Diet

Dietary Hypotheses and Mechanisms

Epidemiological research on diet and lung cancer has been both hypothesis driven and descriptive, exploring associations between foods or nutrient indexes and lung cancer risk. Interest in macro-nutrients has emphasized indices of dietary fat, which was long ago noted to have the capacity to act as a tumor promoter. Micronutrients have been extensively studied, spurred initially by the pioneering epidemiological work of Bjelke and the original vitamin A and ft-carotene hypotheses. Bjelke and subsequent researchers originally focused on vitamin A because of its role in cellular differentiation and the promise of the initial observational findings, but this line of inquiry was subsequently expanded to include antioxidant micronutrients, with an emphasis on ft-carotene. The more general hypothesis has been advanced that antioxidant micronutrients may protect against oxidative damage to DNA and thereby protect against cancer. Hypotheses concerning specific beverages have also been proposed; for example, animal studies have shown alcohol consumption to be associated with changes in lung lipids, including surfactant, and in levels of enzymes that can activate procarci-nogens and mutagens. Another epidemiologic approach, empirical rather than hypothesis driven, has been to explore the intakes of several specific foods or food groups for associations with lung cancer risk. The identification of protective associations between fruit and vegetable consumption and lung cancer resulted from the use of this more empirical approach.

Certain methodological issues are relevant to a discussion of diet and lung cancer. When investigating a potential link between diet and lung cancer, the potent role of cigarette smoking in the etiology of lung cancer, along with the current differences in the diets of smokers compared with nonsmokers, makes the potential confounding effects of cigarette smoking an acute concern. Even when there is an attempt to control for smoking, residual confounding of diet-lung cancer associations may still occur. Cigarette smoke can directly affect circulating concentrations of dietary factors (Figure 1); for example, smokers tend to have lower levels of circulating antioxidant micronutrients even after accounting for differences in dietary intake.

Aspects of the design and conduct of epidemiolog-ical studies in general further limit interpretation of

Cigarette _ Lung Cigarette smoking is the

Smoking Cancer principal cause of lung cancer.

Cigarette _ Lung

Smoking Cancer

| Cigarette smokers tend to have i ? poorer diets than nonsmokers.

Dietary factor

Cigarette _ Lung

Smoking Cancer Cigarette smoking can directly affect

| \ the circulating concentrations of i ? dietary factors, e.g., depletion of

Dietary antioxidant micronutrients.

factor

Figure 1 Cigarette smoking complicates the study of diet and lung cancer.

specific dietary studies. Approaches to dietary assessment are not fully standardized, and there may be differences between studies in the number of foods queried, the measurement of serving sizes, and the interview approach employed. There is also uncertainty regarding the biologically relevant exposure window or windows for lung cancer, and dietary agents may plausibly act in early and/or later stages of carcinogenesis. Clinically diagnosed lung cancer reflects a series of complex molecular genetic events that occur over a long period, and the relevant windows for dietary exposures are uncertain. Case-control studies usually measure past diet during some reference period, whereas cohort studies tend to focus on current diet. Most of the epidemiologic research has taken the form of case-control studies, many of which focus on diet during the 5 years preceding diagnosis. These studies provide direct information concerning dietary factors in the later stages of carcinogenesis. To the extent that such measures reflect usual adult (or lifetime) diet, the results of these studies may also be relevant to the role of diet in earlier stages of carci-nogenesis. However, because lung cancer tends to be rapidly fatal, many case-control studies include data collected from deceased subjects' next-of-kin. Data from surrogate respondents are probably less accurate than self-reported data, and using such information is certain to introduce substantial misclassification.

Evidence concerning relationships between lung cancer and fruits, vegetables, micronutrients, phyto-chemicals, fat, body mass index, beverages, and meat intake is reviewed here. For these agents, there is no basis for anticipating that some threshold of intake is relevant to protection (or risk). Rather, a dietary factor that protects against lung cancer would theoretically be expected to confer greater protection when present in greater amounts, and vice versa. Consequently, this review emphasizes dose-response trends, with a monotonic dose-response relationship considered to provide the strongest evidence favoring an association. To focus on the most relevant evidence, the summary tables include only studies that controlled for age and cigarette smoking and case-control studies with more than 200 lung cancer cases. Smaller studies would not be expected to have sufficiently precise estimates to be informative.

