Epidemiology of upper gastrointestinal malignancies

Epidemiology of Upper Gastrointestinal Malignancies Katherine D. Crew and Alfred I. Neugut The demographics of esophageal and gastric cancer have been changing dramatically in the United States over the past several decades. While incidence rates for esophageal squamous cell carcinoma and distal gastric carcinoma have been declining, the trends for adenocarcinoma of the esophagus and proximal stomach have been rising rapidly, particularly among white males. The incidence of these upper gastrointestinal (GI) malignancies varies widely based on geographic location, race, and socioeconomic status. The primary causes of squamous cell carcinoma of the esophagus are tobacco use and alcohol consumption, whereas the main risk factors for adenocarcinoma of the esophagus are gastroesophageal reflux disease and obesity. Dietary factors and Helicobacter pylori infection play an important role in the development of gastric cancer. Understanding the epidemiology and etiologies of esophageal and gastric carcinomas will lead to the development of interventions for screening and prevention in high-risk populations. Semin Oncol 31:450-464. © 2004 Elsevier Inc. All rights reserved.

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N THIS REVIEW, we will cover the epidemiology of malignancies of the upper gastrointestinal (GI) tract. The focus will be on the two main histologic types of esophageal cancer, ie, squamous cell carcinoma and adenocarcinoma, and the two main tumor sites of gastric adenocarcinomas, proximal (cardia) and distal (noncardia) stomach cancers. These tumors have some similar, as well as some contrasting, characteristics and risk factors. In addition, the incidence rates of these tumors have changed dramatically over the past several decades and show significant geographic variations. For example, the incidence rate of squamous cell carcinoma of the esophagus has been steady or declining, whereas the incidence rate of esophageal adenocarcinoma has been rising rapidly, par-

From the Department of Medicine and the Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY. K.D.C. is the recipient of a postdoctoral fellowship (T32 CA09529) and A.I.N. is the recipient of a K05 award (CA89155) from the National Cancer Institute. Address reprint requests to Alfred I. Neugut, MD, PhD, New York-Presbyterian Hospital, 722 West 168th St, MSPH 725, New York, NY 10032. © 2004 Elsevier Inc. All rights reserved. 0093-7754/04/3104-0011$30.00/0 doi:10.1053/j.seminoncol.2004.04.021 450

ticularly among white males from Western countries. Overall gastric cancer incidence and mortality have fallen dramatically over the past 70 years. Despite a decline in distal gastric cancers, proximal tumors of the gastric cardia have been increasing in incidence, particularly in developed countries. Adenocarcinomas of the distal esophagus, gastroesophageal (GE) junction, and gastric cardia share certain epidemiologic features, which suggests that they represent a similar disease entity. The purpose of this review is to examine the epidemiology and etiologies of these upper GI malignancies, and to discuss strategies for their screening and prevention. PATHOLOGIC CONSIDERATIONS

Esophageal cancer (predominantly squamous cell carcinoma) ranks among the 10 most common malignancies in the world, with more than 300,000 cases diagnosed each year.1 Adenocarcinoma in the distal esophagus is still a relatively uncommon tumor. However, during the past 25 years, the incidence of esophageal adenocarcinoma in white males in the United States and other Western countries has risen faster than any other malignancy.2 In these populations, the incidence of adenocarcinoma of the esophagus now exceeds that of squamous cell carcinoma. Similarly, the incidence of adenocarcinoma of the gastric cardia has been increasing. Gastric cardia tumors now account for nearly half of all stomach cancers among American men.3 Cancers arising from the GE junction are often difficult to classify. Therefore, changes in diagnostic and classification practices may account for some of this increase in rates of esophageal adenocarcinoma. Despite its recent decline in the United States, gastric cancer remains the world’s second leading cause of cancer mortality, surpassed only by lung cancer.4 About 90% of stomach tumors are adenocarcinomas, which are subdivided into two main histologic types: (1) well-differentiated or intestinal type, and (2) undifferentiated or diffuse type. The intestinal type is more common in males and older age groups, whereas diffuse type carcinomas have a more equal male-to-female ratio and are more frequent in younger individuals.5 The intestinal type tumors predominate in high-risk Seminars in Oncology, Vol 31, No 4 (August), 2004: pp 450-464

