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Gastric cancer: global pattern of the disease and an overview of environmental risk factors
Best Practice & Research Clinical Gastroenterology Vol. 20, No. 4, pp. 633e649, 2006 doi:10.1016/j.bpg.2006.04.008 available online at http://www.sciencedirect.com
1 Gastric cancer: global pattern of the disease and an overview of environmental risk factors D. Forman*
PhD Cancer Epidemiology Group, Centre for Epidemiology and Biostatistics, University of Leeds, Leeds LS2 9LN, UK
V.J. Burley
PhD
Nutritional Epidemiology Group, Centre for Epidemiology and Biostatistics, University of Leeds, Leeds LS2 9LN, UK
This first part of this chapter looks at the worldwide burden of gastric cancer at the beginning of the 21st century and summarises available population-based routine data that describes the variation in incidence of the disease in relation to age, sex, geography and time period. Consideration is also given to the differences in the descriptive epidemiology of gastric cancer arising in the proximal cardia region of the stomach. In the second part of the chapter, a brief review of the main identified environmental risk factors is conducted drawing, where available, on published systematic literature overviews and meta-analyses. Evidence relating the aetiology of gastric cancer to Helicobacter pylori infection, dietary factors, smoking, occupation, physical activity and anthropometry is presented. Key words: incidence; mortality; geographical variation; time trends; Helicobacter pylori; diet; environmental risk factors; cardia; smoking; alcohol; obesity; physical activity.
CURRENT GLOBAL INCIDENCE AND MORTALITY RATES OF GASTRIC CANCER Gastric cancer (cancer of the stomach) is a disease in which malignant cells arise in the tissues of the stomach. Since most malignant tumours of the stomach are epithelial in origin the overwhelming majority of cancers of the stomach are adenocarcinomas and most of the routine statistics about gastric cancer refer to this histological entity. Table 1 shows that in 2002 there were an estimated 930,000 new diagnoses and 700,000 deaths from gastric cancer worldwide.1 Overall age-standardised incidence rates were 22.0 and 10.3 per 100,000 per annum in males and females, respectively, with corresponding mortality rates being 14.3 and 8.3 per 100,000.1 Gastric cancer * Corresponding author. Tel.: þ44 113 392 4309; Fax: þ44 113 392 4178. E-mail addresses: [email protected] (D. Forman), [email protected] (V.J. Burley). 1521-6918/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.
634 D. Forman and V. J. Burley
Table 1. Estimated number of new registrations and deaths (000s) and age-standardiseda incidence and mortality rates from gastric cancer by sex; more-developed countries, less-developed countries and world for 2002. Estimated number of new registrations
Estimated number of deaths
Age-standardised incidence rate per 100,000
Age-standardised mortality rate per 100,000
More-developed countries Males 195.8 Females 115.4 Total 311.2
128.7 83.5 212.2
22.3 10.0 e
14.5 6.9 e
Less-developed Males Females Total
countries 404.8 213.8 618.6
315.2 169.8 482.0
21.5 10.4 e
17.0 8.3 e
World Males Females Total
603.0 303.3 933.3
445.7 254.1 699.8
22.0 10.3 e
16.3 7.9 e
Source: Ref. 1. a Standardised to world standard population.
was the third most common cause of male cancer (after lung and prostate cancers) and the second most common cause of male cancer death (after lung cancer). It was the fifth most common cause of female cancer (after breast, cervix, large bowel and lung cancers) and the fourth most common cause of female cancer death.1 As with most of the common cancers, there is considerable geographic variation in the incidence of gastric cancer throughout the world with some of the lowest rates seen in North America and Western Europe and the highest in East Asia, South America and Eastern Europe. Results for gastric cancer from the most recent edition of Cancer Incidence in Five Continents, reporting incidence rates from population-based cancer registries worldwide meeting minimum defined quality standards, are presented in Figure 1.2 This shows age-standardised rates for gastric cancer, diagnosed in the period 1993e1997, from selected cancer registries. In both sexes, there was more than a 10-fold variation in incidence between the lowest (USA whites) and highest (Japanese from the Miyagi prefecture) risk populations. The distribution of gastric cancer does not, however, always follow a clear geographical pattern. Thus although some of the world’s highest risk populations are in Asian countries, such as Japan, Korea and China, other Asian countries have relatively low rates (e.g. India). There are also some very high-risk groups within low-risk populations (e.g. Koreans living in the USA). Gastric cancer cannot readily be categorised as being associated with relatively under developed economies. Although approximately two-thirds of all cases arise in ‘less-developed’ countries, in 2002 overall age-standardised incidence rates were comparable between such countries and those defined as ‘more developed’ (Table 1). Several countries in the latter category have high gastric cancer incidence rates, notably Japan but also those in Eastern and, to a lesser extent, Southern Europe. Contrariwise, many of the world’s poorest economies, especially in Africa, appear to have relatively
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Japan, Miyagi Prefecture USA, California, Los Angeles: Korean Costa Rica Portugal, Vila Nova de Gaia China, Shanghai Estonia Colombia, Cali Singapore: Chinese Slovenia Females Males
Poland, Lower Silesia Mali, Bamako USA, SEER: Black UK, England Finland Denmark USA, SEER: White India, Mumbai (Bombay) The Gambia
0
20
40
60
80
Figure 1. Age-standardised (world standard population) gastric cancer incidence rates per 100,000 for selected cancer registries worldwide by sex, cases diagnosed 1993e1997. Source: Ref. 2.
low incidence rates of gastric cancer. It is difficult to exclude the suggestion that poor standards of diagnosis and reporting in such countries are responsible for such low reported rates especially for cancers arising in internal body organs such as the stomach. Rates do, however, remain low in countries such as The Gambia (Figure 1) where particular efforts have been made to establish reliable cancer registration and where other internal cancers, such as primary liver cancer, are reported to be extremely high.
636 D. Forman and V. J. Burley
Figure 2. Gastric cancer incidence rates per 100,000 by 5-year age group and sex for (a) Japan (Miyagi) and (b) USA White SEER populations, cases diagnosed 1993e1997. Source: Ref. 2.
As with most solid tumours the incidence rate of gastric cancer increases with age and the cancer is relatively rare in males or females under 45 years. Most patients are between 60 and 80 years old at diagnosis (Figure 2). One feature that is, however, consistently observed in all populations (reflected in a comparison of the sexes in Figure 1) is the approximately doubling of the age-standardised risk in males compared to females. In general, female incidence rates at a given age are equivalent to male rates at an age 10 years younger. The consistency of this difference has never been adequately explained although theories have been advanced in which female sex-specific hormones may play a protective role.3 A further consistent feature of the epidemiology of gastric cancer is that, within any population, rates of the disease tend to be higher in those who are relatively poorer and socio-economically deprived.4e9 TIME TRENDS IN GASTRIC CANCER INCIDENCE Figures 3 and 4 provide information, for males and females, on gastric cancer incidence trends over time for many of the cancer registry populations shown in Figure 1 where comparable data have been available for a number of years. In virtually all of these populations, the underlying pattern, for both sexes, is one of the rapidly declining incidence rates over the entire time period considered irrespective of whether the background risk of gastric cancer is high or low. The two exceptions to this pattern are for the Japanese population (Miyagi prefecture) where, at least in males, the very high rates remained high until the early 1990s and the Indian population (Bombay) where rates remained constantly very low. Declining incidence rates for gastric cancer
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Figure 3. Age-standardised (world standard population) male gastric cancer incidence rates per 100,000 for selected cancer registries worldwide by time period. Source: Parkin, D.M., Whelan, S.L., Ferlay, J., and Storm, H. Cancer Incidence in Five Continents, Vol. IeVIII IARC CancerBase No. 7, Lyon, 2005. (http:// www-dep.iarc.fr/).
represent, therefore, the dominant global epidemiological pattern for this disease and, as mortality is closely associated with incidence, mortality rates have shown a very similar pattern. It has, however, been suggested that mortality may have declined at a faster rate than incidence at least in some populations.10 In many countries, where gastric cancer used to be the leading cause of cancer-related death in the early or mid20th century, the decline in incidence has resulted in other emergent cancers, especially lung, breast and prostate cancers, becoming relatively more important. In certain instances, notably among the white US population, gastric cancer has now become an extremely rare diagnosis, the decline being hailed as an ‘unplanned triumph’.11 Despite this notable decline, it needs to be remembered that the 2002 incidence and mortality estimates, cited above, still make gastric cancer an important component of the global cancer burden. It is also not necessarily the case that, in absolute terms, the disease will become uniformly rare. Even assuming the current decline in incidence will continue in the future, the predicted growth in world population combined with increased longevity will most likely result in a net increase in the overall number of gastric cancers being diagnosed for several decades to come.Table 2 provides a comparison of the overall number of new cases and deaths from gastric cancer in 2002 compared with that estimated for 2020 in both ‘more-’ and ‘less-developed countries’.
638 D. Forman and V. J. Burley
Figure 4. Age-standardised (world standard population) female gastric cancer incidence rates per 100,000 for selected cancer registries worldwide by time period. Source: Parkin, D.M., Whelan, S.L., Ferlay, J., and Storm, H. Cancer Incidence in Five Continents, Vol. IeVIII IARC CancerBase No. 7, Lyon, 2005. (http:// www-dep.iarc.fr/).
Table 2. Estimated number (000s) of new registrations and deaths from gastric cancer in 2002 and projectionsa for 2010 and 2020; more-developed countries, less-developed countries and world. 2002
2010
2020
More-developed countries Registrations Deaths
311.2 212.2
297.1 202.6
282.5 127.7
Less-developed countries Registrations Deaths
618.6 482.0
659.7 517.9
723.4 573.3
World Registrations Deaths
933.3 699.8
960.1 720.0
1009.8 762.6
Source: Ref. 1. a With assumption of average e 2.0% decrease per annum in age-specific incidence/mortality rates.