Dietary Associations with Lung Cancer

Fruit In total, the evidence favors a protective association between greater fruit consumption and lower lung cancer risk, with associations in the protective direction in 18 of 31 studies (Table 1). When stratified by gender, the overall protective association holds more often than not for both males and females. No clear pattern emerges when studies have examined specific fruits or classes of fruits. For example, apples and citrus fruits are associated with reduced risk of lung cancer in some studies but not in others.

Vegetables Evidence for a protective association for vegetable consumption parallels the evidence for fruit consumption, with 18 of 33 studies showing associations at least weakly in the protective direction (Table 1). The overall evidence thus points strongly toward a protective association, which has been observed in both males and females. In addition to vegetable intake as a whole, the results for a number of specific vegetables, such as carrots and cruciferous vegetables, have been consistently associated with a reduced risk of lung cancer, at least for the highest versus the lowest categories of consumption.

Micronutrients Two different strategies have been used to evaluate the relationship of micronutrients to lung cancer. One approach has been to use data summarized from food-frequency questionnaires to estimate micronutrient intake. A second approach has been to draw blood samples from study participants and assay the concentrations of micronutrients in circulation. The former approach provides a better average measure of micronutrient 'exposure,' whereas the latter approach has the advantage of measuring micronutrient concentrations closer to the level of cells, where the biologic effect is postulated to occur. However, a single assay of circulating micronutrient concentrations may not reflect the biologically appropriate window of exposure. The evidence is most abundant for vitamins A, C, and E and for total carotenoids and ^-carotene. A body of evidence is also accumulating for a-carotene, /3-cryptoxanthin, lutein, and lycopene.

The majority of studies on dietary retinol show no association with lung cancer risk (Table 2). On the other hand, studies of dietary intake of ^-carotene, total carotenoids, and vitamin C point more consistently toward an inverse association, with results at least equally divided between showing some evidence of protective association and showing no association (Table 2). As with ^-carotene, studies of additional provitamin A carotenoids a-carotene and /3-cryptox-anthin have also been evenly divided between showing no association and showing a protective association with lung cancer. Conversely, only a minority of studies of the non-provitamin A carotenoids lycopene and lutein have suggested that higher intakes are associated with decreased risk of lung cancer.

Studies based on micronutrients measured from blood samples drawn after an individual is diagnosed with lung cancer showed that lung cancer

Table 1 Estimated relative risk of lung cancer according to frequency of fruit and vegetable consumptiona

First author (year) Sex Fruits Vegetables Also adjusted for

Table 1 Estimated relative risk of lung cancer according to frequency of fruit and vegetable consumptiona

First author (year) Sex Fruits Vegetables Also adjusted for

1

2

3

4

5

1

2

3

4

5

Case-control

studies

Alavanja (1993)

F

1.0

1.1

0.8

1.1

1.0

0.8

0.9

0.8

1.0

Previous lung disease, daily

energy intake

Axelsson (1996)

M

1.0

0.8

0.7

1.0

0.7

0.4

Marital status, occupation

Brennan (2000)

M/F

1.0

0.9

1.0

1.0

0.9

0.7

Sex, center (all nonsmokers)

Darby (2000)

M/F

1.0

0.8

0.9

0.9

Sex

De Stefani (1999)

M

1.0

0.6

0.5

1.0

0.7

0.5

Residence, education, family

history, body mass index,

total energy and fat intake

Dorgan (1993)

M/F

1.0

1.0

0.9

1.0

0.9

0.7

Passive smoking, education,

occupation

Fontham (1988)

M/F

1.0

0.8

0.7

1.0

0.8

0.7

Race, sex

Gao (1993)

M

1.0

0.8

0.5

1.0

0.7

0.6

Hu (1997)

M/F

1.0

1.1

0.8

Sex, area of residence, income

Jain (1990)

M/F

1.0

0.9

1.0

1.1

1.0

0.7

0.7

0.6

Kreuzer (2002)

F

1.0

0.6

0.7

1.0

0.6

0.5

Region (all nonsmokers)

Kubik (2002)

F

1.0

0.7

1.0

0.8

Residence, education

Le Marchand (1989)

M

1.0

0.9

0.7

0.4

Ethnicity, cholesterol intake

Mayne (1994)

M

1.0

0.4

0.7

0.7

1.0

1.1

1.3

0.6

F

1.0

0.6

0.5

0.6

1.0

1.0

0.8

0.5

Mohr (1999)

