Every year an estimated 11 million people are diagnosed with cancer (excluding skin cancers) and nearly 7 million people are recorded as dying from cancer. Projections for 2030 predict that these figures will double. Cancer is increasing at rates faster than the increase in global population. It is becoming more common in high-income but also — and most of all — in middle- and low-income countries, absolutely and also relative to other diseases.
The scientific community is convinced that inherited high susceptibility to cancer accounts for only a small proportion of cases. Although we are all more or less susceptible to various diseases, most adult cancers are caused mainly by environmental factors. This means that most cancers are at least in theory preventable.
One important cause of cancer is smoking, or other exposure to, tobacco. Infection, infestation, solar radiation, and other factors are also important. Food and nutrition, physical activity, body composition, and other associated factors are also individually and collectively important modifiers of cancer risk. But there is a difference. Smoking and exposure to tobacco, and these other factors, are all causes of cancer. By contrast, this and the previous chapters show that food and nutrition, and physical activity can protect against cancer. When we are able to do so, we can choose ways of life that protect both ourselves and the next generation against cancer. So our nutritional state — what we eat and drink, how active we are, and how much body fat we carry — not only as adults but also from and before birth, vitally affects our risk of many cancers.
This chapter follows those on foods and drinks, physical activity, and body composition, growth, and development. Its purpose is to summarise the evidence derived from independently commissioned and presented systematic literature reviews (SLRs), and the Panel’s judgements and conclusions, as they relate to cancers of 17 sites. Together, these amount to roughly 80 per cent of the incidence of, and deaths from, all cancers worldwide. Evidence on a number of other cancers is also summarised briefly, based on narrative reviews.
The sequence of the sections of this chapter corresponds roughly with the body’s systems, or with sites that have anatomical, metabolic, hormonal, or other features in common, and generally follows the sequence of the previous report.
The structure of all the sections, where evidence derives from these systematic reviews, is identical. After brief introductions, matrices display the Panel’s judgements. In this chapter, the Panel’s judgements also include the ‘Limited — no conclusion’ category, where evidence is, in the Panel’s view, of such poor quality, or too sparse, confused, or conflicting, to allow a conclusion.
Footnotes to these matrices include important explanations or qualifications.
Then follow subsections on trends, incidence, and survival; pathogenesis; and other established causes. The next subsection concerns interpretation of the evidence, in which issues and problems related to specific cancer sites are summarised.
This is followed by the Panel’s judgements, which take into account matters of quality and interpretation.
Then follows a subsection comparing the judgements of this Report with those of the previous report, with indications of why these differ when they do. All sections conclude with the Panel’s judgements for each cancer site.
7.1 Mouth, pharynx, and larynx
Cancers of the mouth, pharynx, and larynx, taken together, are the seventh most commonly occurring types of cancer worldwide. These cancers are three times more common in men than in women. Over 550 000 cases were recorded in 2002, accounting for around 5 per cent of cancer cases overall. In general, the rates of these cancers are decreasing. These cancers tend to recur. Survival rates are variable and average around 50 per cent at 5 years.
Cancers of the mouth, pharynx, and larynx are the seventh most common cause of death from cancer.
Overall, the Panel judges that food and nutrition play an important role in the prevention and causation of cancers of the mouth, pharynx, and larynx.
The Panel judges as follows:
The evidence that alcoholic drinks are a cause of cancers of the mouth, pharynx, and larynx is convincing. The risk is multiplied when drinkers of alcohol also smoke tobacco.
Non-starchy vegetables, fruits, and also foods containing carotenoids probably protect against these cancers.
There is limited evidence suggesting that maté, a herbal infusion traditionally drunk scalding hot through a metal straw in parts of South America, is a cause of oral cancer.
The main single cause of these cancers is smoking tobacco. It has been estimated that up to half of these cancers are preventable by appropriate diets and associated factors.
In final summary, the strongest evidence, corresponding to judgements of “convincing” and “probable”, shows that alcoholic drinks are a convincing cause of these cancers; and that non-starchy vegetables, fruits, and foods containing carotenoids are probably protective.
There are several different tissues and organs in and around the mouth, pharynx, and larynx. These include the lips, the tongue, the inside lining of the cheeks (buccal mucosa), the floor of the mouth, the gums (gingiva), the palate, and the salivary glands. The pharynx (or throat) is the muscular cav- ity leading from the nose and mouth to the larynx, which includes the vocal cords.
Ninety per cent of cancers of the mouth, pharynx, and lar- ynx are squamous cell carcinomas, the type discussed here. Cancers of the oropharynx (including the tonsils) and the hypopharynx are also included. For cancer of the nasopharynx, the cavity from the back of the mouth to the nose.