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This shows that while there will be a decrease in cases and deaths in the former, this will be outweighed by an increase in the latter and thus, worldwide, there will be a modest increase in gastric cancer. This is based on the assumption that age-specific rates for both incidence and mortality continue to decline by 2% per annum, as has been the situation over the last two decades. GASTRIC CANCER SURVIVAL RATES In general survival rates from gastric cancer have been poor. The EUROCARE study12 estimated average European survival for cases diagnosed in the period 1990e1994 to be around 42% at 12 months and 24% at 5 years after diagnosis. Considerable variation between countries, from 11 to 30% at 5 years, was reported with only marginal improvements over the preceding decade. Survival rates in countries outside Europe are broadly within the range observed in European countries,13,14 the notable exception being in Japan where rates can be considerably higher due to the impact of population-based screening in some localities and the diagnosis of ‘early gastric cancer’.15 GASTRIC CANCER: SUB-SITE DISTRIBUTION The above descriptive epidemiology all relates to gastric cancer considered as a single entity. Until recently, relatively little attention was directed towards differences between the sub-site distribution of gastric cancer and the majority of existing epidemiology studies have not distinguished between the major anatomic divisions within the stomach. However, some studies over the last 10e15 years have identified cancers within the region adjoining the oesophago-gastric junction (the gastric cardia) as having a different epidemiology from cancers in more distal (non-cardia) regions. In most populations and in all but the most recent time periods, gastric cardia cancers represented a relatively small proportion of the total gastric cancer incidence and thus the overall trends, presented in Figures 1e4, largely reflect those for non-cardia cancer. There have been numerous reports indicating that gastric cardia cancers have been increasing in incidence in recent decades16e19 thus providing a contrasting trend from that observed for gastric cancer overall. The geographical pattern of gastric cardia cancer is somewhat more complex. As seen in Figure 5, populations such as those in Japan, which have had high rates of gastric cancer overall also have reported relatively high rates of cardia cancer. This was also the case, however, for populations, such as whites in the USA that have had low rates of gastric cancer overall. As a proportion of the total gastric cancer incidence, the contribution from the cardia is, therefore, much higher in such low-risk populations. Because gastric cardia cancers are not readily distinguished from lower oesophageal adenocarcinomas, there has undoubtedly been some variation in pathology practice in the organ to which these cancers have been assigned for classification purposes. Such variation may be present both between countries and over different time periods, thereby complicating interpretation of geographical and secular trends.20 The recent interest in cardia cancer has also resulted in an increased use of sub-site specific codes in routine data sets and it is, therefore, difficult to disentangle any genuine increases in incidence from artefactual improvements in reporting practice.21 Comparisons within the same populations over the same time period may, therefore, be more informative. Thus within the SEER cancer registries in the USA, whites have had higher rates of cardia cancer than blacks in contrast to the pattern for gastric
640 D. Forman and V. J. Burley
Japan, Miyagi Prefecture
China, Shanghai
Portugal, Vila Nova de Gaia
Costa Rica USA, California, Los Angeles: Korean UK, England
Denmark
USA, SEER: White Females
Slovenia
Males
Finland
Estonia
Singapore: Chinese
Poland, Lower Silesia
USA, SEER: Black
Colombia, Cali
India, Mumbai (Bombay)
Mali, Bamako
0
2
4
6
8
Figure 5. Age-standardised (world standard population) gastric cancer of the cardia incidence rates per 100,000 for selected cancer registries worldwide by sex, cases diagnosed 1993e1997. Source: Ref. 2.
cancer overall. Comparisons by sex (Figure 5) also show that male cardia cancer rates were three to four times greater than those in females indicating a larger excess than the 2:1 ratio for gastric cancer overall. Also unlike the situation for gastric cancer overall, and although relatively little data have been published, there would appear to be no association between gastric cardia cancer and poor socio-economic status.9 Survival rates from gastric cardia cancer tend to be slightly less favourable than those for gastric cancer overall14,22 and this means that populations, such as within
Gastric cancer 641
the USA, where cardia cancer represents a relatively high proportion of the total have an adverse overall survival in comparison with other populations with lower rates of cardia cancer.13 RISK FACTORS FOR GASTRIC CANCER Helicobacter pylori H. pylori is a gram-negative bacterium which has been aetiologically linked with gastric cancer in numerous ecologic, cohort and caseecontrol studies over the last two decades. Infection rates tend to be highest in those of lower socio-economic status, matching the incidence of gastric cancer,23 and the fall in gastric cancer incidence in developed countries has been paralleled by the declining H. pylori infection rates. However, the strongest evidence to support the role of H. pylori in gastric cancer development comes from prospective cohort studies. A pooled analysis of data from 12 prospective cohort studies demonstrated a 6-fold elevation in risk occurring after 10 years of follow-up.24 It should be noted that there were differences in the risk estimates according to the age of the cases and also notably by cancer sub-site.24 More recent evidence indicates that the use of more sensitive methods to detect H. pylori infection results in substantially higher risk estimates for gastric cancer.25 Although there are a variety of proposed mechanisms whereby H. pylori infection may increase the risk of gastric cancer, it is thought that the primary mode of action is through the induction of long-term chronic inflammation.26 Relatively few studies have examined the joint effects of both H. pylori infection and diet as causes of gastric cancer although one caseecontrol study from Sweden suggests that infection may act as an effect modifier for dietary risk factors.27 The role of H. pylori in the aetiology of gastric cancer will be considered in detail elsewhere in this volume (Chapter 6). Dietary factors There is a comprehensive body of literature investigating the interactions between dietary factors and the development of gastric cancer and there are a number of clearly identifiable dietary exposures that have been strongly implicated in gastric cancer causation and prevention. One conclusion to emerge from many studies has been that a diet high in fruit and vegetables reduces the risk of developing gastric cancer.28,29 A recent meta-analysis of studies reporting on fruit and vegetable intake in relation to the risk of gastric cancer is broadly in agreement with these conclusions. Riboli and Norat30 found that for each 100 g increase in vegetable intake the pooled estimate of relative risk was 0.81 (95% CI: 0.75, 0.87) and for fruit it was 0.74 (95% CI: 0.69, 0.81) indicative of a protective effect. The risk estimates were, however, closer to unity and no longer statistically significant when considering only the more reliable prospective studies 0.89 (95% CI: 0.75, 1.05) for vegetable intake and 0.89 (95% CI: 0.73, 1.09) for fruit intake. These results did not include the recently published data from the large European Prospective Study (EPIC)31 which again reported the absence of any effect associated with vegetable 0.91 (95% CI: 0.65, 1.28) or fruit intake 1.04 (95% CI: 0.91, 1.02) per 100 gm increase. Whilst it is apparent that there are many potential mechanisms through which a diet high in fruit and vegetables may be protective against cancer,32 what the active
642 D. Forman and V. J. Burley
component is in the case of stomach cancer is by no means clear. One possibility is related to the antioxidant capacity of fruit and vegetables, which is related to the content of beta-carotene, alpha-tocopherol and vitamin C content. Recently, Bjelakovic et al,33,34 using Cochrane Collaboration methodology, reviewed all randomised trials comparing antioxidant supplements with placebo for prevention of gastrointestinal cancers. They did not find evidence that antioxidant supplements prevent gastrointestinal cancers in general, or stomach cancer specifically. Two randomised vitamin supplementation trials that were included in the review35,36 suggested that any protective effect of micronutrient supplementation is likely to be restricted to those with existing poor nutrient status. The relationship between vitamin C intakes, vitamin C status and risk of gastric cancer is further complicated by the relationship of this nutrient to H. pylori infection. Infection with H. pylori is known to substantially reduce the bioavailability of vitamin C and, when combined with the reduced vitamin C intake in H. pylori-positive people, this markedly reduces plasma vitamin C concentrations.37 This lower circulating level of vitamin C may be in itself a potential causative factor in the development of gastric cancer. Successful eradication of H. pylori in a small patient sample has been shown to improve secretion of vitamin C into gastric juice. The speculation that this approach might increase protection against gastric cancer is supported by the results of a randomised controlled trial conducted in Columbia, in which treatment of patients at high risk of gastric cancer with a combination of vitamin C, beta-carotene and H. pylori eradication successfully promoted the regression of pre-malignant lesions.38 Due to differences in type and amount of phytochemicals (isothiocyanates, polyphenols, phytoestrogens, flavonoids etc.) it may be that certain types of vegetable have a more potent impact on risk of stomach cancer than others. In particular, there has been a considerable epidemiological research focus on the effects of vegetables from the Allium family (onions, garlic, leeks). A recent meta-analysis on the effects of garlic intake found a risk estimate of 0.53 (95% CI: 0.31, 0.92) associated with high levels of consumption,39 indicating a protective effect. However, the authors caution that since there was significant heterogeneity among studies the validity of this summary estimate is questionable. Interestingly, an aqueous extract of garlic cloves standardised for its thiosulphinate concentration and tested for its antimicrobial activity on H. pylori has been shown to exhibit a potent antimicrobial action even at low concentrations.40 In a cross-sectional survey of 214 adults who participated in a gastroscopic screening survey in Cangshan County in China (an area with low cancer risk) consumption of garlic showed non-significant protective effects and an inverse association with H. pylori infection.41 A possible increase in risk of gastric cancer associated with alcohol intake has been suggested from a meta-analysis of 16 cohort and caseecontrol studies of gastric cancer. Bagnardi et al,42 reported a pooled relative risk of 1.3 for a high intake of alcohol (100 g/day) but on the basis of the significant heterogeneity observed between studies the authors concluded that it was not possible to infer causality from these data. Evidence is still insufficient to establish whether cancer of the cardia or proximal region of the stomach is related to alcohol intake to any different extent than the rest of the stomach. However, one prospective study43 and four caseecontrol studies that reported a quantitative assessment of alcoholic drinks found no association with cancer of the gastric cardia.44e47 What is clear is that in direct contrast to the cardiovascular system, there is less evidence that moderate consumption of alcoholic beverages has beneficial health effects on the stomach.