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Fig 1. Trends in age-adjusted incidence rates among US males for (A) esophageal cancer by race and histologic type, and (B) gastric cancer by race and tumor site. (Adapted with permission from Devesa et al.3)

geographic areas compared to diffuse type adenocarcinomas, which have a more uniform geographic distribution.6 A decrease in the incidence of intestinal type tumors in the corpus of the stomach accounts for most of the recent decline in gastric cancer rates worldwide.7 DEMOGRAPHIC TRENDS

Epidemiology in the United States According to data from the Surveillance, Epidemiology and End Results (SEER) program, a set of cancer registries covering about 10% of the US population, the incidence of esophageal squamous cell carcinoma has been declining. The annual age-adjusted incidence rates per 100,000 decreased from 3.4 during the period 1974 to 1976 to 2.2 from 1992 to 1994.3 The incidence of these tumors began to decline in US white males after the mid 1970s and in black males after the mid 1980s (Fig 1A). Prior to the 1970s, distal esophageal adenocarcinomas were uncommon, representing 0.8% to 3.7% of esophageal cancers.8-10 Over the past three decades, there has been a sevenfold increase

in the incidence of esophageal adenocarcinoma among US white males, now accounting for more than half of the cases of esophageal cancer (Fig 1A).11 Through the 1980s, the increases in the rates of these tumors have been on the order of 5% to 10% per year, a faster pace than for virtually any other cancer.2 Numerous population-based studies from the United States and Western Europe have confirmed the rising incidence of adenocarcinoma of the esophagus and GE junction.12-14 The annual incidence rate of esophageal adenocarcinoma is 3 to 5 per 100,000 in the United States compared to 12 to 16 per 100,000 in the United Kingdom.3,15 In 1930, gastric cancer was the most common cause of cancer death in the United States. Currently, this tumor is the 14th most common malignancy and the 8th leading cause of cancer mortality in the United States.16 The sharp decline in gastric cancer incidence over the past 70 years is largely due to unplanned prevention through changes in environmental factors.16,17 Meanwhile, the incidence of gastric cardia adenocarcinoma rose by five- to sixfold in the past few decades.13 Gastric cardia tumors now account for nearly half

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Fig 2. Cumulative incidence rates in males by country. (A) Esophageal squamous cell carcinoma. (B) Esophageal adenocarcinoma. (C) Gastric cardia adenocarcinoma. (Data adapted from Corley et al.18)

of all stomach cancers among US males (Fig 1B).2,3 International Distribution Esophageal cancer rates vary substantially (about 60-fold) from country to country, more so than any other malignancy (Fig 2A and B).18 High-prevalence areas include Asia, southern and eastern Africa, and northern France, where annual rates of esophageal cancer mortality are up to 100 per 100,000.19,20 Similar to the United States, increases in esophageal adenocarcinoma rates have been reported in Norway,21 Denmark,22 Sweden,23 England,24,25 Switzerland,26,27 New Zealand,28 and Australia29,30 (Fig 2B). The highest rates have been seen among white men from Great Britain, Australia, the Netherlands, the United States, and Denmark.31 Similar rapid increases were seen in the incidence of gastric cancer localized to the cardia in developed countries (Fig 2C).21,22,24-28,30 Noncardia gastric adenocarcinoma also shows marked geographic variation in incidence.32,33 High-incidence areas include China, Japan, and Central and South America. In Japan, gastric cancer remains the most common type of cancer

among both men and women. In contrast to the increasing incidence of proximal tumors in the West, distal tumors continue to predominate in Japan. In the 1990s, gastric cancer mortality rates in Japan were 52.6 per 100,000 in men and 27.5 per 100,000 in women, compared to the United States, which had an incidence of 6.3 and 4.3 per 100,000 in men and women, respectively.34 A substantial migration effect is observed in individuals who move from high- to low-risk areas and adopt a risk of gastric cancer intermediate between that of their homeland and that of their new country. Subsequent generations acquire risk levels approximating those of the host country.32,33 Sex, Race, and Age Distribution Esophageal squamous cell carcinoma has a male predominance in almost all countries, with rates two to four times higher among males compared to females (Table 1).17 The incidence of squamous cell carcinoma of the esophagus is more than five times higher among US black men than white men.2 After adjustment for alcohol use, cigarette smoking, and diet, low income was the social class variable most strongly associated with increased risk in blacks.35

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Table 1. Demographics of Upper GI Malignancies Based on Sex and Race Esophageal Esophageal Cardia Noncardia Squamous Adenocarcinoma Gastric Gastric Male:female ratio White:black ratio

