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Cancer of the oesophagus Explined – the eighth most common type of cancer worldwide

Cancer of the oesophagus Explined – the eighth most common type of cancer worldwide

HEALTH

Cancer of the oesophagus Explined – the eighth most common type of cancer worldwide

Cancer of the oesophagus Explined – the eighth most common type of cancer worldwide

        Oesophagus

   
DECREASES RISK INCREASES RISK
 

Convincing

  Alcoholic drinks Body fatness1
Probable Non-starchy vegetables2

Fruits2

Foods containing beta-carotene3

Foods containing vitamin C3

Maté4

 

Cancer of the oesophagus is the eighth most common type of cancer worldwide. Around 460 000 cases occurred in 2002, accounting for over 4 per cent overall. There are two common types of oesophageal cancer, adenocarcinoma and squamous cell carcinoma, which have different         patterns of occurrence. In general this cancer is not increasing, except for adenocarcinomas, which are increasing in high-income countries. Oesophageal cancer  is twice as common in men as in women. It is usually fatal and is the sixth most common cause of death from cancer.

Overall, the Panel judges that food and nutrition and body fatness play an important role in the prevention and causation of cancer of the oesophagus.

 

The Panel judges as follows:

Limited — suggestive Foods containing dietary fibre3

Foods containing folate3

Foods containing pyridoxine3 5

Foods containing vitamin E3

Red meat6 Processed meat7

High-temperature drinks

Limited —

no conclusion

Cereals (grains) and their products; starchy roots, tubers, and plantains; pulses (legumes); soya and soya products; herbs, spices, and condiments; poultry; fish; eggs; milk and dairy products; total fat; saturated fatty acids; monounsaturated fatty acids; polyunsaturated fatty acids; sugary foods and drinks; salt; salting; fermenting; pickling; smoked and cured foods; nitrates and nitrites; frying; grilling (broiling) and barbecuing (charbroiling); protein; vitamin A; retinol; thiamin; riboflavin; calcium; iron; zinc; pro-vitamin A carotenoids;

beta-cryptoxanthin; Seventh-day Adventist diets; adult attained height; energy intake

 

The evidence that alcoholic drinks are a cause of cancer of the oesophagus is convincing. The risk is multiplied when drinkers of alcohol also smoke tobacco. The evidence that greater body fatness is a cause of oesophageal adenocarcinoma is also convincing. Maté, a herbal infusion, when drunk scalding hot through a metal straw, as is traditional in parts of South America, is probably a cause of this cancer.

Non-starchy vegetables, fruits, and foods containing beta-carotene and/or vitamin C probably protect against oesophageal cancer.

There is limited evidence suggesting that foods containing dietary fibre, folate, pyridoxine, or vitamin E protect against this cancer, and that red meat, processed meat, and high-temperature drinks are causes of this cancer.

 

Other causes of this cancer include smoking tobacco and chewing betel quid. It has been estimated that most cases of oesophageal cancer are preventable by appropriate diets and associated factors, together with not smoking.

In final summary, the strongest evidence, corresponding to judgements of “convincing” and “probable”, shows that alcoholic drinks and body fatness are a cause of this cancer (adenocarcinoma only); that non-starchy vegetables, fruits, and foods containing beta-carotene and/or vitamin C are probably protective; and that maté, as traditionally drunk in parts of South America, is probably a cause of this cancer.

 

 

The oesophagus is the muscular tube through which food passes from the pharynx to the stomach.

The oesophagus is lined over most of its length by squa- mous epithelial cells, where squamous cell carcinomas occur. The portion just above the gastric junction (where the oesophagus  meets  the  stomach)  is  lined  by  columnar

 

epithelial cells, from which adenocarcinomas can develop.4 Adenocarcinoma of the oesophagus shows similarities with adenocarcinoma of the gastric cardia . Each type accounts for around half of all cases and both types are included in this Report.

 

 

7.3.1    Trends, incidence, and survival

 

Age-adjusted rates of oesophageal squamous cell carcinomas are generally declining, although in some high-income regions, overall rates of oesophageal cancer are increasing. For instance, the incidence of oesophageal adenocarcinoma is rising rapidly in Europe and North America.39 In the USA, adenocarcinomas in white men increased fivefold between 1974 and the end of the 20th century, making it the fastest increasing cancer studied in that country.40

Oesophageal cancer is, however, mainly a disease of low- income countries, occurring around four times more com- monly in low- to middle- than in high-income countries. Around the world, age-adjusted incidence rates range from more than 20 per 100 000 people in parts of eastern and southern Africa and eastern and south-central Asia to less than 5 per 100 000 in northern, western, and middle Africa, Central America, and south-eastern Asia. Localised peaks in incidence have been reported to exceed 100 per 100 000. For instance, in rural Linxian, China, oesophageal cancer is the leading cause of death.41 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 five to two. In most populations, risk increases with age, with few cases diagnosed in people under 40.

