Chapter 23

Epidemiology of Stomach Cancer

Hermann Brenner , Dietrich Rothenbacher, and Volker Arndt

Abstract

Despite a major decline in incidence and mortality over several decades, stomach cancer is still the fourth most common cancer and the second most common cause of cancer death in the world. There is a 10-fold variation in incidence between populations at the highest and lowest risk. The incidence is particularly high in East Asia, Eastern Europe, and parts of Central and South America, and it is about twice as high among men than among women. Prognosis is generally rather poor, with 5-year relative survival below 30% in most countries. The best established risk factors for stomach cancer are Helicobacter pylori infection, the by far strongest established risk factor for distal stomach cancer, and male sex, a family history of stomach cancer, and smoking . While some factors related to diet and food preservation, such as high intake of salt-preserved foods and dietary nitrite or low intake of fruit and vegetables, are likely to increase the risk of stomach cancer, the quantitative impact of many dietary factors remains uncertain, partly due to limitations of exposure assessment and control for confounding factors. Future epidemiologic research should pay particular attention to differentiation of stomach cancer epidemiology by sub-site, and to exploration of potential interactions between H. pylori infection, genetic, and environmental factors.

Key words: Gastric cancer , Helicobacter pylori , incidence , mortality , smoking , stomach cancer .

Stomach cancer (gastric cancer) emerges from gastric tissue. More than 90% of stomach cancers are adenocarcinomas, and the remaining gastric malignancies are lymphomas or originate from gastrointestinal stromal tissue (sarcomas). Still, stomach cancer is

1. Introduction1. Introduction

M. Verma (ed.), Methods of Molecular Biology, Cancer Epidemiology, vol. 472© 2009 Humana Press, a part of Springer Science + Business Media, Totowa, NJBook doi: 10.1007/978-1-60327-492-0

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one of the leading causes of cancer related deaths in the world, although a permanent decrease in incidence has been recorded within the past decades. Furthermore, on a global scale, large geographic differences exist (1) . The underlying reasons for these differences are still not very well understood.

In addition, the reasons for the overall observed declining incidence are not clear yet. Notably, this decline is especially related to gastric carcinoma located in the distal stomach. The relatively small proportion of gastric cancers related to the prox-imal stomach and to the gastroesophageal junction seems to be on a constant rise. As proximal and distal stomach cancer seem to have different pathogenesis, a change of precursor conditions or related environmental risk factors may most likely explain these changes. What is good for one entity may not be good for the other.

Nutritional factors had long been under suspect as main risk factors of stomach cancer. However, studies investigating the role of preserved foods, low intake of fruits, and other nutritional fac-tors often showed inconsistent results, and dietary factors may only explain a small part of the variation in stomach cancer risk. Since the year 1994, infection with the gastric bacterium Helico-bacter pylori has been classified as a definite carcinogen for stom-ach cancer (2) . Recent evidence suggests the role of this agent to be even more important than initially suspected. However, only distal cancers are related to H. pylori infection, cancers located proximally are not. Furthermore, some large populations with high prevalence of H. pylori infection have low gastric cancer rates (3) , indicating that other factors may be of importance, too.

Undoubtedly, during the last 20 years, important contri-butions have been made to shed light on the risk factors of stomach cancers, but there is still an urgent need for a better understanding of the underlying causes of this important can-cer in order to define successful means of cancer prevention. This is of especial urgency, as the prognosis of the affected patients is still rather poor (4) .

Until recently, gastric cancer was the second most common can-cer worldwide. But now with an estimated number of 900,000 – 950,000 new cases per year at the beginning of the 21st century, it is in forth place behind cancers of the lung, breast, colon, and rectum (5) . Due to its poor prognosis, gastric cancer is the sec-ond most common cause of death from cancer and accounts for

2. Descriptive Epidemiology2. Descriptive Epidemiology

2.1. Global Burden2.1. Global Burden

Epidemiology of Stomach Cancer 469

700,000 deaths annually. As with most other solid tumors, the incidence rate of gastric cancer increases with age and the cancer is relatively rare in male or female patients younger than 45 years. Most patients are between 60 and 80 years old at diagnosis. In general, incidence and mortality rates in men are approximately double to those in women.

