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Cancer of the lung Explained – the most common type of cancer worldwide (excluding non-melanoma skin cancer)

Cancer of the lung Explained – the most common type of cancer worldwide (excluding non-melanoma skin cancer)

Lung

Cancer of the lung is the most common type of cancer worldwide (excluding non-melanoma skin cancer). Around

DECREASES RISK INCREASES RISK
 

Convincing

Arsenic in drinking water1

Beta-carotene supplements2

Probable Fruits3

Foods containing carotenoids4

 

1.4 million cases were recorded in 2002, accounting for over 12 per cent of all cancers. Three-quarters of all cases occur in men. The disease is most common in high-income countries and is increasing in some low-income countries such as China. It is almost always fatal, and is the chief cause of death from cancer: nearly 18 per cent of all deaths from cancer are from this type.

Overall, the Panel emphasises that the principal cause of lung cancer is smoking tobacco.

 

The Panel judges as follows:

Limited — suggestive Non-starchy vegetables3

Foods containing selenium4

Foods containing quercetin4

Selenium5 Physical activity6

Red meat7 Processed meat8 Total fat

Butter

Retinol supplements2 Low body fatness

Limited —

no conclusion

Cereals (grains) and their products; starchy tubers; dietary fibre; pulses (legumes); poultry; fish; eggs; milk and dairy products; total fat; animal fats; plant oils; soft drinks; coffee; tea; alcohol; preservation, processing, and preparation; carbohydrate; protein vitamin A; thiamin; riboflavin; niacin; vitamin B6; folate; vitamin C; vitamin E; multivitamins; calcium; copper; iron; zinc; pro-vitamin A carotenoids; lycopene; flavonoids; culturally-defined diets;

body size, shape, and composition (except low body fatness); energy intake

 

The evidence that arsenic in drinking water and (in smokers only) pharmacological doses of beta-carotene are a cause of this cancer is convincing.

Fruits, and also foods containing carotenoids, probably protect against lung cancer.

There is limited evidence suggesting that non-starchy vegetables, selenium and foods containing it, foods containing quercetin, and physical activity protect against lung cancer.

There is also limited evidence suggesting that red meat, processed meat, total fat, butter, pharmacological doses of retinol (smokers only), and low body fatness are causes of lung cancer.

In final summary, the strongest evidence, corresponding to judgements of “convincing” and “probable”, shows that arsenic in drinking water and pharmacological doses of beta-carotene (smokers only) are causes of lung cancer; and that fruits and foods containing carotenoids probably protect against this cancer.

 

 

The lungs are part of the aerodigestive system. They contain hundreds of lobules, and each lobule contains a bronchiole, its branches, and clusters of alveoli. This is where carbon dioxide (a product of respiration) is removed from the blood and replaced with oxygen, to fuel further respiration, pro- ducing energy.

About 90–95 per cent of lung cancers are either small-cell carcinoma or non-small-cell carcinoma. The latter has three major subtypes: squamous cell carcinoma, adenocarcinoma, and large-cell carcinoma.4 Squamous cell carcinomas account for 30–35 per cent, adenocarcinomas 30–45 per cent, and large-cell carcinomas about 9 per cent of all lung cancers. Small cell lung cancer (SCLC) accounts for 10–15 per cent of all lung cancers; this form is considered a distinct clinical pathological entity due to its characteristic aggressive biol- ogy, diffuse nature, propensity for early metastasis, and over- all poor prognosis. Mesothelioma, which affects the pleura (layer of cells covering the lung and chest cavity), is almost always caused by previous exposure to asbestos.

 

7.4.1     Trends, incidence, and survival

 

Smoking and other exposure to tobacco smoke are the prin- cipal causes of lung cancer. The trend and incidence patterns are explained largely by these exposures. Age-adjusted rates of lung cancer are decreasing in many high-income countries due to decreased smoking. Global and regional trends in inci- dence have mirrored the prevalence of smoking, with a time lag of around 35 years.63 Lung cancer was rare until the end of the 19th century, with only 140 cases reported in the world  literature  before  1898,  and  only  374  by  1912.63 Incidence peaked in most high-income countries in the sec- ond half of the 20th century, and later for women than men. The relative incidence of the various types of lung cancer  is gradually changing. Between 1980 and 2000, the pro- portion of squamous cancers decreased as the proportion of adenocarcinomas  increased,  possibly  due  to  changes  in smoking habits or products.64  Adenocarcinoma is now the most frequently diagnosed type in the USA and Japan; while it is also showing signs of increasing in Europe, squamous

cell carcinoma continues to be the predominant type.