Oesophageal cancer does not usually produce symptoms at the early stages, so the disease is generally at an advanced stage when diagnosed. Survival rates are poor: around 10 per cent at 5 years.3 6 This type of cancer accounts for a lit- tle over 4 per cent of all cancer incidence, but almost 6 per cent of all cancer deaths worldwide.

 

 

7.3.2     Pathogenesis

 

The epithelial cells lining the oesophagus are exposed direct- ly to carcinogens in food. Repeated exposures, for instance, to burns from very high-temperature drinks or irritation from the direct action of alcohol, may cause inflammation.

The role of irritation and inflammation in the development of oesophageal cancer is supported by the finding that gas- tro-oesophageal reflux (where stomach acid flows upwards to the oesophagus) increases the risk of adenocarcinomas by as much as 40-fold.42 Barrett’s oesophagus is a probable intermediate stage between gastro-oesophageal reflux dis- ease, with repeated gastro-oesophageal reflux, and devel- oping oesophageal adenocarcinoma.43 Barrett’s oesophagus is an acquired condition in which squamous cells are replaced by columnar epithelial cells; autopsy studies sug- gest that it usually remains undiagnosed.44 The increasing use of endoscopes to investigate abdominal symptoms has resulted in the earlier detection of a small proportion of ade-

nocarcinomas in people with Barrett’s oesophagus.4

Some people have an abnormally strong lower oesophageal sphincter (a condition called oesophageal achalasia), which means swallowed food is retained in the oesophagus. It causes a 15-fold increase in the risk of squa- mous cell carcinomas, which may be due to chronic irrita- tion of the lining of the oesophagus or its increased contact with food-borne carcinogens.45 46

Tylosis A is the late-onset, inherited familial disease where the outer horny layer of the skin thickens, affecting the palms and soles (hyperkeratosis). Palmar and plantar hyperker- atosis is the single proven genetic abnormality associated with a 25 per cent lifetime incidence of squamous cell can- cer of the oesophagus.47

 

 

7.3.3     Other established causes

 

 

 

Other diseases. Gastric reflux and oesophageal achalasia both increase the risk of, and thus can be seen as a cause of, this cancer. Barrett’s oesophagus can be seen as a precan- cerous condition.

 

Tobacco use. Smoking is a cause both of oesophageal squa- mous cell carcinoma and of adenocarcinomas, increasing the risk approximately twofold.10 39 Smoking is estimated to cause around 40 per cent of all cases. Chewing betel quid (on its own and also with tobacco quid) is also a cause of oesophageal cancers.11

 

Infectious agents. HPV  is also a cause of this cancer, and is estimated to be a cause of almost 25 per cent of squamous cell carcinomas. Like other infectious agents, it may be a necessary cause but is not a sufficient cause. It may also play a role in the divergent geographical distributions of this cancer.48

 

 

7.3.4     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 oesophagus include:

 

Classification. There are different types of oesophageal can- cer. Squamous cell carcinomas have different geographical and time trends from adenocarcinomas. Each follows a dif- ferent disease path, and may have different associated risk factors. However, there were only sufficient data to conduct separate analyses for body fatness. Therefore the ratio of

 

squamous cell carcinomas to adenocarcinomas in each study is a potential cause of heterogeneity in all other summaries. The oesophageal-gastric junction and gastric cardia are also lined with columnar epithelial cells. Cancers in these areas are often grouped with oesophageal cancers, although they may also be classed as stomach cancers

.4 Different approaches or definitions in different studies are another potential source of heterogeneity.

 

Confounding. Smoking is the main single cause of this can- cer. High-quality studies adjust for smoking.

 

 

7.3.5     Evidence and judgements

 

In total, 262 publications were included in the SLR for oesophageal cancer. Fuller summaries of the epidemiologi- cal, experimental, and mechanistic evidence are to be found in Chapters 4–6.

The full SLR is contained on the CD included with this Report.

 

  • Foods containing dietary fibre

 

 

One cohort study, nine case-control studies, and two eco- logical studies investigated dietary fibre. Most were sugges- tive of a relationship with decreased oesophageal cancer incidence. Data come predominantly from dietary sources, not supplements; therefore no specific effect can be attrib- uted specifically to dietary fibre itself, which is interpreted simply as a marker of consumption of foods containing it.