Gastric cancer 643
Evidence that salt intake is inversely associated with risk of stomach cancer has accumulated over many decades. Salt intake has been assessed in numerous ways, including salt preference, consumption of salted foods, use of table salt, salt added during cooking and more accurately urinary sodium excretion. There are of course many problems regarding the evaluation of studies of this particular exposure. In particular, the measurement of salt intakes poses particular problems since dietary survey methodology may not accurately capture salt added at the table and during cooking. However, 24 h urinary sodium excretion, which is generally regarded as a better reflection of salt intake is also not devoid of measurement bias and error.48 Furthermore, since the mechanism of action of salt on gastric cancer risk is thought to be via irritation of the stomach lining49 and ultimately the development of atrophic gastritis, and this is also thought to occur with H. pylori infection, the effects of salt intake may be readily confounded by lack of adjustment for infection. Additionally, the consumption of salted foods commonly correlates with the intake of secondary amines and fresh vegetables as well as the method of preservation and storage of foods such as refrigeration and curing. There is consequently further potential for significant confounding of this exposure with other diet-related exposures. Adverse effects of a number of dietary exposures (particularly cured or salted meat and fish), are thought to be linked to the N-nitroso model of gastric carcinogenesis. N-nitroso compounds are potent carcinogens formed in vivo by the nitrosation of amides or amines in the stomach by nitrites, a process that is inhibited by vitamin C in gastric juice. In the stomach, nitrites are mainly derived from food and water sources, with the proportions varying according to dietary pattern and water source. For example, in one UK-based survey, approximately 90% of the nitrate intake was derived from vegetables. Cured meats provided about 65% of the nitrite intake.50 The contribution from drinking water was estimated to add a further 13.5 mg, about 12% of total intake. However, in the USA, about 80% of nitrite intake is vegetable in origin and about 10% is derived from drinking water. Despite continuing concern that the formation of nitrosamines from dietary pre-cursors may be causally related to gastrointestinal cancer, the epidemiological literature has failed to support this link with any degree of conviction.29 Smoking The recent IARC Monograph on Tobacco Smoke and Involuntary Smoking concluded that the results from both cohort and caseecontrol studies are consistent with a causal role of tobacco smoking in the development of stomach cancer.51 In a recent publication from a large European prospective Study (EPIC), an estimated 17.6% (95% CI ¼ 10.5e29.5%) of gastric cancer cases were attributable to smoking.52 This is somewhat higher than the worldwide estimated 11% attributable risk derived from a 1997 meta-analysis of smoking and stomach cancer. This meta-analysis suggested a risk of stomach cancer among smokers compared to non-smokers of the order of 1.5e1.6, with a somewhat higher summary estimate in males than in females.53 Medical conditions A number of medical conditions have been suggested to increase risk of stomach cancer. These include pernicious anaemia, peptic ulcer disease, and also prior experience
644 D. Forman and V. J. Burley
of gastric surgery.54 However, the use of non-steroidal anti-inflammatory drugs (NSAIDS) has been suggested to reduce risk of stomach cancer. In a meta-analysis of nine studies (eight caseecontrol and one cohort) with a total of 2831 gastric cancer cases, NSAID use was associated with a reduced risk of gastric cancer, with a summary odds ratio of 0.78 (95% CI ¼ 0.69 to 0.87).55 Occupation Occupational factors have been regarded as playing a smaller part in the aetiology of gastric cancer than dietary and other environmental exposures, although they may interact with various non-occupational factors at key stages in the development of gastric cancer.56 According to epidemiological studies, occupational exposures reported to increase the risk of stomach cancer include dusts, nitrogen oxides, N-nitroso compounds, and ionising radiation.56 Excess risks have been found for several occupational groups, including miners and quarrymen, farmers, fishermen, masonry and concrete workers, machine operators, nurses, food industry workers, cooks, launderers and dry cleaners.57e61 Anthropometry Whilst measures of obesity are generally positively related to risk of cancer, for stomach cancer there is a lack of consistency in the epidemiological literature. Variation in the impact of obesity on stomach cancer risk could be attributed to problems in obtaining unbiased reports of pre-disease weight, to differential risk according to tumour location and to publication bias. Within caseecontrol studies, measures of obesity are generally lower in stomach cancer cases than in control populations,62e66 but this may be due to bias in reporting in individuals who have experienced pre-diagnostic weight loss or a reflection of confounding by other factors, such as smoking, rather than indicating a benefit of excess adiposity. Large prospective cohort studies that reported risk of stomach cancer without differentiation according to tumour site also tend to show either negative or no association with body mass index (kg/m2) or other indices of obesity.67e73 However, some more recent prospective studies that have been able to report risk according to site of tumour origin have tended to suggest that risk of cancer occurring in the cardia or proximal region of the stomach may be somewhat elevated in obese individuals68,74,75 but reduced for cancers occurring in the noncardia or distal region of the stomach.43,75,76 Physical activity Compared to the literature base for a number of other gastrointestinal cancers, there are relatively few studies that have examined the relationship between physical activity and stomach cancer. One prospective cohort study of Japanese residents of Hawaii found an elevated risk of stomach cancer associated with the highest levels of both recreational and occupational physical activity when compared with mostly sedentary activity levels.77 However, neither resting heart rate nor activity during a 24 h period were related to stomach cancer risk. Within the UK, neither the Whitehall Study of London civil servants78 or the British Regional Heart Study79 found any relationship with self-reported
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recreational physical activity levels. While currently there is insufficient evidence to indicate whether this lack of association will also be found in studies that are able to examine risk according to gastric tumour location, one recent population-based caseecontrol study found no significant association for cancer of the gastric cardia with occupational activity even after comprehensive adjustment for socio-economic variables.80
SUMMARY Worldwide, there are currently over 900,000 new diagnoses of gastric cancer each year making this the third and fifth most common form of cancer in males and females, respectively. Incidence rates in males are approximately double those in females and, in both sexes, are strongly related to age. There is a 10-fold variation in incidence between the highest and lowest risk populations and rates are notably high in East Asia, South America and Eastern Europe. Incidence rates in most populations have been declining substantially over several decades. Gastric cancer arising in the proximal cardia region of the stomach has been reported, however, to show different trends from that of the disease elsewhere in the stomach. This form of the cancer may be increasing in incidence in some populations and it also has a different geographical distribution and a higher male to female incidence ratio compared with distal non-cardia cancer. Classification problems and variation in recording practice complicate accurate reporting of cardia cancer. The main identified environmental risk factors for gastric cancer are Helicobacter pylori infection, associated with at least a 6-fold risk of cancer and various dietary exposures. Of the latter, much evidence relates increased consumption of fruit and vegetables to a decreased risk of gastric cancer although more recent prospective studies are failing to confirm this relationship. There is no evidence that vitamin supplementation reduces the risk of gastric cancer. Although much research has been carried out into the role of dietary salt and nitrate intake and alcohol consumption in the aetiology of gastric cancer there is no clear consensus about the importance of these risk factors. Smoking is, however, associated with a modest increased risk of gastric cancer.
Practice points Despite a worldwide decline in incidence gastric cancer remains as a major malignant disease in many populations. Helicobacter pylori is an established cause of gastric cancer. High intake of fruit and vegetables has been associated with a reduced risk of gastric cancer although recent data have failed to confirm this relationship. Adherence to recommendations to consume at least five portions of fruits and vegetables daily remains, however, strongly advisable. There is no evidence that antioxidant vitamin supplements are useful in the prevention of gastric cancer. Smoking contributes to the risk of gastric cancer.
646 D. Forman and V. J. Burley
Research agenda Further work is required to improve the consistency in the recording of gastric cancer by sub-site in order to understand the descriptive epidemiology of cardia cancer in more detail. More results from large prospective studies of diet and gastric cancer making use of appropriate biomarkers are required to understand the role of fruit, vegetables, salt and other foods and nutrients in the aetiology of the disease. Exploration of potentially synergistic interactions between dietary variables, Helicobacter pylori infection and genetic polymorphisms is warranted. Although important in other cancers, the role of obesity and physical activity in the aetiology of gastric cancer remains unclear and requires further investigation.
REFERENCES 1. Ferlay J, Bray F, Pisani P et al. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide, Version 2.0. IARC CancerBase No. 5. Lyon: IARC Press; 2004. 2. Parkin DM, Whelan SL, Ferlay J et al. Cancer Incidence in Five Continents, Vol. VIII. Lyon: IARC; 2002. IARC Scientific Publications. No. 155. 3. Sipponen P & Correa P. Delayed rise in incidence of gastric cancer in females results in unique sex ratio (M/F) pattern: etiologic hypothesis. Gastric Cancer 2002; 5: 213e219. 4. Naess O, Claussen B, Thelle DS et al. Four indicators of socioeconomic position: relative ranking across causes of death. Scand J Public Health 2005; 33: 215e221. 5. Power C, Hypponen E & Smith GD. Socioeconomic position in childhood and early adult life and risk of mortality: a prospective study of the mothers of the 1958 British birth cohort. Am J Public Health 2005; 95: 1396e1402. 6. Hemminki K, Zhang H & Czene K. Socioeconomic factors in cancer in Sweden. Int J Cancer 2003; 105: 692e700. 7. Howard G, Anderson RT, Russell G et al. Race, socioeconomic status, and cause-specific mortality. Ann Epidemiol 2000; 10: 214e223. 8. van Loon AJ, Goldbohm RA & van den Brandt PA. Socioeconomic status and stomach cancer incidence in men: results from The Netherlands Cohort Study. J Epidemiol Community Health 1998; 52: 166e171. 9. Brewster DH, Fraser LA, McKinney PA et al. Socioeconomic status and risk of adenocarcinoma of the oesophagus and cancer of the gastric cardia in Scotland. Br J Cancer 2000; 83: 387e390. *10. Ferretti S & Gafa L. Upper gastrointestinal tract cancers: oesophagus, stomach, liver, gallbladder and biliary ducts, pancreas. Epidemiol Prev 2004; 28: 34e42. 11. Howson CP, Hiyama T & Wynder EL. The decline in gastric cancer: epidemiology of an unplanned triumph. Epidemiol Rev 1986; 8: 1e27. 12. Berrino F. The EUROCARE Study: strengths, limitations and perspectives of population-based, comparative survival studies. Ann Oncol 2003; 14(supplement 5): v9ev13. 13. Gatta G, Capocaccia R, Coleman MP et al. Toward a comparison of survival in American and European cancer patients. Cancer 2000; 89: 893e900. *14. Verdecchia A, Mariotto A, Gatta G et al. Comparison of stomach cancer incidence and survival in four continents. Eur J Cancer 2003; 39: 1603e1609. 15. Forman D, Everett S & Moayyedi P. Screening for stomach cancer. Evidence Based Oncology. London: BMJ Publications; 2003. 16. Botterweck AA, Schouten LJ, Volovics A et al. Trends in incidence of adenocarcinoma of the oesophagus and gastric cardia in ten European countries. Int J Epidemiol 2000; 29: 645e654.