Lung cancer is mainly a disease of high-income countries, where the smoking epidemic began earlier, and overall rates are nearly double those in middle- to low-income countries. Around the world, age-adjusted incidence ranges from more than 60 per 100 000 people in North America and across much of Europe, to less than 5 per 100 000 in much of mid- dle Africa. Within Europe, rates are highest in eastern European countries. In the USA, rates are higher among African-American people than in white people. Worldwide, rates are higher in men than in women, by around three to one. The incidence of lung cancer increases with age. Rates will continue to rise in middle- and low-income countries as tobacco smoking increases.

The early stages of lung cancer do not usually produce symp- toms, so the disease is generally at an advanced stage when it is diagnosed. Survival rates are poor, around 10 per cent at 5 years, and are usually higher in women than men.3 6 SCLC has a worse prognosis than non-SCLC (a survival rate of only around 5 per cent at 5 years), because SCLC has a tenden- cy to metastasise (spread) early, and surgery is not usually successful.4 65  Lung cancer accounts for somewhat over 12 per cent of all cancer incidence, but for nearly 18 per cent of all cancer deaths.

 

 

7.4.2     Pathogenesis

 

Carcinogens in tobacco smoke, or other inhaled particles such as coal tar or asbestos, can interact directly with the DNA of lung cells. Because the whole lung is exposed to inhaled carcinogens, several sites may accumulate different cancerous changes, leading to multiple cancers originating in different types of cell.4

Inflammation may also play a role in the development of lung cancer, with cancerous changes occurring as a response to chronic exposure to irritants and repeated injury. Columnar epithelial cells are replaced with stratified squa- mous epithelial cells, which may also increase cancer risk.

The division of these new cells increases, and this eventual- ly is followed by dysplasia of the lung mucosa. When this process involves the full thickness of the mucosa, these dys- plastic lesions become carcinoma in situ. Further invasion to the depth of the basement membrane, and the subsequent infiltration of the underlying stroma by malignant cells, sig- nals invasive cancer. This process may take 10–20 years.4

People with adenocarcinomas may have an associated his- tory of chronic lung disease, such as scleroderma, rheuma- toid disease, sarcoidosis, or tuberculosis.4

 

 

7.4.3     Other established causes

 

 

Tobacco use. Smoking is the principal cause of lung cancer; it is estimated to be responsible for 85 per cent of all types of this cancer.66 In populations with a history of long-term cigarette use, the proportion has reached 90 per cent.10 Involuntary exposure to tobacco smoke (‘passive smoking’) is also a cause of lung cancer, including in people who have never smoked.10

 

Industrial chemicals. Carcinogens that are causes of lung can- cer include aluminium; arsenic; asbestos (both lung cancer and mesothelioma); chloromethyl methyl ether and/or bis- chloromethyl ether; coal-tar fumes; erionite (mesothe- lioma); pollutants from iron and steel founding; untreated mineral oils; mustard gas; soot; talc containing asbestiform tremolite; and vinyl chloride.67

 

 

7.4.4      Interpretation of the evidence

 

  • General

 

‘Relative risk’ is used in this Report to denote ratio mea- sures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard ratios’, and ‘odds ratios’.

 

  • Specific

Considerations specific to cancer of the lung include:

 

Measurement. Due to low survival rates, both incidence and mortality can be assessed. Low survival times and rates decrease the reliability of case-control studies, which often rely on proxy reporting.

 

Confounding. Smoking tobacco is the predominant cause of lung cancer, and smokers tend also to have less healthy diets, more sedentary ways of life, and to be leaner than non-smok- ers. Therefore a central task in assessing the results of dietary studies is to evaluate the degree to which observed associations in smokers may be due to confounding/residual confounding by cigarette smoking; that is, not a direct result of the dietary exposure examined. A high proportion of the studies assessed below are appropriately adjusted for smoking.