It is not clear whether there is an as yet unknown mech- anism through which dietary fibre could exert a direct effect on oesophageal cancer, or whether the effect is mediated through other constituents of the foods (such as cereals (grains), vegetables, and fruits) that contain dietary fibre.

 

There is limited evidence, from sparse and inconsistent case-control studies only, suggesting that foods containing dietary fibre protect against oesophageal cancer.

 

  • Non-starchy vegetables

 

 

 

A total of 5 cohort studies, 37 case-control studies, and 6 eco- logical studies investigated non-starchy vegetables. Other groupings examined were vegetable and fruit consumption (combined) (8 case-control), raw vegetables (16 case-con- trol), cruciferous vegetables (1 cohort, 5 case-control), alli- um vegetables (1 cohort, 8 case-control), green, leafy vegetables (1 cohort, 11 case-control), and tomatoes (1 cohort, 9 case-control). All of the studies of raw vegetables and most of the other studies showed decreased risk with increased intake. Meta-analysis of case-control data showed a 31 per cent decreased risk per 50 g of raw vegetables per day (figures 4.2.6 and 4.2.7). Raw vegetables have a more consistent definition than non-starchy vegetables, which may include preserved vegetables and a variety of cooking meth- ods, leading to increased 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, glucosi- nolates, dithiolthiones, indoles, coumarins, ascorbate, chlorophyll, flavonoids, allylsulphides, flavonoids, and phy- toestrogens, some of which are potentially antioxidants. Antioxidants trap free radicals and reactive oxygen mole- cules, protecting against oxidation damage. It is difficult to unravel the relative importance of each constituent and it is likely that any protective effect may result from a combina- tion of influences on several pathways involved in carcino- genesis.

 

There is more evidence, including on vegetable subtypes, from case-control studies than from cohort studies, but both are moderately consistent, and there is some evidence for a dose-response relationship.

There is evidence for plausible mechanisms . Non-starchy vegetables probably protect against oesophageal cancer.

 

The Panel is aware that since the conclusion of the SLR, one cohort49 and two case-control studies17 50 have been published. This new information does not change the Panel judgement. 

 

  • Fruits

 

A total of 4 cohort studies, 36 case-control studies, and 7 ecological studies investigated fruits; and 1 cohort study, 16 case-control studies, and 1 ecological study investigated cit- rus fruits. All of the cohort studies and most of the other studies showed decreased risk with increased intake. Meta- analysis of case-control data showed a 22 per cent decreased risk per 50 g of fruit per day, and 30 per cent decreased risk per 50 g of citrus fruit per day (figures 4.2.22 and 4.2.24). A dose-response relationship was apparent. Heterogeneity could not be fully explained.

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 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, 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 oesophageal cancer.

 

The Panel is aware that since the conclusion of the SLR, one cohort49 and two case-control studies50 51 have been published. This new information does not change the Panel judgement. 

 

 

  • Foods containing folate

 

 

Eight case-control studies investigated dietary folate and two case-control studies investigated red-cell and plasma folate. All studies showed a relationship with decreased cancer inci- dence. Data come predominantly from dietary sources, not supplements; therefore no effect can be attributed to folate separate from foods.

Folate plays an important role in the synthesis, repair, and methylation of DNA. Abnormal DNA methylation has been linked to aberrant gene expression and to cancers at sever- al sites. Folate may also reduce HPV proliferation in cells.

 

The evidence, from case-control studies only, is sparse. There is limited evidence suggesting that folate protects against oesophageal cancer.

 

The Panel is aware that since the conclusion of the SLR, one case-control study52 has been published. This new information does not change the Panel judgement.

 

 

  • Foods containing pyridoxine (vitamin B6)

 

 

Six case-control studies investigated foods containing pyri- doxine and oesophageal cancer.

All six studies showed a relationship between pyridoxine consumption and reduced risk of oesophageal cancer, with none reporting contrary results.

Together with folate and cobalamin (vitamin B12), vita- min B6 is involved in one-carbon metabolism and is impor- tant for DNA synthesis, repair, and methylation.

 

The evidence, from case-control studies only, was sparse. There is limited evidence suggesting that pyridoxine protects against oesophageal cancer.

 

The Panel is aware that since the conclusion of the SLR, one case-control study52 has been published. This new information does not change the Panel judgement.

 

 

 

  • Foods containing vitamin C

 

 

One cohort study, 19 case-control studies, and 3 ecological studies investigated vitamin C. The single cohort study and nearly all of the case-control studies showed decreased risk with increased intake.

Vitamin C traps free radicals and reactive oxygen mole- cules, protecting DNA from mutagenic attack, protecting against lipid peroxidation, reducing nitrates, and stimulat- ing the immune system.