Gastric cancer 647 *17. Devesa SS, Blot WJ & Fraumeni Jr. JF. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998; 83: 2049e2053. 18. Kubo A & Corley DA. Marked multi-ethnic variation of esophageal and gastric cardia carcinomas within the United States. Am J Gastroenterol 2004; 99: 582e588. 19. Vizcaino AP, Moreno V, Lambert R et al. Time trends incidence of both major histologic types of esophageal carcinomas in selected countries, 1973e1995. Int J Cancer 2002; 99: 860e868. 20. Forman D. Counting cancers at the junction e a problem of routine statistics. Eur J Gastroenterol Hepatol 2002; 14: 99e101. 21. Corley DA & Kubo A. Influence of site classification on cancer incidence rates: an analysis of gastric cardia carcinomas. J Natl Cancer Inst 2004; 96: 1383e1387. 22. Verdecchia A, Corazziari I, Gatta G et al. Explaining gastric cancer survival differences among European countries. Int J Cancer 2004; 109: 737e741. 23. Moayyedi P, Axon ATR, Feltbower R et al. Relation of adult lifestyle and socioeconomic factors to the prevalence of Helicobacter pylori infection. Int J Epidemiol 2002; 31: 624e631. *24. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001; 49: 347e353. 25. Ekstrom AM, Held M, Hansson LE et al. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology 2001; 121: 784e791. 26. Naumann M & Crabtree JE. Helicobacter pylori-induced epithelial cell signalling in gastric carcinogenesis. Trends Microbiol 2004; 12: 29e36. 27. Ekstrom AM, Serafini M, Nyren O et al. Dietary antioxidant intake and the risk of cardia cancer and noncardia cancer of the intestinal and diffuse types: a population-based caseecontrol study in Sweden. Int J Cancer 2000; 87: 133e140. 28. Committee on Medical Aspects of Food and Nutrition Policy. Nutritional Aspects of the Development of Cancer. Report of the Working Group on Diet and Cancer of the Committee on Medical Aspects of Food and Nutrition Policy. 48. London: The Stationery Office; 1998. 29. World Cancer Research Fund, American Institute for Cancer Research. Food, Nutrition and the Global Prevention of Cancer: A Global Perspective. Washington, USA: American Institute for Cancer Research; 1997. *30. Riboli E & Norat T. Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk. Am J Clin Nutr 2003; 78: 559Se569S. 31. Gonzalez CA, Pera G, Agudo A et al. Fruit and vegetable intake and the risk of stomach and oesophagus adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Int J Cancer 2006; 118: 2559e2566. 32. Steinmetz KA & Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc 1996; 96: 1027e1039. *33. Bjelakovic G, Nikolova D, Simonetti RG et al. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis (see comment). (review) (71 refs). Lancet 2004; 364: 1219e1228. 34. Bjelakovic G, Nikolova D, Simonetti RG et al. Antioxidant supplements for preventing gastrointestinal cancers: a systematic review and meta-analysis (see comment). (review) [167 refs]. Cochrane Database Syst Rev 2004 (CD004183). 35. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994; 330: 1029e1035. 36. Blot WJ, Li JY, Taylor PR et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993; 85: 1483e1492. 37. Woodward M, Tunstall-Pedoe H & McColl K. Helicobacter pylori infection reduces systemic availability of dietary vitamin C. Eur J Gastroenterol Hepatol 2001; 13: 233e237. 38. Correa P, Fontham ET, Bravo JC et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-helicobacter pylori therapy. J Natl Cancer Inst 2000; 92: 1881e1888. 39. Fleischauer AT, Poole C & Arab L. Garlic consumption and cancer prevention: meta-analyses of colorectal and stomach cancers. Am J Clin Nutr 2000; 72: 1047e1052. 40. Sivam GP, Lampe JW, Ulness B et al. Helicobacter pylori e in vitro susceptibility to garlic (Allium sativum) extract. Nutr Cancer 1997; 27: 118e121.
648 D. Forman and V. J. Burley 41. You WC, Zhang L, Gail MH et al. Helicobacter pylori infection, garlic intake and precancerous lesions in a Chinese population at low risk of gastric cancer. Int J Epidemiol 1998; 27: 941e944. *42. Bagnardi V, Blangiardo M, La Vecchia C et al. A meta-analysis of alcohol drinking and cancer risk. Br J Cancer 2001; 85: 1700e1705. 43. Tran GD, Sun XD, Abnet CC et al. Prospective study of risk factors for esophageal and gastric cancers in the Linxian general population trial cohort in China. Int J Cancer 2005; 113: 456e463. 44. Unakami M, Hara M, Fukuchi S et al. Cancer of the gastric cardia and the habit of smoking. Acta Pathol Jpn 1989; 39: 420e424. 45. Palli D, Bianchi S, Decarli A et al. A caseecontrol study of cancers of the gastric cardia in Italy. Br J Cancer 1992; 65: 263e266. 46. Wu AH, Wan P & Bernstein L. A multiethnic population-based study of smoking, alcohol and body size and risk of adenocarcinomas of the stomach and esophagus (United States). Cancer Causes Control 2001; 12: 721e732. 47. Gammon MD, Schoenberg JB, Ahsan H et al. Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia (see comment). J Natl Cancer Inst 1997; 89: 1277e1284. 48. Johansson G, Bingham S & Vahter M. A method to compensate for incomplete 24-hour urine collections in nutritional epidemiology studies. Public Health Nutr 1999; 2: 587e591. 49. Charnley G & Tannenbaum SR. Flow cytometric analysis of the effect of sodium chloride on gastric cancer risk in the rat. Cancer Res 1985; 45: 5608e5616. 50. Knight TM, Forman D, Al Dabbagh SA et al. Estimation of dietary intake of nitrate and nitrate in Great Britain. Food Chem Toxicol 1987; 25: 277e285. *51. Tobacco Smoke and Involuntary Smoking. Lyon, France: World Health Organisation; 2004. 52. Gonzalez CA, Pera G, Agudo A et al. Smoking and the risk of gastric cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC). Int J Cancer 2003; 107: 629e634. 53. Tredaniel J, Boffetta P, Buiatti E et al. Tobacco smoking and gastric cancer: review and meta-analysis. Int J Cancer 1997; 72: 565e573. 54. Kelley JR & Duggan JM. Gastric cancer epidemiology and risk factors. J Clin Epidemiol 2003; 56: 1e9. 55. Wang WH, Huang JQ, Zheng GF et al. Non-steroidal anti-inflammatory drug use and the risk of gastric cancer: a systematic review and meta-analysis. J Natl Cancer Inst 2003; 95: 1784e1791. 56. Cocco P, Palli D, Buiatti E et al. Occupational exposures as risk factors for gastric cancer in Italy. Cancer Causes Control 1994; 5: 241e248. 57. Aragones N, Pollan M & Gustavsson P. Stomach cancer and occupation in Sweden: 1971e89. Occup Environ Med 2002; 59: 329e337. 58. Simpson J, Roman E, Law G et al. Women’s occupation and cancer: preliminary analysis of cancer registrations in England and Wales, 1971e1990. Am J Ind Med 1999; 36: 172e185. 59. Kang S-K, Burnett CA, Freund E et al. Gastrointestinal cancer mortality of workers in occupations with high asbestos exposures. Am J Ind Med 1997; 31: 713e718. 60. Swanson GM & Burns PB. Cancer incidence among women in the workplace: a study of the association between occupation and industry and 11 cancer sites. J Occup Environ Med 1995; 37: 282e287. 61. Chow W-H, McLaughlin JK, Malker HSR et al. Occupation and stomach cancer in a cohort of Swedish men. Am J Ind Med 1994; 26: 511e520. 62. Chatenoud L, La Vecchia C, Franceschi S et al. Refined-cereal intake and risk of selected cancers in italy. Am J Clin Nutr 1999; 70: 1107e1110. 63. De Stefani E, Correa P, Boffetta P et al. Dietary patterns and risk of gastric cancer: a caseecontrol study in Uruguay. Gastric Cancer 2004; 7: 211e220. 64. Huang XE, Tajima K, Hamajima N et al. Comparison of lifestyle and risk factors among Japanese with and without gastric cancer family history. Int J Cancer 2000; 86: 421e424. 65. Inoue M, Ito LS, Tajima K et al. Height, weight, menstrual and reproductive factors and risk of gastric cancer among Japanese postmenopausal women: analysis by subsite and histologic subtype (see comment). Int J Cancer 2002; 97: 833e838. 66. Munoz N, Plummer M, Vivas J et al. A caseecontrol study of gastric cancer in Venezuela. Int J Cancer 2001; 93: 417e423. 67. Calle EE, Rodriguez C, Walker-Thurmond K et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults (see comment). N Engl J Med 2003; 348: 1625e1638.
Gastric cancer 649 68. Kuriyama S, Tsubono Y, Hozawa A et al. Obesity and risk of cancer in Japan. Int J Cancer 2005; 113: 148e157. 69. Lukanova A, Bjor O, Kaaks R et al. Body mass index and cancer: results from the Northern Sweden Health and Disease Cohort. Int J Cancer 2006; 118: 458e466. 70. Sauvaget C, Lagarde F, Nagano J et al. Lifestyle factors, radiation and gastric cancer in atomic-bomb survivors (Japan). Cancer Causes Control 2005; 16: 773e780. 71. Tulinius H, Sigfusson N, Sigvaldason H et al. Risk factors for malignant diseases: a cohort study on a population of 22,946 Icelanders. Cancer Epidemiol Biomarkers Prev 1997; 6: 863e873. 72. Wolk A, Gridley G, Svensson M et al. A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control 2001; 12: 13e21. 73. Zhang J, Su XQ, Wu XJ et al. Effect of body mass index on adenocarcinoma of gastric cardia. World J Gastroenterol 2003; 9: 2658e2661. 74. Jansson C, Johansson AL, Bergdahl IA et al. Occupational exposures and risk of esophageal and gastric cardia cancers among male Swedish construction workers. Cancer Causes Control 2005; 16: 755e764. 75. Lindblad M, Rodriguez LA & Lagergren J. Body mass, tobacco and alcohol and risk of esophageal, gastric cardia, and gastric non-cardia adenocarcinoma among men and women in a nested caseecontrol study. Cancer Causes Control 2005; 16: 285e294. 76. Tretli S & Robsahm TE. Height, weight and cancer of the oesophagus and stomach: a follow-up study in Norway. Eur J Cancer Prev 1999; 8: 115e122. 77. Severson RK, Nomura AM, Grove JS et al. A prospective analysis of physical activity and cancer. Am J Epidemiol 1989; 130: 522e529. 78. Smith GD, Shipley MJ, Batty GD et al. Physical activity and cause-specific mortality in the Whitehall study. Public Health 2000; 114: 308e315. 79. Wannamethee SG, Shaper AG & Walker M. Physical activity and risk of cancer in middle-aged men. Br J Cancer 2001; 85: 1311e1316. 80. Vigen C, Bernstein L & Wu AH. Occupational physical activity and risk of adenocarcinomas of the esophagus and stomach. Int J Cancer 2006; 118: 1004e1009.