 

7.4.5     Evidence and judgements

 

 

 

  • Non-starchy vegetables

 

A total of 17 cohort studies, 27 case-control studies, and 6 ecological studies investigated total vegetables. Other group- ings examined were non-starchy vegetables specifically (3 cohort, 1 case-control); green, leafy vegetables, excluding cruciferous (5 cohort, 17 case-control); non-starchy root veg- etables and tubers (2 cohort); and carrots (6 cohort, 21 case- control, 1 ecological). Most studies showed decreased risk with increased intake. Data are particularly consistent when stratified for carrots. A pooled analysis of 8 cohort studies (more than 430 000 participants, followed up for 6–16 years, with more than 3200 lung cancer cases) showed a non-sig- nificant decreased risk for the groups that ate the most veg- etables. There was considerable heterogeneity, not all readily explained.

This is a wide and disparate category, and many different plant food constituents are represented that could contribute to a protective effect of non-starchy vegetables. These include dietary fibre, carotenoids, folate, selenium, glucosinolates, dithiolthiones, indoles, coumarins, ascorbate, chlorophyll, flavonoids, allylsulphides, flavonoids, and phytoestrogens, some of which are potentially antioxidants. Antioxidants trap free radicals and reactive oxygen molecules, protecting against oxidation damage. It is difficult to unravel the rela- tive importance of each constituent and it is likely that any protective effect may result from a combination of influences on several pathways involved in carcinogenesis.

 

A substantial amount of evidence is available but some studies were not adjusted for smoking. A dose response is apparent from both cohort and case- control studies. There is limited evidence suggesting that non-starchy vegetables protect against lung cancer.

 

  • Fruits

 

Twenty-five cohort studies, 32 case-control studies, and 7 ecological studies investigated fruit consumption. Most of these showed decreased risk with increased intake. Meta- analysis of cohort data showed a 6 per cent decreased risk per 80 g serving/day; meta-analysis of case-control data showed a 20 per cent decreased risk per serving/day (figure 4.2.25). A pooled analysis of 8 cohort studies (more than 430 000 participants, followed up for 6–16 years, with more than 3200 lung cancer cases) showed a 23 per cent decreased risk for the groups that ate the most fruit. There is considerable heterogeneity, perhaps explained by the broad and disparate nature of this category.

Fruits are sources of vitamin C and other antioxidants, such as carotenoids, phenols, and flavonoids, as well as other potentially bioactive phytochemicals. Antioxidants trap free radicals and reactive oxygen molecules, protecting against oxidation damage. In addition, flavonoids found in fruit directly inhibit the expression of a cytochrome P450 enzyme. This helps to metabolise toxins and has been asso- ciated with increased risk of lung cancer, primarily in smok- ers.68 It is difficult to unravel the relative importance of each constituent, and it is likely that any protective effect may result from a combination of influences on several pathways involved in carcinogenesis.

 

The evidence is ample and consistent. A dose-response relationship is apparent from both cohort and case- control studies and there is evidence for plausible mechanisms operating in humans. The evidence that fruits protect against lung cancer is convincing.

 

3.8.

 

  • Foods containing carotenoids

 

A total of 11 cohort studies, 16 case-control studies, and 1 ecological study investigated total dietary carotenoids; 4 cohort studies and 5 case-control studies investigated serum or plasma carotenoids. Other groupings examined were dietary beta-cryptoxanthin (7 cohort, 8 case-control, 1 eco- logical), and serum/plasma beta-cryptoxanthin (6 cohort, 1 case-control). Nearly all cohort studies and most case-con- trol studies showed decreased risk with increased intake. Meta-analysis of cohort data showed a 2 per cent decreased risk per 1 mg dietary carotenoid intake per day, or per 10 µg beta-cryptoxanthin intake per day (figure 4.2.28). A pooled analysis of 7 cohort studies (almost 400 000 partic- ipants, followed up for 7–16 years, with more than 3100 lung cancer cases) showed a 24 per cent decreased risk for the groups that consumed the most beta-cryptoxanthin. Several case-control studies did not adjust for smoking. Data come predominantly from dietary sources, not supplements; therefore no effect can be attributed to carotenoids separate from foods.