2-4:1

7:1

5:1

2:1

1:5

5:1

2:1

1:2

Esophageal adenocarcinoma is characterized by a very high male-to-female ratio, about 7:1, the largest for any cancer except lip cancer.2,36-38 In contrast to squamous cell carcinoma, adenocarcinoma of the esophagus is about five times as high among whites as blacks.3,39-41 In a retrospective review of patients diagnosed with esophageal cancer in Atlanta, GA, adenocarcinoma was the predominant histology in whites (66%) compared to blacks (8%).40 In addition, a study using the US SEER database found a significant increase in incidence among younger persons aged 45 to 65 years and higher incidence rates among more recent birth cohorts.41 The incidence of esophageal adenocarcinoma increases with age, with a peak age of 55 to 65 years.11 For gastric cardia carcinomas, men are affected five times more than women and whites twice as much as blacks.41 Unlike esophageal adenocarcinoma rates, which continued to rise for white males through 1998, gastric cardia adenocarcinoma rates stabilized after 1988.42 For gastric cardia tumors, no increase in younger persons and no birth cohort effect was observed, illustrating certain epidemiologic differences between adenocarcinoma of the esophagus and gastric cardia.41 Noncardia gastric cancer has a male-to-female ratio of approximately 2:1.32,33 Incidence rises progressively with age, with a peak incidence between the ages of 50 and 70 years. Incidence rates are significantly higher among blacks and lower socioeconomic groups, and in developing nations.32 In contrast, incidence rates of adenocarcinoma of the esophagus and gastric cardia are relatively higher in the professional classes.24 SURVIVAL

In the 1990s, the 5-year survival rate for esophageal cancer was about 11%, with little difference

between histologic types.17 Since most patients are at an advanced stage at diagnosis, the incidence and mortality rates are nearly equal. Even with early-stage disease, survival is relatively poor. For gastric cancer, 5-year survival rates have been increasing slowly over the past 40 years. However, 5-year relative survival rates in the United States are still less than 20%.17 Tumors located in the gastric cardia have a much poorer prognosis compared to those in the pyloric antrum, with lower 5-year survival and higher operative mortality.43 In the United States, few gastric cancers are discovered at an early stage. By contrast, in Japan, where mass screening programs are in place, mortality rates for gastric cancer in men have more than halved since the early 1970s.44 A US study showed that gastric cancers in persons of Asian descent had a better prognosis than in nonAsians, suggesting that host-related factors may also affect prognosis.45 RISK FACTORS

Helicobacter pylori Infection Helicobacter pylori is a gram-negative bacillus that colonizes the human stomach and was first reported in 1983.46 It is one of the most common human pathogens infecting about half of the world’s population. There is marked geographic variation in the prevalence of infection, with more than 80% infection rates among adults in developing countries, compared to 20% to 50% in industrialized nations.47 Infection is mainly acquired during early childhood, likely through oral ingestion. Seropositivity increases with age and infection persists throughout life.47 By 1994, H pylori was classified as a type I (definite) carcinogen in humans.48 Infection is associated with an increased risk of developing peptic ulcer disease and noncardia gastric cancer. Countries with high gastric cancer rates typically have a high prevalence of H pylori infection49 and the decline in H pylori prevalence in developed countries parallels the decreasing incidence of gastric cancer.50,51 Numerous epidemiologic studies have demonstrated that H pylori infection increases the risk of developing distal noncardia gastric cancer. Several case-control studies have shown significant associations between H pylori seropositivity and gastric cancer risk, which is about 2.1- to 16.7-fold greater than for seronega-