M/F

1.0

1.0

1.2

0.8

1.0

1.0

1.0

1.0

Sex, race, education

Swanson (1992)

M

1.0

0.7

1.5

0.9

Income, education

Swanson (1997)

F

1.0

1.0

1.0

0.9

0.8

1.0

0.9

0.7

0.8

0.6

Takezaki (2001)

M

1.0

1.2

1.0

1.0

— (AC)

1.0

1.1

1.1

1.0

— (AC)

Season and year of visit,

1.0

0.9

0.8

0.6

— (SCC)

1.0

1.3

0.7

0.8

— (SCC)

prior lung disease, green

F

1.0

0.7

0.8

0.7

— (AC)

1.0

0.7

0.9

0.8

— (AC)

vegetable and meat

intake

Wu-Williams (1990)

F

1.0

1.0

1.4

1.5

1.0

1.1

1.0

0.9

Education

Prospective studies

Breslow (2000)

M/F

1.0

1.2

0.8

0.9

1.0

1.0

1.3

0.9

Sex

Chow (1992)

M

1.0

0.8

0.8

0.7

1.0

1.1

1.1

1.2

Occupation

Feskanich (2000)

M/F

1.0

1.1

1.0

1.1

0.9

1.0

0.9

0.8

0.9

0.8

Energy intake

Fraser (1991)

M/F

1.0

0.3

0.3

1.0

1.4

1.1

Sex

Hirvonen (2001)

M

1.0

0.9

0.9

0.7

1.0

1.0

0.9

0.7

Group

Jansen (2001)

M

1.0

0.6

0.7

1.0

0.7

0.9

Country, energy and fruit/

vegetable intake

Knekt (1999)

M

1.0

0.9

0.6

1.0

0.9

0.8

Kromhout (1987)

M

1.0

1.1

1.0

Neuhouser (2003)

M/F

1.0

0.8

0.7

0.7

0.6

1.0

0.6

0.8

0.6

0.8

Sex, asbestos exposure,

ethnicity, enrollment center

Ocke (1997)

M

1.0

0.5

0.5

1.0

0.8

0.9

Energy intake

Shibata (1992)

M

1.0

1.1

1.0

1.0

1.1

1.0

F

1.0

0.8

0.7

1.0

0.7

0.6

Steinmetz (1983)

F

1.0

0.8

0.5

0.8

1.0

0.7

0.5

0.5

Voorips (2000)

M/F

1.0

0.7

0.6

0.6

0.8

1.0

1.1

1.0

1.0

0.7

Sex, family history, education

a1 = lowest consumption category. The exposure categories of low to high are for summary purposes only and do not correspond to identical categories across studies.

AC, adenocarcinoma; F, female; M, male; SCC, squamous cell carcinoma.

cases had circulating concentrations of retinol, ^-carotene, total carotenoids, vitamin E, and vitamin C that were 20% or more lower than those of noncases. However, the possibility that preclinical and clinically diagnosed lung cancer and concomitant changes in diet can lead to decreases in circulating micronutrient levels limits the inferences that may be drawn from studies based on blood samples taken after the diagnosis of lung cancer.

Data from prospective cohort studies are not subject to the previous limitation. In these studies, blood is collected from a population that is initially cancer-free and the population is then followed for the occurrence of lung cancer. The results of such

Table 2 Estimated relative risk of lung cancer according to intake of selected micronutrients®

First author (year)

Sex Retinol 1 2

Total carotenoids 1 2 3

Vitamin C 5 12 3

De Stefani (1999) Fontham (1988) Hinds (1984) Jain (1990) Le Marchand (1989) Mayne (1994)

Mettlin (1979) Mettlin (1989) Samet (1985) Ziegler (1986)

Chow (1992) Holick (2002) Knekt (1999) Kromhout (1987) Michaud (2000) Neuhouser (2003) Ocke (1997) Paganini-Hill (1987)

Rohan (2002) Shekelle (1981) Shibata (1992)

Speizer (1999) Steinmetz (1993) Voorrips (2000) Yong (1997)

Case-control studies

Alavanja (1993)

F

1.0

1.4

0.8

Bond (1987)

M

1.0

0.9

0.9

1.0

0.8

0.5

Byers (1984)

M

1.0

0.8

0.7

(SCC)

1.0

0.9

0.6

1.0

1.0

1.2

Byers (1987)