Almost two thirds of the cases of gastric cancer occur in developing countries and 42% in China alone. However, gastric cancer cannot readily be categorized as being associated with less developed economies (6) . As can be seen from Table 23.1 , over-all age-standardized incidence rates are comparable between so-called “ more developed ” and “ less developed ” countries.

As with most of the common forms of cancer, there is consider-able geographic variation in incidence of gastric cancer around the world. High-risk areas (age-standardized rates in men >20 per 100,000) include East Asia, Eastern Europe, and parts of Central and South America (5) . Incidence rates are low in South-ern Asia, North and East Africa, North America, Australia, and New Zealand (Fig. 23.1 ). Patterns in women are broadly similar to those in men.

2.2. Geographic Variation2.2. Geographic Variation

Table 23.1 Global gastric cancer incidence and mortality estimates (rates per 100,000) for 2002

Men Women

Region Cases Crude rate ASR(W) a Cases Crude rate ASR(W) a

Incidence

World 603,419 19.3 22.0 330,518 10.7 10.4

More developed regions

195,782 33.7 22.4 115,372 18.8 10.0

Less developed regions

405,211 15.9 21.5 214,024 8.7 10.4

Mortality

World 446,052 14.3 16.3 254,297 8.3 7.9

More developed regions

128,721 22.2 14.5 83,515 13.6 6.9

Less developed regions

315,603 12.4 17.0 169,972 6.9 8.3

a ASR(W), age-standardized rate according to world standard population From ref. (1)

470 Brenner et al.

The distribution of gastric cancer does not, however, 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) (6 , 7) .

In contrast to many other cancer sites, for which impressive improvements in prognosis have been reported (4) , survival rates for patients with gastric cancer are poor, in general (5) . The EUROCARE study estimated European survival for cases diag-nosed in the period 1990 – 1994 to be around 24% at 5 years after diagnosis (8) . Similar survival rates have been observed for most other industrialized countries outside of Europe (9 , 10) . Prog-nosis for gastric cancer is moderately good only in Japan (52%), where mass screening by photofluoroscopy has been practiced since the 1960s (5) .

In the 1930s, gastric cancer was the most common cause of cancer death in the USA and Europe (11) . Incidence as well as mortal-ity rates have substantially declined over the past decades in many countries (Fig. 23.2 ). The most recent worldwide estimates of age adjusted incidence (22.0 per 100,000 in men and 10.3 per 100,000 in women) are about 15% lower than the values estimated in 1985

2.3. Survival2.3. Survival

2.4. Time Trends2.4. Time Trends

Fig. 23.1. Age-standardized incidence rates (per 100,000) of gastric cancer in men in 2002 (1) .

Epidemiology of Stomach Cancer 471

(5) . This decline may be related to improvements in preservation and storage of foods; it may also represent changes in the prevalence of H. pylori by birth cohort, perhaps as a result of reduced trans-mission in childhood, following a trend to improved hygiene and reduction of crowding (12 , 13) . As, in case of gastric cancer, mortal-ity is closely associated with incidence, the trend in mortality rates has shown a very similar pattern.

Despite this notable decline in incidence rates, gastric cancer will remain an important component of the global cancer burden in absolute terms. Even if 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 (6) .