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tive individuals.52-58 Prospective studies have also supported H pylori infection as a risk factor for gastric cancer.59-62 Perhaps the most compelling evidence for the link between H pylori and gastric cancer comes from a prospective study of 1,526 Japanese patients who underwent endoscopy for duodenal or gastric ulcers, gastric hyperplasia, or nonulcer dyspepsia and were tested for H pylori infection.63 After a mean follow-up of 7.8 years, gastric cancers developed in 2.9% of infected patients and none of the uninfected individuals. Subjects with severe gastric atrophy, corpus-predominant gastritis, and intestinal metaplasia were at significantly higher risk for gastric cancer. In addition, none of the patients with duodenal ulcers developed stomach cancer, whereas gastric carcinomas were detected in 4.7% of patients with nonulcer dyspepsia. However, the majority of infected individuals are asymptomatic. Cancer risk is believed to be related to differences in H pylori strains and host inflammatory responses. Colonization by H pylori causes chronic gastritis in virtually all infected persons.64,65 H pylori–associated gastritis may progress to severe atrophic gastritis and on to intestinal metaplasia, dysplasia, and finally adenocarcinoma (Fig 3A).66 Gastric cancer risk is particularly enhanced for individuals infected with H pylori carrying the cag island, a 40-kb locus that identifies a strain of H pylori that has a more intimate interaction with the stomach epithelium.67,68 Compared to cagA⫺ strains, infection by H pylori cagA⫹ strains significantly increases the risk of developing peptic ulcer disease, severe atrophic gastritis, and distal gastric cancer.69-72 A recent study found that infection by H pylori cagA⫹ strains was associated with a greater risk of intestinal gastric carcinoma (odds ratio [OR], 4.1; 95% confidence interval [CI], 2.2 to 7.7) compared to cagA⫺ strains (OR, 2.7; 95% CI, 1.3 to 5.6).73 About 60% of H pylori isolates in Western countries are cagA⫹.74-76 Host factors associated with increased risk of gastric cancer include several human polymorphisms within immune response genes, such as those causing high-level expression of interleukin-1␤.77 The falling incidences of H pylori infection and noncardia gastric cancer in developed countries have been diametrically opposed to the rapid increase in incidence of adenocarcinoma of the esophagus and gastric cardia. A nested case-con-

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Fig 3. Pathways of carcinogenesis for (A) gastric and (B) esophageal adenocarcinomas. (Data from Correa66 and Montgomery et al.165)

trol study showed a statistically significant inverse association between H pylori infection and the development of gastric cardia cancer (OR, 0.40; 95% CI, 0.20 to 0.77).78 Another study showed that infection by cagA⫹ strains was associated with a reduced risk for esophageal and gastric cardia adenocarcinomas (OR, 0.4; 95% CI, 0.2 to 0.8), but found no association with cagA⫺ strains.79 H pylori, particularly cagA⫹ strains, may have a protective effect against gastroesophageal reflux disease, Barrett’s esophagus, and esophageal adenocarcinoma. Gastrointestinal Reflux Disease and Barrett’s Esophagus The rising incidence of esophageal adenocarcinoma may be due to an increasing frequency of gastroesophageal reflux disease (GERD) in the general population. GERD is a common chronic condition that affects up to 30% of the Western population on a monthly basis.80 A case-control study by Chow et al found a greater than twofold increased risk of adenocarcinoma of the esophagus and GE junction in patients with a prior history of esophageal reflux, hiatal hernia, esophagitis, or dysphagia.81 A Swedish study found a strong asso-

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ciation between the risk of esophageal adenocarcinoma and symptomatic GERD, which correlated with the frequency and severity of symptoms.80 About 62% of cases of esophageal adenocarcinoma have evidence of Barrett’s esophagus, a metaplastic change in the lining of the esophagus from normal squamous epithelium to columnar intestinal epithelium.82 Barrett’s esophagus is an acquired condition caused by longstanding GERD.83 Long-segment Barrett’s esophagus extends more than 3 cm above the GE junction, whereas shorter segments of columnar epithelium are defined as short-segment disease. Virtually all esophageal adenocarcinomas are thought to arise from Barrett’s esophagus, with progression from low-grade to high-grade dysplasia and finally carcinoma (Fig 3B). The incidence of esophageal adenocarcinoma in patients with Barrett’s esophagus is approximately 0.5% per year, a 30- to 125-fold higher risk compared to the general populaion.84,85 Similar to esophageal adenocarcinoma, risk factors for Barrett’s esophagus include male sex, white race, age greater than 50 years, and a history of GERD symptoms for more than 5 years.86 The number of patients diagnosed with Barrett’s esophagus has risen dramatically in the past decade, from 22.6 per 100,000 in 1987 to 82.6 per 100,000 in 1998.87 Part of this increase probably reflects a detection bias, since the use of endoscopy has also gone up since the 1970s. However, autopsy data from Olmsted County, MN showed that the prevalence of Barrett’s esophagus was 376 per 100,000, suggesting that the majority of cases go undetected in the general population.88 Smoking and obesity may increase the risk of reflux disease and Barrett’s esophagus. In addition, medications that relax the lower esophageal sphincter may increase the risk of esophageal adenocarcinoma. One study showed that daily, long-term users of these medications, particularly anticholinergics, had an increased risk of adenocarcinoma of the esophagus compared with persons who had never used these drugs.89 In Western countries, where the prevalence of H pylori infection is falling, GERD and its sequelae are increasing in incidence. Patients with reflux esophagitis and Barrett’s esophagus have a significantly lower prevalence of H pylori colonization, particularly the cagA⫹ strains.75 Studies have shown that severe atrophic gastritis and reduced