M

1.0

1.1

1.1

F

1.0

0.8

1.0

0.9

0.9

1.0

0.8

0.9

0.7

1.0

1.0

0.1

1.2

1.0

1.0

1.1

1.1

1.0

0.9

1.0

1.0

1.0

0.9

0.6

1.0

0.9

0.9

0.9

1.3

1.0

1.5

1.1

1.3

1.5

1.0

1.0

0.9

1.0

0.7

0.4

1.0

1.0

0.9

0.8

1.0

1.0

0.9

0.8

1.0

0.7

1.1

0.9

1.0

0.9

0.7

0.9

1.0

0.8

0.6

0.4

1.0

0.9

1.0

1.0

1.0

1.0

0.9

1.0

0.9

0.7

1.0

0.8

0.7

0.6

1.0

0.8

0.8

0.8

1.0

0.9

0.8

1.1

1.0

1.0

0.5

0.4

1.0

1.0

0.5

0.4

1.0

0.9

0.8

1.0

0.9

0.8

1.0

0.2

1.5

Prospective studies

1.0

0.8

1.0

1.0

0.9

0.9

1.0

1.1

0.8

1.0

0.5

0.7

1.0

1.1

1.0

1.0

0.9

0.9

1.0

0.7

0.7

1.0

1.3

0.7

1.0

0.3

0.7

1.0

1.8

1.0

1.0

0.8

1.0

1.0

0.9

1.0

1.2

0.9

1.0

0.4

0.4

1.0

1.0

1.0

1.0

1.0

1.4

1.0

0.9

1.1

1.0

0.7

0.6

1.0

1.1

0.8

1.0

1.0

0.8

0.7

0.8

1.0

0.8

0.9

1.0

1.0

0.8

0.4

1.0

0.9

1.1

1.0

0.8

0.6

1.0

1.2

1.0

1.0

1.1

a1 = lowest consumption category. The exposure categories of low to high are for summary purposes only and do not correspond to identical categories across studies. AD, adenocarcinoma; F, female; M, male: SCC, squamous cell carcinoma; SM, small cell carcinoma.

prospective studies bolster the evidence supporting the premise that in general, the higher the circulating concentrations of carotenoids (a-carotene, /3-caro-tene, /3-cryptoxanthin, lutein, lycopene, and total carotenoids), the lower the risk of lung cancer. Circulating concentrations of retinol, tocopherol, and selenium have not been associated with a reduced risk of lung cancer in most studies.

Studies of both dietary intake and prediagnostic blood concentrations favor a protective association between provitamin A carotenoids (specifically ^-carotene, a-carotene, and /3-cryptoxanthin) and lung cancer. It is not known, however, if a generally protective association is specific to these carotenoids or whether carotenoid intake merely serves as a marker of the intake of other protective substances or healthier dietary habits in general. The evidence for vitamin C is scant but suggestive of a protective association, whereas the data on vitamin A, vitamin E, and selenium have yielded null findings.

Phytochemicals Phytochemicals are low-molecular-weight molecules produced by plants. Of the many classes of phytochemicals, those studied in relation to lung cancer include phytoestrogens, flavonoids, and glucosinoids.

The tumor-promoting effects of steroid hormones can be blocked by phytoestrogens. Soybeans are a primary source of a specific class of phytoestrogens known as isoflavonoids. The relatively few studies on isoflavonoids in relation to lung cancer have not provided evidence of a link.

Flavonoids exhibit potent antioxidant activity. Flavonoid intake has been at least weakly associated with reduced risk of lung cancer in three out of four studies to date.

Isothiocyanates are metabolites of the class of phy-tochemcials known as glucosinolates. Isothiocyanates could exert anticancer effects by blocking carcinogens via induction of phase II detoxification enzymes, such as glutathione S-tranferase. Cruciferous vegetables contain high concentrations of glucosinolates, and hence consumption leads to higher endogenous iso-thiocyanate levels. As with cruciferous vegetables, lung cancer risk is also consistently lower with higher intakes or urinary levels of isothiocyanates.