1 Gastric cancer: global pattern of the disease and an overview of environmental risk factors D. Forman*
PhD Cancer Epidemiology Group, Centre for Epidemiology and Biostatistics, University of Leeds, Leeds LS2 9LN, UK
V.J. Burley
PhD
Nutritional Epidemiology Group, Centre for Epidemiology and Biostatistics, University of Leeds, Leeds LS2 9LN, UK
This first part of this chapter looks at the worldwide burden of gastric cancer at the beginning of the 21st century and summarises available population-based routine data that describes the variation in incidence of the disease in relation to age, sex, geography and time period. Consideration is also given to the differences in the descriptive epidemiology of gastric cancer arising in the proximal cardia region of the stomach. In the second part of the chapter, a brief review of the main identified environmental risk factors is conducted drawing, where available, on published systematic literature overviews and meta-analyses. Evidence relating the aetiology of gastric cancer to Helicobacter pylori infection, dietary factors, smoking, occupation, physical activity and anthropometry is presented. Key words: incidence; mortality; geographical variation; time trends; Helicobacter pylori; diet; environmental risk factors; cardia; smoking; alcohol; obesity; physical activity.
CURRENT GLOBAL INCIDENCE AND MORTALITY RATES OF GASTRIC CANCER Gastric cancer (cancer of the stomach) is a disease in which malignant cells arise in the tissues of the stomach. Since most malignant tumours of the stomach are epithelial in origin the overwhelming majority of cancers of the stomach are adenocarcinomas and most of the routine statistics about gastric cancer refer to this histological entity. Table 1 shows that in 2002 there were an estimated 930,000 new diagnoses and 700,000 deaths from gastric cancer worldwide.1 Overall age-standardised incidence rates were 22.0 and 10.3 per 100,000 per annum in males and females, respectively, with corresponding mortality rates being 14.3 and 8.3 per 100,000.1 Gastric cancer * Corresponding author. Tel.: þ44 113 392 4309; Fax: þ44 113 392 4178. E-mail addresses: [email protected] (D. Forman), [email protected] (V.J. Burley). 1521-6918/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.
634 D. Forman and V. J. Burley
Table 1. Estimated number of new registrations and deaths (000s) and age-standardiseda incidence and mortality rates from gastric cancer by sex; more-developed countries, less-developed countries and world for 2002. Estimated number of new registrations
Estimated number of deaths
Age-standardised incidence rate per 100,000
Age-standardised mortality rate per 100,000
More-developed countries Males 195.8 Females 115.4 Total 311.2
128.7 83.5 212.2
22.3 10.0 e
14.5 6.9 e
Less-developed Males Females Total
countries 404.8 213.8 618.6
315.2 169.8 482.0
21.5 10.4 e
17.0 8.3 e
World Males Females Total
603.0 303.3 933.3
445.7 254.1 699.8
22.0 10.3 e
16.3 7.9 e
Source: Ref. 1. a Standardised to world standard population.
was the third most common cause of male cancer (after lung and prostate cancers) and the second most common cause of male cancer death (after lung cancer). It was the fifth most common cause of female cancer (after breast, cervix, large bowel and lung cancers) and the fourth most common cause of female cancer death.1 As with most of the common cancers, there is considerable geographic variation in the incidence of gastric cancer throughout the world with some of the lowest rates seen in North America and Western Europe and the highest in East Asia, South America and Eastern Europe. Results for gastric cancer from the most recent edition of Cancer Incidence in Five Continents, reporting incidence rates from population-based cancer registries worldwide meeting minimum defined quality standards, are presented in Figure 1.2 This shows age-standardised rates for gastric cancer, diagnosed in the period 1993e1997, from selected cancer registries. In both sexes, there was more than a 10-fold variation in incidence between the lowest (USA whites) and highest (Japanese from the Miyagi prefecture) risk populations. The distribution of gastric cancer does not, however, always follow a clear geographical pattern. Thus although some of the world’s highest risk populations are in Asian countries, such as Japan, Korea and China, other Asian countries have relatively low rates (e.g. India). There are also some very high-risk groups within low-risk populations (e.g. Koreans living in the USA). Gastric cancer cannot readily be categorised as being associated with relatively under developed economies. Although approximately two-thirds of all cases arise in ‘less-developed’ countries, in 2002 overall age-standardised incidence rates were comparable between such countries and those defined as ‘more developed’ (Table 1). Several countries in the latter category have high gastric cancer incidence rates, notably Japan but also those in Eastern and, to a lesser extent, Southern Europe. Contrariwise, many of the world’s poorest economies, especially in Africa, appear to have relatively
Gastric cancer 635
Japan, Miyagi Prefecture USA, California, Los Angeles: Korean Costa Rica Portugal, Vila Nova de Gaia China, Shanghai Estonia Colombia, Cali Singapore: Chinese Slovenia Females Males
Poland, Lower Silesia Mali, Bamako USA, SEER: Black UK, England Finland Denmark USA, SEER: White India, Mumbai (Bombay) The Gambia
0
20
40
60
80
Figure 1. Age-standardised (world standard population) gastric cancer incidence rates per 100,000 for selected cancer registries worldwide by sex, cases diagnosed 1993e1997. Source: Ref. 2.
low incidence rates of gastric cancer. It is difficult to exclude the suggestion that poor standards of diagnosis and reporting in such countries are responsible for such low reported rates especially for cancers arising in internal body organs such as the stomach. Rates do, however, remain low in countries such as The Gambia (Figure 1) where particular efforts have been made to establish reliable cancer registration and where other internal cancers, such as primary liver cancer, are reported to be extremely high.
636 D. Forman and V. J. Burley
Figure 2. Gastric cancer incidence rates per 100,000 by 5-year age group and sex for (a) Japan (Miyagi) and (b) USA White SEER populations, cases diagnosed 1993e1997. Source: Ref. 2.
As with most solid tumours the incidence rate of gastric cancer increases with age and the cancer is relatively rare in males or females under 45 years. Most patients are between 60 and 80 years old at diagnosis (Figure 2). One feature that is, however, consistently observed in all populations (reflected in a comparison of the sexes in Figure 1) is the approximately doubling of the age-standardised risk in males compared to females. In general, female incidence rates at a given age are equivalent to male rates at an age 10 years younger. The consistency of this difference has never been adequately explained although theories have been advanced in which female sex-specific hormones may play a protective role.3 A further consistent feature of the epidemiology of gastric cancer is that, within any population, rates of the disease tend to be higher in those who are relatively poorer and socio-economically deprived.4e9 TIME TRENDS IN GASTRIC CANCER INCIDENCE Figures 3 and 4 provide information, for males and females, on gastric cancer incidence trends over time for many of the cancer registry populations shown in Figure 1 where comparable data have been available for a number of years. In virtually all of these populations, the underlying pattern, for both sexes, is one of the rapidly declining incidence rates over the entire time period considered irrespective of whether the background risk of gastric cancer is high or low. The two exceptions to this pattern are for the Japanese population (Miyagi prefecture) where, at least in males, the very high rates remained high until the early 1990s and the Indian population (Bombay) where rates remained constantly very low. Declining incidence rates for gastric cancer
Gastric cancer 637
Figure 3. Age-standardised (world standard population) male gastric cancer incidence rates per 100,000 for selected cancer registries worldwide by time period. Source: Parkin, D.M., Whelan, S.L., Ferlay, J., and Storm, H. Cancer Incidence in Five Continents, Vol. IeVIII IARC CancerBase No. 7, Lyon, 2005. (http:// www-dep.iarc.fr/).
represent, therefore, the dominant global epidemiological pattern for this disease and, as mortality is closely associated with incidence, mortality rates have shown a very similar pattern. It has, however, been suggested that mortality may have declined at a faster rate than incidence at least in some populations.10 In many countries, where gastric cancer used to be the leading cause of cancer-related death in the early or mid20th century, the decline in incidence has resulted in other emergent cancers, especially lung, breast and prostate cancers, becoming relatively more important. In certain instances, notably among the white US population, gastric cancer has now become an extremely rare diagnosis, the decline being hailed as an ‘unplanned triumph’.11 Despite this notable decline, it needs to be remembered that the 2002 incidence and mortality estimates, cited above, still make gastric cancer an important component of the global cancer burden. It is also not necessarily the case that, in absolute terms, the disease will become uniformly rare. Even assuming the current decline in incidence will continue in the future, the predicted growth in world population combined with increased longevity will most likely result in a net increase in the overall number of gastric cancers being diagnosed for several decades to come.Table 2 provides a comparison of the overall number of new cases and deaths from gastric cancer in 2002 compared with that estimated for 2020 in both ‘more-’ and ‘less-developed countries’.
638 D. Forman and V. J. Burley
Figure 4. Age-standardised (world standard population) female gastric cancer incidence rates per 100,000 for selected cancer registries worldwide by time period. Source: Parkin, D.M., Whelan, S.L., Ferlay, J., and Storm, H. Cancer Incidence in Five Continents, Vol. IeVIII IARC CancerBase No. 7, Lyon, 2005. (http:// www-dep.iarc.fr/).
Table 2. Estimated number (000s) of new registrations and deaths from gastric cancer in 2002 and projectionsa for 2010 and 2020; more-developed countries, less-developed countries and world. 2002
2010
2020
More-developed countries Registrations Deaths
311.2 212.2
297.1 202.6
282.5 127.7
Less-developed countries Registrations Deaths
618.6 482.0
659.7 517.9
723.4 573.3
World Registrations Deaths
933.3 699.8
960.1 720.0
1009.8 762.6
Source: Ref. 1. a With assumption of average e 2.0% decrease per annum in age-specific incidence/mortality rates.