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acid production associated with H pylori infection significantly reduces the risk of GERD.90-92 One study demonstrated that H pylori eradication therapy in patients with duodenal ulcers was associated with a doubling in the development of reflux esophagitis over a 3-year period.93 However, other studies showed that H pylori eradication did not negatively influence relapse rates in patients with GERD.94,95 Therefore, the role of H pylori infection in the development of GERD, Barrett’s esophagus, and esophageal adenocarcinoma remains unclear. Tobacco and Alcohol Tobacco smoking and alcohol consumption are established risk factors for esophageal squamous cell carcinoma. Numerous case-control studies have shown that tobacco use and alcohol intake are independent risk factors that have synergistic effects. Esophageal cancer risk depends mainly on the duration of tobacco use and the mean daily intake of alcohol.96 Smoking cessation for 5 years reduces the risk by 50% and abstaining from alcohol for at least 10 years returns the risk of esophageal cancer to the levels of nondrinkers.96,97 Smoking is much more strongly associated with esophageal squamous cell carcinoma (a 10- to 20fold relative risk) than adenocarcinoma (a 1.5- to 4-fold relative risk).98-101 In a study by the US National Cancer Institute, smoking was associated with a 2.2-fold increased risk for esophageal adenocarcinoma and a 2.6-fold increased risk for gastric cardia adenocarcinoma.101 Risk persisted for up to 30 years following smoking cessation, suggesting that smoking may affect an early stage in the carcinogenesis of adenocarcinoma of the esophagus and GE junction. Several studies have failed to find an association between alcohol consumption and esophageal adenocarcinoma.100,101 Smoking is associated with an increased risk of distal gastric cancer, with adjusted rate ratios of 2.0 (95% CI, 1.1 to 3.7) and 2.1 (95% CI, 1.2 to 3.6) for past and current smokers, respectively.102 There is little support for an association between alcohol and gastric cancer.103 Diet and Nutrition Both histologic types of esophageal cancer seem to be affected by diet and nutrition in similar ways. In high-risk populations of developing countries, dietary deficiencies play a major role in the patho-

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genesis of esophageal squamous cell carcinoma. High intake of fresh fruits and vegetables reduced the risk of esophageal squamous cell carcinoma104,105 and adenocarcinoma.106,107Studies of fiber intake have yielded inconsistent results.107,108 There is strong evidence that consumption of salty foods, such as salted pickles and fish, increases the risk of gastric cancer, whereas high intake of fruits and vegetables has protective effects.109 In a Japanese prospective study of about 40,000 men and women followed for 10 years, fruit and vegetable intake was associated with a lower risk of gastric cancer (relative risk, 0.48 to 0.70).110 However, a prospective study from the Cancer Prevention Study II cohort of 1.2 million US men and women with 14 years of follow-up showed only a modest effect for plant foods in reducing the risk of stomach cancer mortality in men, but not in women.111 N-nitroso compounds are carcinogenic in animal experiments and are formed in the human stomach from dietary nitrite found in preserved meats. With the advent of refrigeration, the decreased consumption of preserved foods and increased intake of fresh fruits and vegetables may have contributed to the worldwide decline in gastric cancer incidence. Casecontrol studies have shown a weak, nonsignificant increased risk of gastric cancer for high versus low nitrite intake.112-115 Animal studies have shown that polyphenols in green tea have anticarcinogenic and anti-inflammatory effects. Various case-control studies have demonstrated a protective effect of green tea on the risk of gastric cancer.116 However, two prospective cohort studies from Japan found no association between green tea consumption and the risk of gastric cancer.117,118 Obesity Obesity is a risk factor for a number of malignancies, including breast, colon, and endometrial cancer.119,120 A recent prospective study of more than 900,000 US adults followed for 16 years examined the relationship between body mass index (BMI) and cancer mortality.121 People with a BMI greater than 40 kg/m2 had cancer death rates that were 52% higher in men and 62% higher in women compared to normal-weight individuals. In addition, BMI was significantly associated with higher rates of esophageal cancer mortality in men and women, and death from stomach cancers in men. A Swedish study