A postulated link between isothiocyanates and a common polymorphism in the GSTM1 gene provides an example of a potential gene-diet interaction relevant to lung carcinogenesis. A growing focus in cancer epidemiology is to characterize interindividual susceptibility to cancer by studying polymorphisms in genes involved in DNA repair and in the metabolism and detoxification of potential carcinogens. Of further interest is how such genetic traits interact with environmental exposures to contribute to cancer risk. The role of glutathione S-transferase as a phase II detoxification enzyme has made a common polymorphism in the glutathione S-transferase M1 (GSTM1) gene of interest in relation to lung cancer. Results combined across studies show that compared to people with the GSTM1 present genotype, those with the GSTM1 null genotype had an increased risk of lung cancer.

When isothiocyanates have been studied in combination with GSTM1, the decreased risk of lung cancer associated with isothiocyanates has been especially pronounced in people with the GSTM1 null genotype. This association may represent either the cancer-blocking activity of isothiocyanates playing an enhanced role in GSTM1 null individuals or more efficient metabolism of isothiocyanates in those with the GSTM1 present genotype. Regardless, this is one example of the potential interactions between genetic and dietary factors, an approach that may eventually advance our understanding of the nutritional epidemiology of lung cancer.

Fat and cholesterol Evidence that dietary fat may facilitate tumor growth was reported as early as 1940. Correlation exists between international or regional dietary fat consumption and lung cancer mortality. In case-control studies, total fat intake is consistently associated with lung cancer risk among men and women, but saturated fat, unsaturated fat, and cholesterol intake tend to be associated with lung cancer risk only among men (Table 3). The prospective evidence shows a slightly different picture, with both total fat and saturated fat intake strongly associated with lung cancer in men but not women, and unsaturated fat and cholesterol not consistently associated with lung cancer risk in men or women (Table 3). The equivocal nature of the evidence is reflected in the lack of consistent findings between the sexes and the results of a large, pooled cohort study of both sexes that found lung cancer risk was not strongly associated with fat (total, saturated, or unsaturated) or cholesterol intake.

Regarding cholesterol, there is inconsistency between the dietary data presented previously and serologic data. A review of 33 prospective cohort studies indicated that lower circulating cholesterol levels were predictive of greater lung cancer risk. Similar results were obtained after accounting for the possible preclinical effects of cancer on cholesterol levels by limiting analyses to cases of lung cancer that were diagnosed 5 or more years after the initial cholesterol measurement. This association may be due to a direct effect of cigarette smoking on lipid profiles or to differences in dietary patterns between smokers and non-smokers. The lack of consistency between the serologic

Table 3 Estimated relative risk of lung cancer according to fat intake or cholesterol intake®

First author (Year)

Sex Total fat

Unsaturated fat

Saturated fat

Cholesterol

Goodman (1988) Hinds (1983)

Jain (1990) Swanson (1997)

Bandera (1997)

Heilbrun (1994) Knekt (1991)

Shekelle (1991) Smith-Warner (2002)

Case-control studies

Alavanja (1993)

F

1.0

1.4

1.4

2.2

Byers (1984)

M

1.0

0.9

1.1

1.0

0.8

0.8

1.0

1.2

1.0

Byers (1987)

M

1.0

1.6

1.8

2.0

F

1.0

1.9

1.0

1.4

De Stefani (1997)

M

1.0

1.2

1.4

1.0 1.3 1.7 (monounsaturated) 1.0 1.2 2.2 (polyunsaturated) 1.0 3.5 2.1 1.0 0.5 0.6

Prospective studies

1.0 1.2 1.4 — (monounsaturated) 1.0 1.1 1.0 — (polyunsaturated) 1.0 0.9 1.0 — (monounsaturated) 1.0 0.9 0.9 — (polyunsaturated)

1.0 0.9 1.1 — (monounsaturated) 1.0 0.6 0.9 — (polyunsaturated)

1.0 1.0 1.0 (monounsaturated) 1.0 1.0 1.0 (polyunsaturated)

Speizer (1999)

F

1.0 1.0

0.9

0.9

1.1

Wu (1994)

F

1.0 0.9

0.9

0.8

1.0 0.7

0.6

0.9

(animal)

1.0 0.6

0.7

0.7

— (plant)

1.0

1.3

1.7

1.4

1.0

1.5

1.1

0.9

1.0

1.4

1.3

2.3

1.0

2.3

1.8

2.2

1.0

0.6

1.5

0.9

1.0

1.3

1.4

2.0

1.0

1.2

1.4

2.3

1.0

1.7

1.3

1.2

1.0

0.9

1.0

1.6

1.0

1.2

0.9

1.0

1.2

1.0

1.1

1.1

_

_

1.0

0.8

1.0

a1 = lowest consumption category. The exposure categories of low to high are for summary purposes only and do not correspond to identical categories across studies. AD, adenocarcinoma; F, female; M, male; SCC, squamous cell carcinoma; SM, small cell carcinoma.