H. pylori, a Gram-negative bacterium has been redetected as a common inhabitant of the human stomach in 1984 (14) . Numer-ous ecological, case – control and cohort studies conducted since then have consistently found H. pylori infection to be related to an increased risk of stomach cancer. In 1994, H. pylori was classified as a definite carcinogen for stomach cancer by the International Agency for Research on Cancer (2) . In 2001, a pooled analysis

3. Risk Factors and Preventive Factors3. Risk Factors and Preventive Factors

3.1. Helicobacter pylori Infection3.1. Helicobacter pylori Infection

Fig. 23.2. Age-standardized incidence rate (ASR) (world standard population) of gastric cancer in Finland, USA, and Japan by time period (7) .

ASR (World)

Japan, MiyagiPrefecture Male

Japan, MiyagiPrefecture Female

Finland Male

Finland Female

USA, SEER: WhiteMale

USA, SEER: WhiteFemale

1955 1960 1965 1970 1975 1980 1985 1990 19951

10

100

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from 12 prospective cohort studies demonstrated a sixfold increased risk of stomach cancer after 10 years of follow-up (15) . H. pylori infection specifically increases the risk of cancer in the distal part of the stomach, where the vast majority of stomach cancers have been located in the past, whereas there is no increase in risk of proximal (cardia) cancer. Failure to distinguish proxi-mal cancer from distal gastric cancer in previous studies may thus have led to dilution of effects of H. pylori infection and other risk factors. Furthermore, more recent evidence suggests that the role of H. pylori infection for the risk of distal stomach can-cer may have been strongly underestimated in epidemiological studies due to additional methodological pitfalls, such as the secondary clearance of the infection in the process of stomach cancer development from atrophic gastric epithelium. Estimates of relative risk of distal stomach cancer associated with H. pylori infection increased to about 20 in studies from Sweden and Ger-many, when potential misclassification of infection status from this source was minimized (16 , 17) , and it was even suggested that H. pylori infection may be a (close to) necessary risk factor for distal stomach cancer development.

Given that about half of the adult world population has been infected with H. pylori in the past (18) , this infection is likely to account for a very large share of the global burden of stomach cancer cases and deaths. On the other hand, the high prevalence of the infection also implies that only a small propor-tion of infected subjects will eventually develop stomach cancer, and identification of factors associated with increased risk among infected individuals and of interactions between the infection and other risk factors are therefore crucial for a better understanding of disease etiology and approaches for prevention. On the side of the infectious agent, a number of virulence factors being associ-ated with increased risk have been identified, the best established being carriage of the cytotoxin-associated gene A ( cagA ) (19) . On the host side, genetic predisposition likely plays a major role. For example, the risk of distal stomach cancer has been found to strongly increase with the number of proinflammatory polymor-phisms (20) . In addition, the combination of H. pylori infection with other risk factors, such as smoking or a positive fam-ily history, may lead to strongly elevated risks of distal stomach cancer and may point to approaches for targeted prevention and early detection (21 , 22) .

Regarding potential approaches to targeted prevention and early detection, a number of additional issues have to be addressed. Prevention of the H. pylori infection would have to take place among infants, given that most infections are acquired within the first few years of life (23) . Preventive vaccination might have a large impact, but, despite major research efforts, is not available so far. Fortunately, rates of acquisition of persistent

Epidemiology of Stomach Cancer 473

H. pylori infection in childhood seem to decline rapidly in younger birth cohorts, at least in developed countries, possibly as a side effect of antibiotic therapy for other indications (24) , which may accelerate the decline in incidence of distal stom-ach cancer in future generations of older adults. Given that the mother appears to be the main source for transmission of the infection, at least in developed countries (25) , testing for and eradication of H. pylori infection among young women might be another approach for decreasing infection rates of future genera-tions. To what extent eradication of H. pylori infection among adults may reduce their own cancer risk has yet to be established. A randomized trial from China could not show an overall benefi-cial effect of H. pylori eradication on stomach cancer occurrence, but suggested that prevention might be possible if eradication occurs before the onset of premalignant changes in the gastric mucosa (26) . If confirmed in future studies, potential preventive eradication strategies might be considered. To extend preventive eradication strategies beyond established high-risk groups, while keeping them as cost-effective as possible, further enhanced risk stratification would be highly desirable (27) .