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found that the heaviest quarter of the population had a 7.6-fold increased risk for esophageal adenocarcinoma and a 2.3-fold increased risk for gastric cardia adenocarcinoma compared with the lightest quarter of the population.122 Gastric reflux is more common among obese individuals.123 Obesity may increase episodes of reflux by causing increased intra-abdominal pressure and risk of hiatal hernia. However, obesity is a strong risk factor for esophageal adenocarcinoma independent of reflux.124 In contrast, measures of BMI seem to be inversely related to the risk of squamous cell esophageal cancer.124 Therefore, cancer trends tend to parallel recent increases in the prevalence of obesity in the United States.125 Other Factors Other causes of esophageal cancer include occupational exposures to asbestos,126 perchloroethylene,127 and combustion products.128,129 Exposure to ionizing radiation is associated with an increased risk of esophageal squamous cell carcinoma.130,131 Human papilloma virus (HPV) has been identified in several patients with esophageal cancer. HPV-16 infection may play a causative role in the high incidence of esophageal cancer in certain regions of China.132,133 Additional less common risk factors for gastric cancer include radiation,134 a positive family history,135-137 pernicious anemia,138 blood type A,139 prior gastric surgery for benign conditions,140 and Epstein-Barr virus.141-143 A summary of the main risk factors for upper GI malignancies can be found in Table 2. SCREENING AND PREVENTION

Lifestyle Modifications These epidemiologic studies give us clues as to the etiologies of upper GI malignancies. With this information, the next step is to plan interventions for cancer prevention. Reduction in gastric cancer mortality was largely due to unplanned prevention through changes in environmental factors that occurred since the early 20th century. The widespread introduction of refrigeration led to a decrease in the intake of chemically preserved foods and an increased consumption of fresh fruits and vegetables. In addition, improved housing and living conditions led to a reduction in H pylori infection.14 The decline in cigarette smoking among men in

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Table 2. Epidemiologic Similarities and Differences Among Upper GI Malignancies

Age Male gender Caucasian race Geographic location US/Europe Japan Developing nations Low socioeconomic status H pylori infection GERD Tobacco Alcohol Diet Fruits/vegetables Preserved meat BMI Antioxidants

Esophageal Squamous

Esophageal Adenocarcinoma

Gastric Cardia

Gastric Noncardia

_ 1 2

_ _ 1

_ _ 1

_ 1 2

2 1 1 1 ? 0 _ _

1 2 2 2 2 1 1 0

1 2 2 2 2 ? 1 0

2 1 1 1 1 ? 1 0

2 0 2 2

2 0 1 2

2 1 1 2

2 1 ? 2

NOTE. _ ⫽ strong positive association; 1 ⫽ positive association; 2 ⫽ negative association; ? ⫽ ambiguous studies; 0 ⫽ no association.

the United States parallels the decrease in the incidence of esophageal squamous cell carcinoma.145 Thus, lifestyle modifications such as smoking cessation, a reduction in alcohol use, a decrease in high salt and nitrite consumption, an increased intake of fruits and vegetables, and maintaining a healthy body weight may decrease the risk of esophageal and gastric cancers. Antioxidants High intake of antioxidants, such as vitamins C and E and ␤-carotene, may have a protective effect on the risk of certain upper GI malignancies. In terms of randomized trials, one of the largest intervention trials of vitamin and mineral supplementation occurred in Linxian, China which is known for high rates of esophageal and gastric cancers and a low intake of several micronutrients.146 Overall mortality decreased in those receiving supplementation with ␤-carotene, vitamin E, and selenium, mainly due to lower stomach cancer rates (relative risk, 0.79; 95% CI, 0.64 to 0.99). However, it is unclear whether these results would apply to populations with lower gastric cancer risks. A randomized trial from Finland showed no association with ␣-tocopherol or ␤-carotene supplementation on the prevalence of gastric can-