and dietary cholesterol data is not unreasonable given that dietary cholesterol intake is not strongly associated with serum cholesterol levels. The results of a trial of 846 men living at a veteran's home in Los Angeles showed that compared to men randomized to receive a conventional US diet, those randomized to receive a diet that reduced cholesterol intake by half and reduced serum cholesterol by 13% had a 20% increased risk of lung cancer after 8 years of dietary intervention and 2 additional years of follow-up.

Body mass index Prospective studies consistently show low body mass index (BMI) and relative weight to be associated with an increased risk of lung cancer (Table 4). This association is observed in some case-control studies, which rely on retrospective ascertainment of BMI, but not in others. Confounding by cigarette smoking should be considered as an explanation for these findings because cigarette smoking is strongly associated both with the risk of lung cancer and with leanness. The need to further test the hypothesis that leanness is a susceptibility factor for lung cancer is indicated by the results of studies in which this association is still observed even after potential confounding by cigarette smoking has been carefully addressed by stratifying by smoking status and by the number of cigarettes smoked per day for smokers.

Beverages Confounding by cigarette smoking is ubiquitous to the study of diet and lung cancer, but perhaps no topic better epitomizes the challenges of controlling confounding by smoking than does beverage consumption. Several beverages, including alcohol, coffee, tea, and milk, have been studied for a possible link to lung cancer. The majority of studies that have adjusted for age and cigarette smoking have observed either null or weak associations between alcohol drinking and the risk of lung cancer (Table 5).

Three prospective cohort studies have shown heavy coffee consumption to be associated with an elevated risk of lung cancer after adjustment for cigarette smoking, whereas seven case-control studies have yielded findings that tend to fluctuate around the null (Table 6). The issue of confounding between coffee

Table 4 Relative risk of lung cancer according to body mass index3

First author (year) Sex Average Body mass index Subgroup Adjusted for follow-up -

Table 4 Relative risk of lung cancer according to body mass index3

First author (year) Sex Average Body mass index Subgroup Adjusted for follow-up -

(years)

1

2

3

4

5 6

7

Chyou (1994)

M

25

1.0

0.9

0.9

0.7

——

Age, smoking

Drinkard (1995)

F

6

1.0

0.5

0.5

0.5

——

— Total

Age, smoking, physical activity

1.0

0.6

0.7

——

— Never smokers

1.0

1.2

0.6

——

— Former smokers

1.0

0.8

1.0

——

— Current smokers

Henley (2002)

M F

14

0.9 1.2

1.0 1.0

— Nonsmokers

Age, race, former smoker, marital status, education, asbestos exposure, socioeconomic status, intake of alcohol, fat, fruits, and vegetables

Kark (1995)

M

23

2.3

1.3

1.1

1.1

1.0 —

— Total

Age, smoking, area of residence

3.7

2.1

1.7

2.0

1.0 —

— Smokers

Knekt (1991)

M

15

1.8

1.5

1.4

1.0

——

— Total

Age, smoking, social class, health status, stress

Lee (1992)

M

22/26

1.8

1.5

1.0

11-15 years

Age, cigarettes per day, physical activity

1.0

1.1

1.0

>15 years

Olson (2002)

F

12

1.0

0.9

0.7

0.5

0.4 —

— Total

Age, pack years smoking, smoking status, physical activity, education, beer

consumption, height, BMI at age 18, waist circumference consumption, height, BMI at age 18, waist circumference a1 = lowest BMI. The exposure categories of low to high are for summary purposes only and do not correspond to identical categories across studies.