Gastric cancer 639
This shows that while there will be a decrease in cases and deaths in the former, this will be outweighed by an increase in the latter and thus, worldwide, there will be a modest increase in gastric cancer. This is based on the assumption that age-specific rates for both incidence and mortality continue to decline by 2% per annum, as has been the situation over the last two decades. GASTRIC CANCER SURVIVAL RATES In general survival rates from gastric cancer have been poor. The EUROCARE study12 estimated average European survival for cases diagnosed in the period 1990e1994 to be around 42% at 12 months and 24% at 5 years after diagnosis. Considerable variation between countries, from 11 to 30% at 5 years, was reported with only marginal improvements over the preceding decade. Survival rates in countries outside Europe are broadly within the range observed in European countries,13,14 the notable exception being in Japan where rates can be considerably higher due to the impact of population-based screening in some localities and the diagnosis of ‘early gastric cancer’.15 GASTRIC CANCER: SUB-SITE DISTRIBUTION The above descriptive epidemiology all relates to gastric cancer considered as a single entity. Until recently, relatively little attention was directed towards differences between the sub-site distribution of gastric cancer and the majority of existing epidemiology studies have not distinguished between the major anatomic divisions within the stomach. However, some studies over the last 10e15 years have identified cancers within the region adjoining the oesophago-gastric junction (the gastric cardia) as having a different epidemiology from cancers in more distal (non-cardia) regions. In most populations and in all but the most recent time periods, gastric cardia cancers represented a relatively small proportion of the total gastric cancer incidence and thus the overall trends, presented in Figures 1e4, largely reflect those for non-cardia cancer. There have been numerous reports indicating that gastric cardia cancers have been increasing in incidence in recent decades16e19 thus providing a contrasting trend from that observed for gastric cancer overall. The geographical pattern of gastric cardia cancer is somewhat more complex. As seen in Figure 5, populations such as those in Japan, which have had high rates of gastric cancer overall also have reported relatively high rates of cardia cancer. This was also the case, however, for populations, such as whites in the USA that have had low rates of gastric cancer overall. As a proportion of the total gastric cancer incidence, the contribution from the cardia is, therefore, much higher in such low-risk populations. Because gastric cardia cancers are not readily distinguished from lower oesophageal adenocarcinomas, there has undoubtedly been some variation in pathology practice in the organ to which these cancers have been assigned for classification purposes. Such variation may be present both between countries and over different time periods, thereby complicating interpretation of geographical and secular trends.20 The recent interest in cardia cancer has also resulted in an increased use of sub-site specific codes in routine data sets and it is, therefore, difficult to disentangle any genuine increases in incidence from artefactual improvements in reporting practice.21 Comparisons within the same populations over the same time period may, therefore, be more informative. Thus within the SEER cancer registries in the USA, whites have had higher rates of cardia cancer than blacks in contrast to the pattern for gastric
640 D. Forman and V. J. Burley
Japan, Miyagi Prefecture
China, Shanghai
Portugal, Vila Nova de Gaia
Costa Rica USA, California, Los Angeles: Korean UK, England
Denmark
USA, SEER: White Females
Slovenia
Males
Finland
Estonia
Singapore: Chinese
Poland, Lower Silesia
USA, SEER: Black
Colombia, Cali
India, Mumbai (Bombay)
Mali, Bamako
0
2
4
6
8
Figure 5. Age-standardised (world standard population) gastric cancer of the cardia incidence rates per 100,000 for selected cancer registries worldwide by sex, cases diagnosed 1993e1997. Source: Ref. 2.
cancer overall. Comparisons by sex (Figure 5) also show that male cardia cancer rates were three to four times greater than those in females indicating a larger excess than the 2:1 ratio for gastric cancer overall. Also unlike the situation for gastric cancer overall, and although relatively little data have been published, there would appear to be no association between gastric cardia cancer and poor socio-economic status.9 Survival rates from gastric cardia cancer tend to be slightly less favourable than those for gastric cancer overall14,22 and this means that populations, such as within
Gastric cancer 641
the USA, where cardia cancer represents a relatively high proportion of the total have an adverse overall survival in comparison with other populations with lower rates of cardia cancer.13 RISK FACTORS FOR GASTRIC CANCER Helicobacter pylori H. pylori is a gram-negative bacterium which has been aetiologically linked with gastric cancer in numerous ecologic, cohort and caseecontrol studies over the last two decades. Infection rates tend to be highest in those of lower socio-economic status, matching the incidence of gastric cancer,23 and the fall in gastric cancer incidence in developed countries has been paralleled by the declining H. pylori infection rates. However, the strongest evidence to support the role of H. pylori in gastric cancer development comes from prospective cohort studies. A pooled analysis of data from 12 prospective cohort studies demonstrated a 6-fold elevation in risk occurring after 10 years of follow-up.24 It should be noted that there were differences in the risk estimates according to the age of the cases and also notably by cancer sub-site.24 More recent evidence indicates that the use of more sensitive methods to detect H. pylori infection results in substantially higher risk estimates for gastric cancer.25 Although there are a variety of proposed mechanisms whereby H. pylori infection may increase the risk of gastric cancer, it is thought that the primary mode of action is through the induction of long-term chronic inflammation.26 Relatively few studies have examined the joint effects of both H. pylori infection and diet as causes of gastric cancer although one caseecontrol study from Sweden suggests that infection may act as an effect modifier for dietary risk factors.27 The role of H. pylori in the aetiology of gastric cancer will be considered in detail elsewhere in this volume (Chapter 6). Dietary factors There is a comprehensive body of literature investigating the interactions between dietary factors and the development of gastric cancer and there are a number of clearly identifiable dietary exposures that have been strongly implicated in gastric cancer causation and prevention. One conclusion to emerge from many studies has been that a diet high in fruit and vegetables reduces the risk of developing gastric cancer.28,29 A recent meta-analysis of studies reporting on fruit and vegetable intake in relation to the risk of gastric cancer is broadly in agreement with these conclusions. Riboli and Norat30 found that for each 100 g increase in vegetable intake the pooled estimate of relative risk was 0.81 (95% CI: 0.75, 0.87) and for fruit it was 0.74 (95% CI: 0.69, 0.81) indicative of a protective effect. The risk estimates were, however, closer to unity and no longer statistically significant when considering only the more reliable prospective studies 0.89 (95% CI: 0.75, 1.05) for vegetable intake and 0.89 (95% CI: 0.73, 1.09) for fruit intake. These results did not include the recently published data from the large European Prospective Study (EPIC)31 which again reported the absence of any effect associated with vegetable 0.91 (95% CI: 0.65, 1.28) or fruit intake 1.04 (95% CI: 0.91, 1.02) per 100 gm increase. Whilst it is apparent that there are many potential mechanisms through which a diet high in fruit and vegetables may be protective against cancer,32 what the active
642 D. Forman and V. J. Burley
component is in the case of stomach cancer is by no means clear. One possibility is related to the antioxidant capacity of fruit and vegetables, which is related to the content of beta-carotene, alpha-tocopherol and vitamin C content. Recently, Bjelakovic et al,33,34 using Cochrane Collaboration methodology, reviewed all randomised trials comparing antioxidant supplements with placebo for prevention of gastrointestinal cancers. They did not find evidence that antioxidant supplements prevent gastrointestinal cancers in general, or stomach cancer specifically. Two randomised vitamin supplementation trials that were included in the review35,36 suggested that any protective effect of micronutrient supplementation is likely to be restricted to those with existing poor nutrient status. The relationship between vitamin C intakes, vitamin C status and risk of gastric cancer is further complicated by the relationship of this nutrient to H. pylori infection. Infection with H. pylori is known to substantially reduce the bioavailability of vitamin C and, when combined with the reduced vitamin C intake in H. pylori-positive people, this markedly reduces plasma vitamin C concentrations.37 This lower circulating level of vitamin C may be in itself a potential causative factor in the development of gastric cancer. Successful eradication of H. pylori in a small patient sample has been shown to improve secretion of vitamin C into gastric juice. The speculation that this approach might increase protection against gastric cancer is supported by the results of a randomised controlled trial conducted in Columbia, in which treatment of patients at high risk of gastric cancer with a combination of vitamin C, beta-carotene and H. pylori eradication successfully promoted the regression of pre-malignant lesions.38 Due to differences in type and amount of phytochemicals (isothiocyanates, polyphenols, phytoestrogens, flavonoids etc.) it may be that certain types of vegetable have a more potent impact on risk of stomach cancer than others. In particular, there has been a considerable epidemiological research focus on the effects of vegetables from the Allium family (onions, garlic, leeks). A recent meta-analysis on the effects of garlic intake found a risk estimate of 0.53 (95% CI: 0.31, 0.92) associated with high levels of consumption,39 indicating a protective effect. However, the authors caution that since there was significant heterogeneity among studies the validity of this summary estimate is questionable. Interestingly, an aqueous extract of garlic cloves standardised for its thiosulphinate concentration and tested for its antimicrobial activity on H. pylori has been shown to exhibit a potent antimicrobial action even at low concentrations.40 In a cross-sectional survey of 214 adults who participated in a gastroscopic screening survey in Cangshan County in China (an area with low cancer risk) consumption of garlic showed non-significant protective effects and an inverse association with H. pylori infection.41 A possible increase in risk of gastric cancer associated with alcohol intake has been suggested from a meta-analysis of 16 cohort and caseecontrol studies of gastric cancer. Bagnardi et al,42 reported a pooled relative risk of 1.3 for a high intake of alcohol (100 g/day) but on the basis of the significant heterogeneity observed between studies the authors concluded that it was not possible to infer causality from these data. Evidence is still insufficient to establish whether cancer of the cardia or proximal region of the stomach is related to alcohol intake to any different extent than the rest of the stomach. However, one prospective study43 and four caseecontrol studies that reported a quantitative assessment of alcoholic drinks found no association with cancer of the gastric cardia.44e47 What is clear is that in direct contrast to the cardiovascular system, there is less evidence that moderate consumption of alcoholic beverages has beneficial health effects on the stomach.