7.1.1 Trends, incidence, and survival
Rates of cancers of the mouth and pharynx (age adjusted) are stable or decreasing in many high-income countries. There was a sharp increase between 1950 and 1980 in sev- eral European countries, such as Germany and France, although this has since reached a plateau and started to decrease. Laryngeal cancer rates appear to have been generally stable or decreasing since 1970.1
Age-adjusted incidence rates of oral cancers range from 20–40 per 100 000 people in parts of south-central Asia, Europe, Oceania, and southern Africa, to less than 3 per 100 000 in parts of eastern Asia, northern and western Africa, and Central America. Pharyngeal cancers (other than those of the nasopharynx) follow broadly similar incidence patterns, although the overall incidence is lower, with highs of more than 10 per 100 000 in south-central Asia and west- ern Europe, to a low of less than 1 per 100 000 in northern Africa. Age-adjusted incidence rates of laryngeal cancer range from more than 10 per 100 000 in South America, south-central and western Asia, and southern, central, and western Europe to less than 1 per 100 000 in many African countries.2 Rates are higher in men than in women by approximately three to one.2 In the USA, rates are higher among African-American people than in white people.3
Risk increases with age, and diagnoses of these three types of cancer are most common in people aged 50 or over.4
Although cure rates are high for early-stage cancers of the mouth, pharynx, and larynx, second primary tumours are rel- atively common at these sites.5 More than 60 per cent of patients do not seek medical advice until the disease is at an advanced stage; in these cases, long-term survival rates are poor, especially if the cancer site is inaccessible.4 Five-year survival rates are around 60 per cent in the USA and 50 per cent in the UK.3 6 These cancers account for just over 5 per
cent of all cancer incidence, but just under 5 per cent of all cancer deaths.
Mouth, pharynx, and larynx cancers, like other types, are the result of genetic alterations that lead to small, localised lesions in the mucous membranes that grow in an abnormal way (dysplasia). These lesions may then progress to carci- noma in situ, and then become invasive cancers.
Exposure to carcinogens, such as those in tobacco, can be prolonged and consistent. The mouth and pharynx are directly exposed to both inhaled carcinogens and those that are ingested by drinking and chewing — including, in the case of chewing tobacco and betel quid, when it is spat out after chewing. Chronic damage and inflammation caused by stomach acid are also implicated; some studies have found that laryngopharyngeal reflux (where stomach acid flows upwards to the larynx and/or pharynx) is associated with laryngeal cancers.7 8
Cancers of the mouth, pharynx, and larynx frequently show multiple, independent, malignant foci — with second primary cancers occurring relatively frequently. This phe- nomenon occurs when an entire region of tissue is repeat- edly exposed to carcinogens. Around 90 per cent of oral cancers occur after exposure to tobacco or alcohol, or a com- bination of both.9
7.1.3 Other established causes
Tobacco use; infec- tious agents; radiation; industrial chemicals; and some med- ications. Other diseases may also increase the risk of cancer. In the same way, life events that modify the risk of cancer
- causative and protective — are also ‘Established’ effectively means ‘beyond reasonable doubt’
- roughly the equivalent of the judgement of ‘convincing’ used in this R Occasionally, authoritative findings that perhaps fall short of ‘established’ are also included here.
Where possible, a note of interactive or multiplicative effects with food, nutrition, and the other factors covered by this Report is added, as is any indication of scale or relative importance. The factors here are almost all causative, where- as much of the evidence on food, nutrition, physical activi- ty, and related factors shows or suggests protection against cancer.
Other diseases. There is substantial evidence that gastric reflux increases the risk of oral cancers.
Tobacco use. Smoking, and other use of and exposure to tobacco, is the most important cause of oral cancers, including those of the mouth, pharynx, and larynx. These factors are estimated to cause around 60 per cent per cent of all laryngeal cancers. While alcoholic drinks are an independent cause of these cancers, risk is multiplied if drinkers smoke tobacco and if smokers drink .10 Chewing of betel quid (with or without added tobacco) also causes oral cancers.11
Infection and infestation. Human papilloma viruses (HPVs) are a cause of oral cancers.12-14
7.1.4 Interpretation of the evidence
‘Relative risk’ is used in this Report to denote ratio mea- sures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard ratios’, and ‘odds ratios’.
Considerations specific to cancers of the mouth, pharynx, and larynx include:
Classification. Some studies did not report separately on can- cers of the mouth, pharynx, or larynx, but grouped these cancers with others as ‘head and neck cancers’ or ‘upper aerodigestive tract cancers’. The term ‘head and neck can- cer’ includes all of these sites plus cancers of the middle ear, the nasal cavity, and the paranasal sinuses. The term ‘upper aerodigestive tract cancer’ includes all head and neck can- cers and oesophageal cancer.