Table 5 Estimated relative risk of lung cancer according to alcohol intake®

First author (year)

Sex Total alcohol

Beer

Wine

Hard liquor

Mettlin (1989) Wu-Williams (1990) Bandera (1992) De Stefani (1993) Mayne (1994) Carpenter (1998) Korte (2002) Dosemeci (1997) Swanson (1997) Murata (1996) Zang (2001)

Pollack (1984) Chow (1992) Potter (1992) Kvale (1983) Gordon (1984)

Kono (1986/87) Stemmermann (1990) Breslow (2000)

1.0

0.5

0.9

1.1

1.0

0.6

1.3

1.1

1.0

1.6

1.7

1.7

1.0

0.6

1.1

1.0

1.0

1.0

2.4

1.8

1.0

1.1

1.2

1.1

1.0

0.7

1.3

1.0 — 1.3 — -1.0 (continuous variable) 0.7 (continuous variable)

Bandera (1997)

M

1.0

0.8

1.1

F

1.0

1.2

1.0

Prescott (1999)

M

1.0

0.8

1.0

F

1.0

0.9

1.0

Woodson (1999)

M

1.0

1.0

1.0

Hirvonen (2001)

M

Djousse (2002)

M/F

1.0

1.2

1.1

Korte (2002)

M/F

1.0

1.0

0.9

CPS I and II, from Korte (2002)

M/F

1.0

1.0

1.0

Omenn (1996)

1.2

2.0

Case-control studies

— 1.0 0.5 0.8 0.9 — — 1.0 0.7 0.6 0.6 — —

1.0 1.3 1.0 1.3 — — 1.0 — — — 1.6 — 1.0 1.4 1.6 2.2 — —

— 0.7 — 1.0 — — — 1.1 1.5 — — 1.0 0.9 1.3 1.1 —

1.0 1.1 0.9 1.2— — — — — — — — — — — — — —

1.0 0.4 0.9 — — — 1.0 0.7 0.8 — — — 1.0 1.2 1.9 — — —

Prospective studies

a1 = lowest consumption category. The exposure categories of low to high are for summary purposes only and do not correspond to identical categories across studies. F, female; M, male.

Table 6 Estimated relative risk of lung cancer according to frequency of tea, coffee, or milk consumption®

First author (year)

Coffee

Milk

Case-control studies

M/F ______ — — — — — — 1.0 0.9 1.1 2.1 — —

M smokers 1.0 0.7 0.7 0.9 0.5 0.3 1.0 1.1 1.3 0.8 1.2 1.2 — — — — — —

F nonsmokers — — — — — — — — — — — — 1.0 1.0 0.7 — — —

F 1.0 1.0 — — — —(black) 1.0 0.6 — — — — 1.0 0.8 — — — —

F nonsmokers 1.0 0.8 0.6 0.5 — —(green) — — — — — — — — — — — —

F smokers 1.0 1.4 0.6 — — —(green) — — — — — — — — — — — —

M/F 1.0 1.0 1.4 1.6 — — 1.0 1.0 1.2 1.3 — — 1.0 1.6 1.8 — — —(whole)

— — — — — — — — — — — — 1.0 0.8 — — — —(2%)

— — — — — — — — — — — — 1.0 0.6 0.7 — — —(skim)

M, AC 1.0 1.1 1.1 1.3 — — 1.0 0.9 1.2 — — — 1.0 1.0 0.9 0.8 — —

F, AC 1.0 1.0 1.1 1.1 — — 1.0 0.8 0.8 1.3 — — 1.0 0.8 1.0 0.7 — —

M, SCC 1.0 1.0 1.2 1.1 — — 1.0 1.0 1.2 1.6 — — 1.0 0.9 0.8 0.7 — —

— — — — — — — — — — — — 1.0 1.3 0.8 0.8 — —(skim) M/F 1.0 0.9 0.9 1.1 — — 1.0 1.0 0.9 1.3 — — 1.0 1.6 1.6 2.1 — —(whole)

— — — — — — — — — — — — 1.0 0.5 0.7 0.5 — —(2%)

— — — — — — — — — — — — 1.0 0.8 0.5 0.7 — —(skim) M 1.0 0.9 1.2 0.7 — — 1.0 0.9 1.2 1.6 — — 1.0 0.9 1.4 1.7 — —

Prospective studies

— — — — — — — — — — — — 1.0 0.9 0.5 — — —(2%)

— — — — — — — — — — — — 1.0 1.0 0.6 — — —(skim) M smokers 1.0 0.7 — — — — ____________

Brennan (2000) Darby (2001) Mendilaharsu (1998) Kreuzer (2002) Kubik (2002)

Swanson (1997) Takezaki (2001)

Tewes (1990) Yoshiyuki (1995) Mayne (1994) Mettlin (1989)

Axelsson (1996)

Goldbohm (1996) Zheng (1996) Breslow (2000)

Hirvonen (2001) Fraser (1991)

a1 = lowest consumption category. The exposure categories of low to high are for summary purposes only and do not correspond to identical categories across studies. AC, adenocarcinoma; F, female; M, male; SCC, squamous cell carcinoma.

drinking and other health behaviors, particularly cigarette smoking, has not been addressed adequately, indicating that much stronger evidence is needed for coffee drinking to be considered a risk factor for lung cancer. Despite numerous in vitro and in vivo studies that have observed potential tumor-inhibitory effects of tea, the epidemiologic evidence does not provide support for a link between tea drinking and the risk of lung cancer (Table 6).