Carotenoids are antioxidants, which can prevent lipid oxi- dation and related oxidative stress. Some, such as beta- carotene, are also pro-vitamin A carotenoids.

 

There is a substantial amount of evidence available from both cohort and case-control studies. A clear dose-response relationship is apparent from cohort studies. Foods containing carotenoids probably protect against lung cancer.

 

  • Foods containing selenium

 

Two cohort studies, 2 case-control studies, and 2 ecological studies investigated dietary selenium; 10 cohort studies, 7 case-control studies, and 4 ecological studies investigated

 

plasma or serum selenium; and 3 cohort studies investigat- ed selenium levels in nails. Most studies showed decreased risk with increased intake. Meta-analysis of cohort data on plasma or serum selenium produced evidence of decreased risk with a clear dose-response relationship.

Dietary selenium deficiency has been shown to cause a lack of selenoprotein expression. Twenty-five selenoproteins have been identified in animals and a number of these have important anti-inflammatory and antioxidant properties. Four are glutathione peroxidases, which protect against oxidative damage to biomolecules such as lipids, lipopro- teins, and DNA. Three are thioredoxin reductases and, among other functions, these regenerate oxidised ascorbic acid to its active antioxidant form.

 

The evidence available is sparse. There is limited evidence to suggest that foods containing selenium protect against lung cancer.

 

  • Foods containing quercetin

 

Two cohort studies and three case-control studies investi- gated quercetin intake. Both cohort studies showed statisti- cally significant decreased risk for the highest intake groups. Data from case-control studies were more heterogeneous.

Quercetin is a flavonoid which directly inhibits expression of a cytochrome P450 enzyme that helps to metabolise tox- ins, resulting in decreased DNA damage in laboratory exper- iments.70

 

The evidence available is sparse and inconsistent. There is limited evidence suggesting that foods containing quercetin protect against lung cancer.

 

  • Red meat

 

One cohort study and nine case-control studies investigated red meat. The single cohort study and most of the case-con- trol studies showed increased risk with increased intake.

 

 

There is limited evidence, mostly from inconsistent case-control studies, suggesting that red meat is a cause of lung cancer.

 

  • Processed meat

 

Four cohort studies and 10 case-control studies investigated processed meat, most of which showed increased risk with increased intake.

N-nitroso compounds are suspected mutagens and car- cinogens that are found in processed meats, and produced in the stomach from nitrates, including those used to pre- serve meats.55 Many processed meats also contain high lev- els of salt and nitrite. When cooked at high temperatures, meats can also contain heterocyclic amines

and polycyclic aromatic hydrocarbons . Haem promotes the formation of N-nitroso compounds and also contains iron. Free iron can lead to production of free radi- cals.

 

There is limited, inconsistent evidence suggesting that processed meat is a cause of lung cancer.

 

  • Total fat

 

Nine cohort studies, 17 case-control studies, and 4 ecologi- cal studies investigated total fat intake. Most studies showed increased risk with increased intake, although cohort data were less suggestive of an effect, and few studies were sta- tistically significant. No evidence for plausible mechanisms was found.

 

The mixed results from cohort studies contrast with the more consistent results from other studies. Overall, there is limited evidence suggesting that consumption of total fat is a cause of lung cancer. The Panel emphasises that the principle cause of lung cancer is smoking tobacco.

 

  • Butter

 

Two cohort studies and eight case-control studies investi- gated butter consumption. Most studies showed increased risk with increased intake, but cohort data were inconsistent. No evidence for plausible mechanisms was found.

 

There is a limited amount of inconsistent evidence suggesting that consumption of butter is a cause of lung cancer.

 

  • Arsenic in drinking water

 

Two cohort studies, 2 case-control studies, and 12 ecologi- cal studies investigated arsenic in drinking water. All cohort and case-control studies, and most ecological studies, showed a relationship between increased levels of arsenic in drinking water and increased incidence. Meta-analysis was not possible, but effect estimates tended to be large (an increased risk of over 300 per cent for the highest levels).