 

A substantial amount of consistent evidence is available, both from cohort and from case-control studies. Foods containing vitamin C probably protect against oesophageal cancer.

 

The Panel is aware that since the conclusion of the SLR, one case-control study53 has been published. This new information does not change the Panel judgement.

 

  • Foods containing vitamin E

 

 

One cohort study, nine case-control studies, and one eco- logical study investigated dietary vitamin E; three cohort studies and four case-control studies investigated serum vit- amin E. All cohort studies and most case-control studies showed decreased risk with increased intake; serum case- control data were inconsistent.

Vitamin E is a family of eight compounds collectively referred to as tocopherols. They can act as antioxidants and free radical scavengers; however, few animal studies support an anti-cancer effect.

 

Much of the evidence on vitamin E, mostly from case- control studies, was of poor quality. There is limited evidence suggesting that foods containing vitamin E protect against oesophageal cancer.

 

  • Foods containing beta-carotene

 

 

 

 

Ten case-control studies investigated dietary beta-carotene; three cohort studies and one case-control study investigat- ed serum beta-carotene; and one cohort study and three case-control studies investigated dietary pro-vitamin A carotenoids. Most of these studies showed a relationship with decreased risk.

Data come predominantly from dietary sources, not sup- plements; 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 consistent evidence available from both cohort and case-control studies. Foods containing beta-carotene probably protect against oesophageal cancer.

 

  • Red meat

 

 

Twelve case-control studies investigated red meat. Most were suggestive of increased risk.

There are several potential underlying mechanisms for a positive association of red meat consumption with oesophageal cancer, including the generation of potentially carcinogenic N-nitroso compounds. Some meats are also cooked at high temperatures, resulting in the production of heterocyclic amines and polycyclic aromatic hydrocarbons

. Red meat contains haem iron. Free iron can lead to the production of free radicals.

 

There is limited evidence, from case-control studies, some of which were poor quality, suggesting that red meat is a cause of oesophageal cancer.

 

The Panel is aware that since the conclusion of the SLR, one cohort study54 has been published. This new information does not change the Panel judgement.

 

 

  • Processed meat

 

 

Two cohort studies and eight case-control studies investi- gated processed meat. Both cohort studies were suggestive of increased risk; case-control data were inconsistent. The definition of processed meat varies, which may increase heterogeneity.

Nitrates are produced endogenously in gastric acid and are added as preservatives to processed meats. This may contribute to production of N-nitroso compounds and increased exposure. These compounds are suspected mutagens and carcinogens.55

Many processed meats also contain high levels of salt and nitrite. Meats cooked at high temperatures can contain het- erocyclic amines and polycyclic aromatic hydrocarbons. Haem promotes the formation of N-nitroso com- pounds and also contains iron. Free iron can lead to the pro- duction of free radicals.

 

There is limited evidence, mostly from case-control studies, suggesting that processed meat is a cause of oesophageal cancer.

 

The Panel is aware that since the conclusion of the SLR, one cohort study54 has been published. This new information does not change the Panel judgement.

  • Maté

 

Eight case-control studies and one ecological study investi- gated maté. Most were suggestive of an increased incidence with higher maté consumption. Meta-analysis of case- control data showed a 16 per cent increased risk per cup/ day (figure 4.7.5). A dose-response relationship was apparent.

There is some biological plausibility. Maté is a tea-like beverage typically drunk very hot through a metal straw. This produces heat damage in the oesophagus. Repeated damage of this nature can lead to cancer. Chemical carcinogenesis from constituents of maté has also been postulated.19 20

 

The evidence from case-control studies is consistent and a dose-response relationship is apparent. There is robust evidence for plausible mechanisms. Regular consumption of maté, as drunk in the traditional style in South America, is a probable cause of oesophageal cancer.

 

  • High-temperature foods and drinks

)

Three cohort studies and 15 case-control studies investigat- ed high-temperature foods and drinks. Most were suggestive of a relationship between them and increased incidence of oesophageal cancer but many were inadequately adjusted for alcohol and smoking.

High-temperature foods and drinks can produce heat dam- age in the oesophagus. Repeated damage of this nature can predispose to the development of oesophageal cancer.

The evidence is inconsistent. There is limited evidence suggesting that high-temperature drinks are a cause of oesophageal cancer.

 

The Panel is aware that since the conclusion of the SLR, two case-control studies50 51 have been published. This new infor- mation does not change the Panel judgement.

  • Alcoholic drinks

Eight cohort studies, 56 case-control studies, and 10 eco- logical studies investigated alcoholic drinks. Most studies showed a relationship between increased consumption and increased cancer incidence. Meta-analysis of case-control data showed a 4 per cent increased risk per drink/week (fig- ure 4.8.6). A dose-response relationship is apparent from case-control data, with no clear threshold.

