with consumption of greater than 2000 g/month, the equivalent of more than 5 "drinks" per day (22).
Studies of heavy drinkers (3,23,24) and several epidemiologic studies (46) have reported a positive relationship between alcohol consumption and lung cancer. The discrepancy between these positive studies and our study could be explained partially by several limitations among studies. First, our study included few heavy drinkers, because most of the subjects consumed alcohol moderately. Second, residual confounding by smokinga major confounder of the association between alcohol consumption and the risk of lung cancer (21,25)may partially account for some of the inconsistencies. Third, because drinking patterns may change over time (26), the use of a single measurement of alcohol intake (baseline value) might introduce bias. Fourth, for casecontrol studies, selection bias and recall bias are inherent issues of the study design and could be very difficult to eliminate. Fifth, different lengths of follow-up time may also play a role. Our study used the risk sets method to match each case patient with lung cancer to control subjects on key potentially confounding factors.
In a secondary analysis, alcohol consumption was suggestive of an increased risk of adenocarcinoma but not of squamous cell carcinoma or other histologic types. The small number of case patients with lung cancer in this study limits our ability to make an inference about the association between alcohol intake and histologic types of lung cancer. There was no apparent doseresponse relationship between alcohol consumption and histologic types of lung cancer, and the estimates were very unstable (wide 95% CIs, all of which included 1.0). We cannot provide a plausible explanation for the suggestive association between alcohol and adenocarcinoma, and chance cannot be excluded as a possible explanation for this association. In a recent casecontrol study by Zang and Wynder (21), no statistically significant association was observed between alcohol and squamous cell, adenocarcinoma, small-cell, or large-cell lung carcinoma. Furthermore, alcohol consumption was not associated with histologic type of lung cancer in another casecontrol study (27).
Our study has several strengths. We used stringent criteria to control confounding by cigarette smoking and other major risk factors for lung cancer. Each case patient with lung cancer was matched to all potential control subjects on smoking status (never smoker, former smoker, or current smokers) and pack-years of smoking (±2 years), and former smokers were matched on years since quitting (±2 years). Information on alcohol consumption collected at several time points was used to evaluate exposure. The prospective nature of our study design, the long duration of follow-up, the completeness of case patient ascertainment, and the wide age range of participants are additional strengths. Nevertheless, our study has some limitations. We have a relatively small number of case patients with lung cancer to allow stratified analyses. Because 89% of our population consumed fewer than three alcoholic drinks per day, our results are limited primarily to light to moderate drinkers, and we could not evaluate the effects of heavy drinking on the risk of lung cancer. Finally, we may have underestimated alcohol consumption among former heavy drinkers who may have quit or reduced their alcohol intake before the initial alcohol assessment.
In conclusion, our data show that alcohol consumption that was generally light to moderate among subjects in the Framingham Study was not statistically significantly associated with the risk of lung cancer.
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NOTES |
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Supported by the National Heart, Lung, and Blood Institutes Framingham Heart Study, National Institutes of Health (NIH/NHLBI Contract N01-HC-38038), the Framingham Heart Study Visiting Scientist Program (which is supported by Servier Amerique), and a grant-in-aid from the Alcoholic Beverage Medical Research Foundation.
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Manuscript received April 3, 2002; revised September 26, 2002; accepted October 15, 2002.
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