The associations observed between milk drinking and lung cancer depend on milk fat content. Milk drinking is not strongly associated with lung cancer risk when milk fat content is ignored. The associations between whole milk and lung cancer tend to be either null or in the direction of increased risk, whereas the associations for reduced fat or nonfat milk tend to be either null or in the protective direction (Table 6). Perhaps milk consumption, including the type of milk, is merely serving as a marker of fat intake.

Meat and fish Associations have been observed between red meat intake and increased lung cancer risk, but this evidence is counterbalanced by an equal number of null studies. The cooking method may play a role because heterocyclic amines from cooked meat may contribute to an increased lung cancer risk. The evidence does not support a strong link between fish consumption and lung cancer.

Diet and Prevention

Chemoprevention trials Three randomized, doubleblind, placebo-controlled trials were undertaken in the 1980s and 1990s to test whether ^-carotene supplementation protects against lung cancer. All three studies indicated that ^-carotene supplementation in later adulthood does not protect against lung cancer (Table 7). To the contrary, ^-carotene supplementation was associated with an increased risk of lung cancer among the high-risk populations of heavy smokers in the ATBC Cancer Prevention Study and smokers and asbestos-exposed workers in the CARET Study. No beneficial effect was observed for a-tocopherol supplementation in the ATBC Cancer Prevention Study.

These experimental results fail to corroborate the evidence from observational studies that favors a protective association between ^-carotene and lung cancer. In fact, it is possible that ^-carotene may exhibit prooxidant properties. Consistent with the results of observational studies, a protective association was noted when the data from the placebo controls in the ATBC Cancer Prevention Study were analyzed according to baseline serum and dietary ^-carotene.

In interpreting the results of the ATBC and CARET studies, it is important to recognize that the studies enrolled older, high-risk individuals who had high cumulative exposure to tobacco smoke and/or asbestos. The results therefore presumably apply mainly to the latter stages of carcinogenesis. The doses administered were far higher than the normal dietary range, and the dose-response relationship for preventive effects, anticipated from the observational evidence, may not be applicable. Because antioxidant nutrients may exert their protective effect in the earlier stages of carcinogenesis, ^-carotene may have been administered too late to halt the evolution of cellular changes that lead to lung cancer. Alternatively, compounds present in fruits and vegetables other than the micro-nutrients studied in the trials may protect against lung cancer. The protective associations for fruit and vegetable consumption were allied to the micronutrient

Table 7 Summary of randomized chemoprevention trials of micronutrients and lung cancer

Study (year)

Location N

Number of Study cases population

Years of Regimen follow-up

Relative risk

Incidence Mortality

ATBC Finland 29 133 876 (1994)

CARET United 18 314 388 (1996) States

PHS United 22 071 170 (1996) States

Male smokers, age 50-69 years

Asbestos-exposed smokers and heavy smokers Males and females, age 45-69 years Male physicians, age 40-84 years

6 (median)

4 (average)

12 (average)

1. Placebo

1. Placebo

1. Placebo

2. BC (50 mg on alternate days)

1.28

0.93

1.17 (all causes)

Not reported

hypothesis, but the results of the chemoprevention trials raise questions about the potential payoff from large trials designed to test single micronutrients, unless there is a strong mechanistic basis or substantial observational evidence pointing to an individual micronutrient as the primary protective agent. Indeed, fruits and vegetables contain an abundance of antioxidants and phytochemicals with diverse anticarcino-genic activities. However, perhaps fruit and vegetable intake is acting as a marker of a healthier lifestyle that is associated with a low risk of cancer.

Fat Burning 101

Fat Burning 101

Easily Burn Fat and Feel Great. Every single state in America has reported an increase in obesity levels for 2009? Not a single state has recorded an obesity rate of less than 20%, and the states are not expecting those levels to go down anytime soon.

Get My Free Ebook


Post a comment