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Evidence that salt intake is inversely associated with risk of stomach cancer has accumulated over many decades. Salt intake has been assessed in numerous ways, including salt preference, consumption of salted foods, use of table salt, salt added during cooking and more accurately urinary sodium excretion. There are of course many problems regarding the evaluation of studies of this particular exposure. In particular, the measurement of salt intakes poses particular problems since dietary survey methodology may not accurately capture salt added at the table and during cooking. However, 24 h urinary sodium excretion, which is generally regarded as a better reflection of salt intake is also not devoid of measurement bias and error.48 Furthermore, since the mechanism of action of salt on gastric cancer risk is thought to be via irritation of the stomach lining49 and ultimately the development of atrophic gastritis, and this is also thought to occur with H. pylori infection, the effects of salt intake may be readily confounded by lack of adjustment for infection. Additionally, the consumption of salted foods commonly correlates with the intake of secondary amines and fresh vegetables as well as the method of preservation and storage of foods such as refrigeration and curing. There is consequently further potential for significant confounding of this exposure with other diet-related exposures. Adverse effects of a number of dietary exposures (particularly cured or salted meat and fish), are thought to be linked to the N-nitroso model of gastric carcinogenesis. N-nitroso compounds are potent carcinogens formed in vivo by the nitrosation of amides or amines in the stomach by nitrites, a process that is inhibited by vitamin C in gastric juice. In the stomach, nitrites are mainly derived from food and water sources, with the proportions varying according to dietary pattern and water source. For example, in one UK-based survey, approximately 90% of the nitrate intake was derived from vegetables. Cured meats provided about 65% of the nitrite intake.50 The contribution from drinking water was estimated to add a further 13.5 mg, about 12% of total intake. However, in the USA, about 80% of nitrite intake is vegetable in origin and about 10% is derived from drinking water. Despite continuing concern that the formation of nitrosamines from dietary pre-cursors may be causally related to gastrointestinal cancer, the epidemiological literature has failed to support this link with any degree of conviction.29 Smoking The recent IARC Monograph on Tobacco Smoke and Involuntary Smoking concluded that the results from both cohort and caseecontrol studies are consistent with a causal role of tobacco smoking in the development of stomach cancer.51 In a recent publication from a large European prospective Study (EPIC), an estimated 17.6% (95% CI ¼ 10.5e29.5%) of gastric cancer cases were attributable to smoking.52 This is somewhat higher than the worldwide estimated 11% attributable risk derived from a 1997 meta-analysis of smoking and stomach cancer. This meta-analysis suggested a risk of stomach cancer among smokers compared to non-smokers of the order of 1.5e1.6, with a somewhat higher summary estimate in males than in females.53 Medical conditions A number of medical conditions have been suggested to increase risk of stomach cancer. These include pernicious anaemia, peptic ulcer disease, and also prior experience
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of gastric surgery.54 However, the use of non-steroidal anti-inflammatory drugs (NSAIDS) has been suggested to reduce risk of stomach cancer. In a meta-analysis of nine studies (eight caseecontrol and one cohort) with a total of 2831 gastric cancer cases, NSAID use was associated with a reduced risk of gastric cancer, with a summary odds ratio of 0.78 (95% CI ¼ 0.69 to 0.87).55 Occupation Occupational factors have been regarded as playing a smaller part in the aetiology of gastric cancer than dietary and other environmental exposures, although they may interact with various non-occupational factors at key stages in the development of gastric cancer.56 According to epidemiological studies, occupational exposures reported to increase the risk of stomach cancer include dusts, nitrogen oxides, N-nitroso compounds, and ionising radiation.56 Excess risks have been found for several occupational groups, including miners and quarrymen, farmers, fishermen, masonry and concrete workers, machine operators, nurses, food industry workers, cooks, launderers and dry cleaners.57e61 Anthropometry Whilst measures of obesity are generally positively related to risk of cancer, for stomach cancer there is a lack of consistency in the epidemiological literature. Variation in the impact of obesity on stomach cancer risk could be attributed to problems in obtaining unbiased reports of pre-disease weight, to differential risk according to tumour location and to publication bias. Within caseecontrol studies, measures of obesity are generally lower in stomach cancer cases than in control populations,62e66 but this may be due to bias in reporting in individuals who have experienced pre-diagnostic weight loss or a reflection of confounding by other factors, such as smoking, rather than indicating a benefit of excess adiposity. Large prospective cohort studies that reported risk of stomach cancer without differentiation according to tumour site also tend to show either negative or no association with body mass index (kg/m2) or other indices of obesity.67e73 However, some more recent prospective studies that have been able to report risk according to site of tumour origin have tended to suggest that risk of cancer occurring in the cardia or proximal region of the stomach may be somewhat elevated in obese individuals68,74,75 but reduced for cancers occurring in the noncardia or distal region of the stomach.43,75,76 Physical activity Compared to the literature base for a number of other gastrointestinal cancers, there are relatively few studies that have examined the relationship between physical activity and stomach cancer. One prospective cohort study of Japanese residents of Hawaii found an elevated risk of stomach cancer associated with the highest levels of both recreational and occupational physical activity when compared with mostly sedentary activity levels.77 However, neither resting heart rate nor activity during a 24 h period were related to stomach cancer risk. Within the UK, neither the Whitehall Study of London civil servants78 or the British Regional Heart Study79 found any relationship with self-reported
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recreational physical activity levels. While currently there is insufficient evidence to indicate whether this lack of association will also be found in studies that are able to examine risk according to gastric tumour location, one recent population-based caseecontrol study found no significant association for cancer of the gastric cardia with occupational activity even after comprehensive adjustment for socio-economic variables.80
SUMMARY Worldwide, there are currently over 900,000 new diagnoses of gastric cancer each year making this the third and fifth most common form of cancer in males and females, respectively. Incidence rates in males are approximately double those in females and, in both sexes, are strongly related to age. There is a 10-fold variation in incidence between the highest and lowest risk populations and rates are notably high in East Asia, South America and Eastern Europe. Incidence rates in most populations have been declining substantially over several decades. Gastric cancer arising in the proximal cardia region of the stomach has been reported, however, to show different trends from that of the disease elsewhere in the stomach. This form of the cancer may be increasing in incidence in some populations and it also has a different geographical distribution and a higher male to female incidence ratio compared with distal non-cardia cancer. Classification problems and variation in recording practice complicate accurate reporting of cardia cancer. The main identified environmental risk factors for gastric cancer are Helicobacter pylori infection, associated with at least a 6-fold risk of cancer and various dietary exposures. Of the latter, much evidence relates increased consumption of fruit and vegetables to a decreased risk of gastric cancer although more recent prospective studies are failing to confirm this relationship. There is no evidence that vitamin supplementation reduces the risk of gastric cancer. Although much research has been carried out into the role of dietary salt and nitrate intake and alcohol consumption in the aetiology of gastric cancer there is no clear consensus about the importance of these risk factors. Smoking is, however, associated with a modest increased risk of gastric cancer.
Practice points Despite a worldwide decline in incidence gastric cancer remains as a major malignant disease in many populations. Helicobacter pylori is an established cause of gastric cancer. High intake of fruit and vegetables has been associated with a reduced risk of gastric cancer although recent data have failed to confirm this relationship. Adherence to recommendations to consume at least five portions of fruits and vegetables daily remains, however, strongly advisable. There is no evidence that antioxidant vitamin supplements are useful in the prevention of gastric cancer. Smoking contributes to the risk of gastric cancer.
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Research agenda Further work is required to improve the consistency in the recording of gastric cancer by sub-site in order to understand the descriptive epidemiology of cardia cancer in more detail. More results from large prospective studies of diet and gastric cancer making use of appropriate biomarkers are required to understand the role of fruit, vegetables, salt and other foods and nutrients in the aetiology of the disease. Exploration of potentially synergistic interactions between dietary variables, Helicobacter pylori infection and genetic polymorphisms is warranted. Although important in other cancers, the role of obesity and physical activity in the aetiology of gastric cancer remains unclear and requires further investigation.
REFERENCES 1. Ferlay J, Bray F, Pisani P et al. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide, Version 2.0. IARC CancerBase No. 5. Lyon: IARC Press; 2004. 2. Parkin DM, Whelan SL, Ferlay J et al. Cancer Incidence in Five Continents, Vol. VIII. Lyon: IARC; 2002. IARC Scientific Publications. No. 155. 3. Sipponen P & Correa P. Delayed rise in incidence of gastric cancer in females results in unique sex ratio (M/F) pattern: etiologic hypothesis. Gastric Cancer 2002; 5: 213e219. 4. Naess O, Claussen B, Thelle DS et al. Four indicators of socioeconomic position: relative ranking across causes of death. Scand J Public Health 2005; 33: 215e221. 5. Power C, Hypponen E & Smith GD. Socioeconomic position in childhood and early adult life and risk of mortality: a prospective study of the mothers of the 1958 British birth cohort. Am J Public Health 2005; 95: 1396e1402. 6. Hemminki K, Zhang H & Czene K. Socioeconomic factors in cancer in Sweden. Int J Cancer 2003; 105: 692e700. 7. Howard G, Anderson RT, Russell G et al. Race, socioeconomic status, and cause-specific mortality. Ann Epidemiol 2000; 10: 214e223. 8. van Loon AJ, Goldbohm RA & van den Brandt PA. Socioeconomic status and stomach cancer incidence in men: results from The Netherlands Cohort Study. J Epidemiol Community Health 1998; 52: 166e171. 9. Brewster DH, Fraser LA, McKinney PA et al. Socioeconomic status and risk of adenocarcinoma of the oesophagus and cancer of the gastric cardia in Scotland. Br J Cancer 2000; 83: 387e390. *10. Ferretti S & Gafa L. Upper gastrointestinal tract cancers: oesophagus, stomach, liver, gallbladder and biliary ducts, pancreas. Epidemiol Prev 2004; 28: 34e42. 11. Howson CP, Hiyama T & Wynder EL. The decline in gastric cancer: epidemiology of an unplanned triumph. Epidemiol Rev 1986; 8: 1e27. 12. Berrino F. The EUROCARE Study: strengths, limitations and perspectives of population-based, comparative survival studies. Ann Oncol 2003; 14(supplement 5): v9ev13. 13. Gatta G, Capocaccia R, Coleman MP et al. Toward a comparison of survival in American and European cancer patients. Cancer 2000; 89: 893e900. *14. Verdecchia A, Mariotto A, Gatta G et al. Comparison of stomach cancer incidence and survival in four continents. Eur J Cancer 2003; 39: 1603e1609. 15. Forman D, Everett S & Moayyedi P. Screening for stomach cancer. Evidence Based Oncology. London: BMJ Publications; 2003. 16. Botterweck AA, Schouten LJ, Volovics A et al. Trends in incidence of adenocarcinoma of the oesophagus and gastric cardia in ten European countries. Int J Epidemiol 2000; 29: 645e654.