Soluble arsenic in drinking water induces lung cancers in animal models.71 In humans, arsenic is a chromosomal muta- gen (an agent that induces mutations involving more than one gene, typically large deletions or rearrangements). It can also act as a synergistic co-mutagen. Arsenic exposure also causes chronic lung disease.71 The Joint FAO/WHO Expert Committee on Food Additives has set a provisional tolerable weekly intake of 0.015 mg/kg of body weight.72

 

The evidence is ample and consistent, from cohort and case-control as well as ecological studies. There is a dose-response relationship, and the effect size is relatively large. There is robust evidence for mechanisms. The evidence that arsenic in drinking water is a cause of lung cancer is convincing.

 

  • Retinol supplements (in smokers)

 

Two trials (one randomised controlled, one non-randomised), two cohort studies, and two case-control studies investigat- ed retinol or retinol supplements. The single randomised con- trolled trial, performed in current and former smokers only, showed a statistically significant increased risk with a high- dose supplement. There was a suggestion of further elevat- ed incidence in heavy smokers and asbestos workers. The non-randomised trial was inconclusive. One cohort, also strat- ified by smoking status, showed a relationship with increased incidence only in current smokers. All other studies failed to stratify by smoking status and were inconclusive.

It is possible that some protective effect present at dietary intake amounts of vitamins is lost or reversed by the higher levels supplied by pharmacologic supplementation.

 

The evidence is sparse and inconsistent. There is limited evidence suggesting that high-dose vitamin A supplements are a cause of lung cancer in current smokers.

 

  • Beta-carotene supplements (in smokers)

 

Four randomised controlled trials and two cohort studies investigated beta-carotene supplements. Of these, one ran- domised controlled trial was performed in smokers. This study showed a statistically significant increased risk of 17 per cent with a daily 20 mg beta-carotene supplement. It also suggested that heavy smoking elevated the risk further. Other trials and studies, either in non-smokers or not strat- ified according to smoking status, were inconclusive.

There is a marked interaction between beta-carotene, heavy smoking, and glutathione S-transferase (GST) geno- type. GST is a carcinogen-detoxifying enzyme. Beta-carotene supplementation among people without GSTM1 (one of the variants of the GST gene) who smoked more than 42 cigarettes per day was compared to beta- carotene supplementation among those without GSTM1 who smoked less than 37 cigarettes per day. A relative risk of 6.01 (95% confidence interval 1.90–19.08) was observed.

It is possible that a protective association present at dietary intake amounts of carotenoids is lost or reversed by the high- er levels that pharmacological supplementation may supply. In one animal study, low-dose beta-carotene was protective against smoking-induced changes in the tumour-suppressor p53 gene, while high doses promoted these changes.73 A second explanation could relate to disturbance of the complex nature of naturally occurring carotenoids. It is possible that the protective associations are not due to the specific agent used in supplement studies, but rather to other carotenoids present in dietary exposure,74 or other associat- ed dietary or health-related behaviour.

 

There is strong evidence from good-quality trials, consistent with cohort studies. An interaction between smoking, genotype, and beta-carotene is apparent. The evidence that beta-carotene supplements cause lung cancer in current smokers is convincing.

  • Selenium supplements

 

One randomised controlled trial investigated selenium sup- plements and lung cancer.

The single trial of more than 1300 participants given 200 µg/day of selenium for 13 years showed a non-signifi- cant decreased risk with supplementation, adjusted for age and smoking. Subgroup analysis indicated that this risk dif- fered according to baseline plasma selenium level, with a sta- tistically significant decreased risk for those with the lowest initial plasma selenium. This is suggestive that selenium sup- plementation may decrease cancer risk in those who have poor selenium status, but that this effect may not extend to those who do not.

Dietary selenium deficiency has been shown to cause a lack of selenoprotein expression. Twenty-five selenoproteins have been identified in animals and a number of these have important anti-inflammatory and antioxidant properties. Four are glutathione peroxidases, which protect against oxidative damage to biomolecules such as lipids, lipopro- teins, and DNA. Three are thioredoxin reductases and, among other functions, these regenerate oxidised ascorbic acid to its active antioxidant form.

 

The evidence is sparse. There is limited evidence suggesting that selenium protects against lung cancer.