Confounding. High-quality studies adjust for smoking but may still be subject to residual confounding. Because of the size of the effect of smoking, and the tendency for the diets of smokers to be low in vegetables and fruits, and for smok- ers to have relatively lower body mass indices, residual con- founding is a particular concern for these exposures. Wherever possible, detailed stratification of the data accord- ing to smoking status was obtained.
7.1.5 Evidence and judgements
In total, 238 publications were included in the systematic lit- erature review (SLR) for cancers of the mouth, pharynx, and larynx.
The full SLR is contained on the CD included with this Report.
- Non-starchy vegetables
A total of 31 case-control studies and 3 ecological studies examined non-starchy vegetables. Other groupings exam-
ined were non-starchy vegetables and fruits (in combination) (1 cohort, 6 case-control); raw vegetables (23 case-control);
cruciferous vegetables (1 cohort, 14 case-control, and 1 eco- logical); green, leafy vegetables (1 cohort, 10 case-control); carrots (3 cohort, 18 case-control); and tomatoes (1 cohort,
12 case-control). Most of the studies for the exposures grouped under non-starchy vegetables showed a decreased risk with increased intake. Meta-analysis showed a 28 per cent decreased risk per 50 g per day (figure 4.2.2). The dose-response relationship suggested that the greatest effect was produced by the first increment; that is, that some vegetable consumption confers a protective effect com- pared with none (figure 4.2.3). However, it is not clear that the effect continues in a linear fashion. It is possible that this is an artificial phenomenon produced by residual confounding due to smoking. There is some unexplained heterogeneity.
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 is likely that any pro- tective effect may result from a combination of influences on several pathways involved in carcinogenesis.
A substantial amount of consistent evidence on non- starchy vegetables, including specific subtypes mostly from case-control studies, shows a dose-response relationship. There is evidence for plausible mechanisms. Non-starchy vegetables probably protect against mouth, pharynx, and larynx cancers.
The Panel is aware that since the conclusion of the SLR, two cohort15 16 and two case-control studies17 18 have been pub- lished. This new information does not change the Panel judge- ment.
A total of 1 cohort study, 35 case-control studies, and 2 eco- logical studies investigated fruits. Other groupings examined were citrus fruits (1 cohort, 23 case-control, 1 ecological), and non-starchy vegetables and fruits (in combination) (1 cohort, 6 case-control). Most studies showed decreased risk. Meta-analysis showed a 18 per cent decreased risk per 100 g per day for general fruits, or 24 per cent per 50 g per day for citrus fruits (figures 4.2.17 and 4.2.18). The dose- response relationship suggested that the greatest effect was produced by the first increment; that is, that some fruit con- sumption confers a protective effect compared to none. However, it is not clear that the effect continues in a linear fashion (figures 4.2.19 and 4.2.20). It is possible that this is an artificial phenomenon produced by residual confounding due to smoking.
Studies that reported on combined intake of non-starchy vegetables and fruits showed evidence of an association with decreased risk.
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. It is difficult to unravel the relative impor- tance of each constituent, and is likely that any protective effect may result from a combination of influences on sev- eral pathways involved in carcinogenesis.
The evidence, including that on fruit subtypes, though mostly from case-control studies, is consistent, with a dose-response relationship. There is evidence for plausible mechanisms. Fruits probably protect against mouth, pharynx, and larynx cancers.
The Panel is aware that since the conclusion of the SLR, two cohort studies15 16 and one case-control study18 have been pub- lished. This new information does not change the Panel judge- ment.
- Foods containing carotenoids
Two cohort studies investigated total serum carotenoids, 10 case-control studies investigated pro-vitamin A carotenoids, and 2 case-control studies investigated total dietary carotenoids. Other groupings examined were dietary alpha- carotene (1 cohort); serum alpha-carotene (3 cohort); dietary beta-carotene (1 cohort, 7 case-control); serum beta- carotene (3 cohort, 2 case-control); dietary lycopene (1
cohort, 4 case-control); and serum lycopene (1 cohort, 1 case-control). All of the serum studies and most of the dietary studies showed decreased risk with increased mea- sures of carotenoids. Meta-analysis was not possible. Information comes predominantly from dietary sources, not supplements; therefore no effect can be attributed to carotenoids separate from foods.
In trials, carotenoids have been effective at reducing cel- lular damage within the mouth, which may act as a precur- sor to cancers in this region. Carotenoids are antioxidants. Oxidative damage is linked to the formation of tumours through several mechanisms. Oxidative stress damages DNA. This might be prevented or limited by dietary antioxidants found in fruits and vegetables.