Gastric cancer 647 *17. Devesa SS, Blot WJ & Fraumeni Jr. JF. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998; 83: 2049e2053. 18. Kubo A & Corley DA. Marked multi-ethnic variation of esophageal and gastric cardia carcinomas within the United States. Am J Gastroenterol 2004; 99: 582e588. 19. Vizcaino AP, Moreno V, Lambert R et al. Time trends incidence of both major histologic types of esophageal carcinomas in selected countries, 1973e1995. Int J Cancer 2002; 99: 860e868. 20. Forman D. Counting cancers at the junction e a problem of routine statistics. Eur J Gastroenterol Hepatol 2002; 14: 99e101. 21. Corley DA & Kubo A. Influence of site classification on cancer incidence rates: an analysis of gastric cardia carcinomas. J Natl Cancer Inst 2004; 96: 1383e1387. 22. Verdecchia A, Corazziari I, Gatta G et al. Explaining gastric cancer survival differences among European countries. Int J Cancer 2004; 109: 737e741. 23. Moayyedi P, Axon ATR, Feltbower R et al. Relation of adult lifestyle and socioeconomic factors to the prevalence of Helicobacter pylori infection. Int J Epidemiol 2002; 31: 624e631. *24. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001; 49: 347e353. 25. Ekstrom AM, Held M, Hansson LE et al. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology 2001; 121: 784e791. 26. Naumann M & Crabtree JE. Helicobacter pylori-induced epithelial cell signalling in gastric carcinogenesis. Trends Microbiol 2004; 12: 29e36. 27. Ekstrom AM, Serafini M, Nyren O et al. Dietary antioxidant intake and the risk of cardia cancer and noncardia cancer of the intestinal and diffuse types: a population-based caseecontrol study in Sweden. Int J Cancer 2000; 87: 133e140. 28. Committee on Medical Aspects of Food and Nutrition Policy. Nutritional Aspects of the Development of Cancer. Report of the Working Group on Diet and Cancer of the Committee on Medical Aspects of Food and Nutrition Policy. 48. London: The Stationery Office; 1998. 29. World Cancer Research Fund, American Institute for Cancer Research. Food, Nutrition and the Global Prevention of Cancer: A Global Perspective. Washington, USA: American Institute for Cancer Research; 1997. *30. Riboli E & Norat T. Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk. Am J Clin Nutr 2003; 78: 559Se569S. 31. Gonzalez CA, Pera G, Agudo A et al. Fruit and vegetable intake and the risk of stomach and oesophagus adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Int J Cancer 2006; 118: 2559e2566. 32. Steinmetz KA & Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc 1996; 96: 1027e1039. *33. Bjelakovic G, Nikolova D, Simonetti RG et al. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis (see comment). (review) (71 refs). Lancet 2004; 364: 1219e1228. 34. Bjelakovic G, Nikolova D, Simonetti RG et al. Antioxidant supplements for preventing gastrointestinal cancers: a systematic review and meta-analysis (see comment). (review) [167 refs]. Cochrane Database Syst Rev 2004 (CD004183). 35. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994; 330: 1029e1035. 36. Blot WJ, Li JY, Taylor PR et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993; 85: 1483e1492. 37. Woodward M, Tunstall-Pedoe H & McColl K. Helicobacter pylori infection reduces systemic availability of dietary vitamin C. Eur J Gastroenterol Hepatol 2001; 13: 233e237. 38. Correa P, Fontham ET, Bravo JC et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-helicobacter pylori therapy. J Natl Cancer Inst 2000; 92: 1881e1888. 39. Fleischauer AT, Poole C & Arab L. Garlic consumption and cancer prevention: meta-analyses of colorectal and stomach cancers. Am J Clin Nutr 2000; 72: 1047e1052. 40. Sivam GP, Lampe JW, Ulness B et al. Helicobacter pylori e in vitro susceptibility to garlic (Allium sativum) extract. Nutr Cancer 1997; 27: 118e121.
648 D. Forman and V. J. Burley 41. You WC, Zhang L, Gail MH et al. Helicobacter pylori infection, garlic intake and precancerous lesions in a Chinese population at low risk of gastric cancer. Int J Epidemiol 1998; 27: 941e944. *42. Bagnardi V, Blangiardo M, La Vecchia C et al. A meta-analysis of alcohol drinking and cancer risk. Br J Cancer 2001; 85: 1700e1705. 43. Tran GD, Sun XD, Abnet CC et al. Prospective study of risk factors for esophageal and gastric cancers in the Linxian general population trial cohort in China. Int J Cancer 2005; 113: 456e463. 44. Unakami M, Hara M, Fukuchi S et al. Cancer of the gastric cardia and the habit of smoking. Acta Pathol Jpn 1989; 39: 420e424. 45. Palli D, Bianchi S, Decarli A et al. A caseecontrol study of cancers of the gastric cardia in Italy. Br J Cancer 1992; 65: 263e266. 46. Wu AH, Wan P & Bernstein L. A multiethnic population-based study of smoking, alcohol and body size and risk of adenocarcinomas of the stomach and esophagus (United States). Cancer Causes Control 2001; 12: 721e732. 47. Gammon MD, Schoenberg JB, Ahsan H et al. Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia (see comment). J Natl Cancer Inst 1997; 89: 1277e1284. 48. Johansson G, Bingham S & Vahter M. A method to compensate for incomplete 24-hour urine collections in nutritional epidemiology studies. Public Health Nutr 1999; 2: 587e591. 49. Charnley G & Tannenbaum SR. Flow cytometric analysis of the effect of sodium chloride on gastric cancer risk in the rat. Cancer Res 1985; 45: 5608e5616. 50. Knight TM, Forman D, Al Dabbagh SA et al. Estimation of dietary intake of nitrate and nitrate in Great Britain. Food Chem Toxicol 1987; 25: 277e285. *51. Tobacco Smoke and Involuntary Smoking. Lyon, France: World Health Organisation; 2004. 52. Gonzalez CA, Pera G, Agudo A et al. Smoking and the risk of gastric cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC). Int J Cancer 2003; 107: 629e634. 53. Tredaniel J, Boffetta P, Buiatti E et al. Tobacco smoking and gastric cancer: review and meta-analysis. Int J Cancer 1997; 72: 565e573. 54. Kelley JR & Duggan JM. Gastric cancer epidemiology and risk factors. J Clin Epidemiol 2003; 56: 1e9. 55. Wang WH, Huang JQ, Zheng GF et al. Non-steroidal anti-inflammatory drug use and the risk of gastric cancer: a systematic review and meta-analysis. J Natl Cancer Inst 2003; 95: 1784e1791. 56. Cocco P, Palli D, Buiatti E et al. Occupational exposures as risk factors for gastric cancer in Italy. Cancer Causes Control 1994; 5: 241e248. 57. Aragones N, Pollan M & Gustavsson P. Stomach cancer and occupation in Sweden: 1971e89. Occup Environ Med 2002; 59: 329e337. 58. Simpson J, Roman E, Law G et al. Women’s occupation and cancer: preliminary analysis of cancer registrations in England and Wales, 1971e1990. Am J Ind Med 1999; 36: 172e185. 59. Kang S-K, Burnett CA, Freund E et al. Gastrointestinal cancer mortality of workers in occupations with high asbestos exposures. Am J Ind Med 1997; 31: 713e718. 60. Swanson GM & Burns PB. Cancer incidence among women in the workplace: a study of the association between occupation and industry and 11 cancer sites. J Occup Environ Med 1995; 37: 282e287. 61. Chow W-H, McLaughlin JK, Malker HSR et al. Occupation and stomach cancer in a cohort of Swedish men. Am J Ind Med 1994; 26: 511e520. 62. Chatenoud L, La Vecchia C, Franceschi S et al. Refined-cereal intake and risk of selected cancers in italy. Am J Clin Nutr 1999; 70: 1107e1110. 63. De Stefani E, Correa P, Boffetta P et al. Dietary patterns and risk of gastric cancer: a caseecontrol study in Uruguay. Gastric Cancer 2004; 7: 211e220. 64. Huang XE, Tajima K, Hamajima N et al. Comparison of lifestyle and risk factors among Japanese with and without gastric cancer family history. Int J Cancer 2000; 86: 421e424. 65. Inoue M, Ito LS, Tajima K et al. Height, weight, menstrual and reproductive factors and risk of gastric cancer among Japanese postmenopausal women: analysis by subsite and histologic subtype (see comment). Int J Cancer 2002; 97: 833e838. 66. Munoz N, Plummer M, Vivas J et al. A caseecontrol study of gastric cancer in Venezuela. Int J Cancer 2001; 93: 417e423. 67. Calle EE, Rodriguez C, Walker-Thurmond K et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults (see comment). N Engl J Med 2003; 348: 1625e1638.
Gastric cancer 649 68. Kuriyama S, Tsubono Y, Hozawa A et al. Obesity and risk of cancer in Japan. Int J Cancer 2005; 113: 148e157. 69. Lukanova A, Bjor O, Kaaks R et al. Body mass index and cancer: results from the Northern Sweden Health and Disease Cohort. Int J Cancer 2006; 118: 458e466. 70. Sauvaget C, Lagarde F, Nagano J et al. Lifestyle factors, radiation and gastric cancer in atomic-bomb survivors (Japan). Cancer Causes Control 2005; 16: 773e780. 71. Tulinius H, Sigfusson N, Sigvaldason H et al. Risk factors for malignant diseases: a cohort study on a population of 22,946 Icelanders. Cancer Epidemiol Biomarkers Prev 1997; 6: 863e873. 72. Wolk A, Gridley G, Svensson M et al. A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control 2001; 12: 13e21. 73. Zhang J, Su XQ, Wu XJ et al. Effect of body mass index on adenocarcinoma of gastric cardia. World J Gastroenterol 2003; 9: 2658e2661. 74. Jansson C, Johansson AL, Bergdahl IA et al. Occupational exposures and risk of esophageal and gastric cardia cancers among male Swedish construction workers. Cancer Causes Control 2005; 16: 755e764. 75. Lindblad M, Rodriguez LA & Lagergren J. Body mass, tobacco and alcohol and risk of esophageal, gastric cardia, and gastric non-cardia adenocarcinoma among men and women in a nested caseecontrol study. Cancer Causes Control 2005; 16: 285e294. 76. Tretli S & Robsahm TE. Height, weight and cancer of the oesophagus and stomach: a follow-up study in Norway. Eur J Cancer Prev 1999; 8: 115e122. 77. Severson RK, Nomura AM, Grove JS et al. A prospective analysis of physical activity and cancer. Am J Epidemiol 1989; 130: 522e529. 78. Smith GD, Shipley MJ, Batty GD et al. Physical activity and cause-specific mortality in the Whitehall study. Public Health 2000; 114: 308e315. 79. Wannamethee SG, Shaper AG & Walker M. Physical activity and risk of cancer in middle-aged men. Br J Cancer 2001; 85: 1311e1316. 80. Vigen C, Bernstein L & Wu AH. Occupational physical activity and risk of adenocarcinomas of the esophagus and stomach. Int J Cancer 2006; 118: 1004e1009.