In addition to H. pylori infection, further environmental factors have long been recognized as potential factors related to risk of stomach cancer. Immigrants coming from high-prevalence coun-tries to low-prevalence countries have still a similar risk to the population of the country from which they origin. Their off-spring, however, have a risk that is more or less already similar to the risk of the population of the country to which they immi-grated, pointing to environmental influences that may already act at early life (28) .

Dietary factors may partly explain these patterns. Certain foods containing large amounts of salt and nitrites for conserva-tional purposes have been suggested to be important contributors to cancer risk. Although most epidemiological studies support these associations, evidence from large, prospective studies is still inconclusive (29) . A diet rich in fruit and vegetables was found to be beneficial as a result of a meta-analysis summarizing the results of observational studies up to the year 2003. However, the results were no more statistically significant if only prospec-tive studies were considered (30) , and were not confirmed by the large-scale European Prospective Investigation Into Cancer and Nutrition (EPIC) study (31) , pointing to potential sources of error in earlier retrospective studies.

The intake of meat and processed meat was both associated with an increased cancer risk in the EPIC study. This increase was related to distal (non-cardia) cancer and affected especially H. pylori -seropositive subjects (32) . Whereas the intake of anti-oxidants, vitamins, and dietary supplementations may play a role

3.2. Other Factors3.2. Other Factors

474 Brenner et al.

in high-risk population such as in China, a prospective study in a US population found no influence on stomach cancer mortality associated with the self-reported intake of such substances (33) . In this area, future studies might profit from the use of biological markers to define the exposure status and overcome some of the limitations of the studies based on self-report.

In contrast, smoking is an established causal risk factor for stomach cancer. An analysis in the EPIC study attributed about every sixth case of gastric cancer to cigarette smoking (34) .

Other comorbid conditions such as pernicious anemia are long known risk factors associated with gastric cancer and the risk in presence of this condition is increased about threefold (35) . Intake of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, shows a preventive effect on stomach cancer in a dose – dependent manner. However, the gastrointestinal com-plications and the associated risk of the long-term use demand a thorough risk – benefit analysis, which may nevertheless result in a useful strategy in a high-risk population (36) .

A positive family history is also associated with an increased risk for stomach cancer. Beside sharing some genetic commonali-ties, it may also express the familial exposure to other risk factors, such as infection with H. pylori (37) .

Obesity is a further associated risk factor of gastric cancer as well as of other cancers (38) . Notably, in a prospective study including over 900,000 US adults, a clear increase in risk was only seen in men in the highest body mass category. It was almost double in the category 35 – 40 kg/m 2 when compared with men of normal weight (18.5 – 24.9 kg/m2).

Several occupational factors such as dusts, exposure to nitro-gen oxides, N -nitroso compounds, and ionizing radiation have been described as related to stomach cancer in certain occupa-tional groups such as carpenters, steel workers and tin miners, and workers of the chemical and coal mining industry (39) . However, their contribution to overall risk on a population-based level seems to be small.

Discovery of H. pylori and disclosure of its key role in the devel-opment of distal stomach cancer within the past 25 years has rev-olutionized the understanding of stomach cancer, which can now be considered, to a large extent, as a disease of infectious origin. However, many of the co-factors leading from infection to devel-opment of stomach cancer among a minority of infected indi-viduals remain poorly understood and need to be focused on in

4. Conclusions4. Conclusions

Epidemiology of Stomach Cancer 475

future epidemiological research. The strong reduction in stomach cancer incidence and mortality in the past decades was achieved without specific, targeted measures of prevention. On the basis of identification of mechanisms and factors leading from H. pylori infection to stomach cancer, specific prevention measures, such as targeted eradication of the infection, especially among high-risk groups, may become a promising strategy for further reduction of the burden of the disease in the future.

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