 

  • Physical activity

 

In total, 5 cohort studies investigated total physical activi- ty; 2 cohort studies investigated non-recreational activity; 4 cohort studies and 2 case-control studies investigated occu- pational activity; and 11 cohort studies and 4 case-control studies investigated recreational activity. Overall, most studies showed decreased risk with increased physical activ- ity. No studies showed a statistically significant increased risk. Of the categories analysed, consistent protective rela- tionships were reported for total physical activity, non-recre- ational activity, and recreational activity. Increased heterogeneity in occupational physical activity may be due to either the extreme variation in exposure definition, or the generally lower levels of occupational activity, meaning that, as a percentage of daily activity, occupational activity is of reduced importance in many high-income countries (where these studies were generally performed).

Sustained, moderate physical activity raises metabolic rate and increases maximal oxygen uptake. In the long term, regular periods of such activity increase the body’s metabolic efficiency and capacity (the amount of work that it can perform), as well as reducing blood pressure and insulin resistance.

 

There is evidence from prospective and case-control studies showing lower risk of lung cancer with higher levels of physical activity, but there is no evidence of plausible mechanisms. The relationship between activity, BMI, and lung cancer makes the evidence difficult to interpret. There is limited evidence suggesting that physical activity protects against lung cancer.

 

 

 

  • Body fatness

 

Twenty-one cohort studies, 24 case-control studies, and 1 ecological study investigated body fatness, as measured by BMI. Nearly all of the cohort and case-control studies showed decreased risk with increased BMI. Meta-analysis of cohort and case-control data provided evidence of a statistically sig- nificant reduced risk, with no heterogeneity in cohort data. Smoking is the principal cause of lung cancer and may also be associated with lower BMI. There is a high potential for confounding due to tobacco smoking, and residual con- founding is therefore possible. In addition, it is possible that people with undiagnosed lung cancer may lose weight, so

giving a spurious association (reverse causation).

There is no known mechanism through which greater body fatness could plausibly protect against lung cancer, or through which low body fatness could increase risk.

 

Although the epidemiological evidence suggests an inverse relationship, this could be caused by confounding by cigarette smoking or reverse causation due to weight loss from undiagnosed cancer. There is limited evidence suggesting that low body fatness is a cause of lung cancer.

 

  • Other exposures

Other exposures were evaluated. However, the data were either of too low quality, too inconsistent, or the number of studies too few to allow conclusions to be reached. These were as follows: cereals (grains) or their products; starchy tubers; pulses (legumes); meat; poultry; fish; eggs; animal fats; milk and dairy products; soft drinks; coffee; tea; alco- hol; processing, preservation, and preparation; carbohydrate; dietary fibre; total fat; protein; vitamin A; retinol; pro-vita- min A carotenoids; lycopene; thiamin; riboflavin; niacin; vit- amin B6; folate; vitamin C; vitamin E; multivitamins; iron; zinc; copper; calcium; selenium; flavonoids; energy intake; plant oils; body size, shape, and composition (except low body fatness); and culturally defined diets.

 

 

7.4.6     Comparison with previous report

 

  • General

 

 

  • Specific

The previous report judged the evidence that vegetables and fruits protect against lung cancer to be convincing. Evidence, particularly from cohort studies published since the mid- 1990s, is more consistent for fruits than for vegetables.

The findings of the previous report for carotenoids, and for pharmaceutical doses of beta-carotene given to smokers, were identical to the current findings (for foods containing carotenoids), although the previous report did not include a

 

matrix entry for beta-carotene supplements. The previous report did not review arsenic.

 

 

7.4.7    Conclusions

 

The Panel concludes:

The evidence that arsenic in drinking water and (in smok- ers only) pharmacological doses of beta-carotene are caus- es of lung cancer is convincing.

Fruits, and also foods containing carotenoids, probably protect against lung cancer.

There is limited evidence suggesting that non-starchy veg- etables, selenium and foods containing it, foods containing quercetin, and physical activity protect against lung cancer. There is also limited evidence suggesting that red meat, processed meat, total fat, butter, pharmacological doses of retinol (in smokers only), and low body fatness are causes

of lung cancer.

Smoking tobacco is the main cause of lung cancer.

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