There is a considerable amount of evidence, and though it is for different carotenoid types, it is generally consistent, with a dose-response relationship. There is evidence for plausible mechanisms. Foods containing carotenoids probably protect against mouth, pharynx, and larynx cancers.
The Panel is aware that since the conclusion of the SLR, one cohort study15 has been published. This new information does not change the Panel judgement.
Six case-control studies were examined. All reported increased risk from drinking maté, which was statistically sig- nificant in four.
There is some biological plausibility. Maté is a herbal infu- sion traditionally drunk very hot through a metal straw. This produces heat damage in the mouth, pharynx, and larynx. Repeated damage of this nature could lead to cancer. Chemical carcinogenesis from constituents of maté has also been postulated.19 20
The evidence is sparse. There is limited evidence suggesting that maté is a cause of mouth, pharynx, and larynx cancers.
- Alcoholic drinks
Five cohort studies, 89 case-control studies, and 4 ecologi- cal studies investigated alcoholic drinks. All cohort studies and nearly all case-control studies showed increased risk. Meta-analysis of cohort data showed a 24 per cent increased risk per drink/week; case-control data showed a 3 per cent increased risk per drink/week (figure 4.8.2). The cohort studies showed a curvilinear dose-response relationship.
It is biologically highly plausible that alcoholic drinks are a cause of mouth, pharynx, and larynx cancers. IARC clas- sifies alcohol as a Class 1 carcinogen. Reactive metabolites of alcohol such as acetaldehyde can be carcinogenic. There is also an interaction with smoking. Tobacco may induce spe- cific mutations in DNA that are less efficiently repaired in the presence of alcohol. Alcohol may also function as a solvent, enhancing penetration of other carcinogenic molecules into mucosal cells. Additionally, the effects of alcohol may be mediated through the production of prostaglandins, lipid peroxidation, and the generation of free radical oxygen species. High consumers of alcohol may also have diets low in essential nutrients, making tissues susceptible to carcinogenesis.
There is ample and consistent evidence, both from case-control and cohort studies, with a dose-response relationship. There is robust evidence for mechanisms operating in humans. The evidence that alcoholic drinks are a cause of mouth, pharynx, and larynx cancers is convincing. Alcohol and tobacco together increase the risk of these cancers more than either acting independently. No threshold was identified.
The Panel is aware that since the conclusion of the SLR, one cohort15 and four case-control studies21-24 have been published. This new information does not change the Panel judgement.
- 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) and their products; starchy
roots, tubers, and plantains; pulses (legumes); foods con- taining dietary fibre; meat; poultry; fish; eggs; milk and dairy products; total fat; foods containing animal fat; plant oils; coffee; tea; frying, grilling (broiling), and barbecuing; pro- tein; vitamin A; retinol; thiamin; riboflavin; niacin; folate; vitamin C; vitamin E; iron; calcium; selenium; energy intake; and body fatness.
Fourteen case-control studies examined body fatness, as measured by body mass index (BMI). Meta-analysis pro- duced a statistically significant decreased risk with increased BMI, and a dose-response relationship, but reverse causality was implicated. That is, cancers of the mouth, pharynx, and larynx cause significant weight loss, often before diagnosis. Smoking is also associated with low BMI. For these reasons, the data were judged insufficient to allow any conclusion to be drawn.
7.1.6 Comparison with previous report
The main differences between this Report and the previous report are summarised here, together with any reasons for these differences. When the findings here and in the previ- ous report are similar, this is usually not mentioned. Minor differences are not always mentioned.
The criteria used by the previous report for gauging the strength of the evidence were not identical to the criteria used for this Report. In particular, a judgement of ‘convinc- ing’ causal association was not conditional on supportive evi- dence from prospective studies. This Report does make that requirement. It also emphasises the special importance of randomised controlled trials when applied appropriately, especially where the results are positive. In these respects, the criteria used for this Report are more stringent.
The previous report separated cancers of the mouth and pharynx from cancer of the larynx. The panel responsible for the previous report judged the evidence that vegetables and fruits protect against cancers of the mouth and pharynx to be convincing. It also judged that these foods probably pro- tect against cancer of the larynx. Vitamin C was judged to be possibly protective against cancers of the mouth and lar- ynx. There is still little information from cohort studies, which weakens the evidence base.
Evidence accumulated since the mid-1990s confirms the previous judgement that the evidence that alcoholic drinks are a cause of oral cancers is convincing. And in the previ- ous report, the evidence that maté is a cause of oral cancers was judged possible for cancers of the mouth and pharynx.
The Panel concludes:
The evidence that alcoholic drinks are a cause of cancers