It is biologically highly plausible that alcoholic drinks are a cause of oesophageal cancer. Reactive metabolites of alco- hol such as acetaldehyde can be carcinogenic. Tobacco may induce specific mutations in DNA that are less efficiently repaired in the presence of alcohol. Alcohol may also func- tion as a solvent, enhancing penetration of other carcino- genic 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. Lastly, heavy consumers of alcohol may have diets low in essential nutrients, making tissues sus- ceptible to carcinogenesis.

 

There is ample and consistent evidence, both from cohort and case-control studies, with a dose-response relationship. There is robust evidence for mechanisms operating in humans. The evidence that alcoholic drinks are a cause of oesophageal cancer is convincing. No threshold was identified.

 

The Panel is aware that since the conclusion of the SLR, one cohort56 and four case-control studies50 51 53 57 have been pub- lished. This new information does not change the Panel judge- ment.

  • Body fatness

 

A sufficient number of studies investigated BMI to allow squamous cell carcinomas and adenocarcinomas to be analysed separately. While results were inconsistent for squa- mous cell carcinomas and for all oesophageal cancers, adenocarcinomas, when analysed separately, showed a con- sistent increased risk with greater BMI. Three cohort stud- ies and eight case-control studies investigated body fatness, as measured by BMI and adenocarcinomas. All of the cohort studies and most of the case-control studies showed increased risk with increased BMI. Meta-analysis of case-con- trol data showed a 55 per cent increased risk per 5 kg/m2 (figure 6.1.2). A dose-response relationship is apparent. This is consistent with known geographical and time trends for both BMI and adenocarcinomas.

It is biologically plausible that body fatness is a cause of

 

oesophageal cancer. High body fatness is associated with increased gastro-oesophageal reflux and Barrett’s oesopha- gus. It also directly affects levels of many circulating hor- mones, such as insulin, insulin-like growth factors, and oestrogens, creating an environment that encourages car- cinogenesis and discourages apoptosis  Body fatness stimulates the body’s inflammatory response, which may contribute to the initiation and progression of several cancers .

 

The epidemiology is consistent with evidence of a dose-response relationship. There is evidence for plausible mechanisms that operate in humans. The evidence that greater body fatness is a cause of oesophageal adenocarcinoma is convincing.

 

The Panel is aware that since the conclusion of the SLR, two cohort58 59 and five case-control studies51 53 60-62 have been pub- lished. This new information does not change the Panel judge- ment.

 

  • Other exposures

Other exposures were evaluated. However, the data were either too sparse, 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 roots, tubers, and plantains; pulses (legumes); soya and soya prod- ucts; herbs, condiments or spices; poultry; fish; eggs; milk and dairy products; sugary foods and drinks; fermenting; pickling; salt; salting; smoked and cured foods; nitrates and nitrites; frying, grilling (broiling), and barbecuing; total fat; saturated fatty acids; monounsaturated fatty acids; polyun- saturated fatty acids; protein; vitamin A; retinol; pro-vitamin A carotenoids; beta-cryptoxanthin; thiamin; riboflavin; iron; calcium; zinc; energy intake; adult attained height; and Seventh-day Adventist diets.

 

 

7.3.6    Comparison with previous report

 

  • General

 

 

  • Specific

The previous report judged the evidence that vegetables and fruits protect against oesophageal cancer to be convincing. Data published since then have been somewhat less consis- tent.

At the time of the previous report, the evidence on body fatness was unclear, because data on adenocarcinomas was inadequate and not analysed separately.

The previous report judged it possible that carotenoids or vitamin C protect against this cancer. The evidence base for foods containing these nutrients is now stronger. The previ- ous report judged it possible that maté and other very hot drinks cause oesophageal cancer. The evidence on maté is now stronger.

 

7.3.7    Conclusions

 

The Panel concludes:

The evidence that alcoholic drinks and body fatness (ade- nocarcinomas only) are causes of cancer of the oesophagus is convincing. The risk is multiplied when drinkers of alco- hol also smoke tobacco.

Non-starchy vegetables, fruits, and foods containing beta- carotene and/or vitamin C probably protect against oesophageal cancer.

Maté, a herbal infusion, when drunk scalding hot through a metal straw as is traditional in South America, is probably a cause of this cancer.

There is limited evidence suggesting that foods contain- ing dietary fibre, folate, pyridoxine, or vitamin E protect against this cancer; and that red meat, processed meat, and high temperature drinks are causes of this cancer.

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