cer in elderly men with atrophic gastritis.147 Another prospective study from the US Cancer Prevention Study II cohort found that vitamin supplementation may not substantially reduce the risk of stomach cancer mortality in the United States where stomach cancer rates are relatively low.148 In a follow-up study from the Linxian, China intervention trial, individuals with esophageal dysplasia who were receiving multivitamin and multimineral supplementation had regression of the dysplasia.149 In a randomized trial from the United States, significant reductions in total cancer mortality (relative risk, 0.50; 95% CI, 0.31 to 0.80), as well as esophageal cancer (relative risk, 0.33; 95% CI, 0.03 to1.84), were observed in subjects receiving selenium.150 Also from the Linxian, China intervention trial, pretrial selenium levels had an inverse association with the incidence of esophageal and gastric cardia tumors.151 Therefore, dietary supplementation may play a role in cancer prevention for certain high-risk populations. Helicobacter pylori Eradication H pylori eradication is a potential strategy for gastric cancer chemoprevention. Eradication therapy usually involves combinations of an antisecre-

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tory agent with two antibiotics given for 7 to 14 days. These regimens have cure rates of about 80% with durable responses.152 In Japanese patients with early gastric cancer, therapy to eliminate H pylori resulted in a significantly lower rate of gastric cancer recurrence and reduced progression of atrophic gastritis.153 A randomized controlled chemoprevention trial showed that antimicrobial therapy directed against H pylori or dietary supplementation with antioxidants increased the regression rate of gastric atrophy and intestinal metaplasia, compared with patients receiving placebo.154 Another randomized trial in which H pylori–infected subjects were randomized to either eradication therapy or placebo showed a significant decrease in acute and chronic gastritis in the treatment arm.155 Several large-scale chemoprevention trials of H pylori eradication therapy with gastric cancer endpoints are ongoing. However, H pylori infection is extremely common and the vast majority of patients are asymptomatic and never develop gastric cancer. Potential downsides of widespread eradication therapy include developing antibiotic-resistant strains of H pylori and perhaps increasing the risk of GERD, Barrett’s esophagus, and esophageal adenocarcinoma. Anti-reflux Interventions Most patients with Barrett’s esophagus are treated with either medical antacid therapy (H2receptor antagonists or proton-pump inhibitors) or surgical anti-reflux procedures, such as fundoplication. These interventions are highly effective for treating symptoms of GERD, but neither intervention has been shown to prevent progression to esophageal adenocarcinoma.156 In a large Swedish cohort study of patients with GERD who were followed for up to 32 years, the relative risk of esophageal adenocarcinoma among men who received medical antireflux therapy was 6.3, compared to 14.1 for surgically treated men.157 A randomized study of medical and surgical therapies for patients with GERD did not show a statistical difference in the incidence of esophageal adenocarcinoma: 2.4% in the medically treated group and 1.2% in the surgical group.158 However, two studies reported encouraging results of partial regression of areas of Barrett’s esophagus with longterm acid suppression using proton pump inhibitors.159,160

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Endoscopic Screening and Surveillance A proposed strategy to decrease mortality from esophageal adenocarcinoma is to use endoscopy to screen patients with chronic GERD for Barrett’s esophagus.156 In patients with chronic GERD, about 3% to 5% are found to have long-segment Barrett’s esophagus86 and 10% to 15% have shortsegment disease161 on endoscopy. The main goal of surveillance is to detect dysplasia, which is currently the strongest predictor of esophageal adenocarcinoma risk. About 32% to 59% of patients with high-grade dysplasia progress to esophageal adenocarcinoma after several years.162,163 However, there is a fair amount of sampling error during endoscopic biopsy and interobserver disagreement on histologic examination.164,165 Currently, there is little evidence that present screening practices have improved survival for esophageal adenocarcinoma. In one series of 143 patients with Barrett’s esophagus who were followed for a mean of 4.4 years, surveillance identified only one patient with asymptomatic esophageal cancer and that patient subsequently died following esophageal surgery.166 Invasive procedures such as esophagectomy are the only therapies that can clearly prevent the progression to invasive cancer. However, esophagectomy is associated with an operative morality rate of 3% to 12% and a postoperative complication rate of 30% to 50%.167 Endoscopic ablative therapies, such as those employing thermal or photochemical energy, are still experimental and about one third of patients subsequently develop esophageal strictures.168,169 The total cost of diagnosing and treating Barrett’s esophagus has more than tripled in the past decade.170-172 In the United Kingdom, the cost of detecting one case of esophageal cancer with endoscopic surveillance was estimated at $23,000 for men with Barrett’s esophagus and $65,000 for women,173 compared to about $38,000 for detecting one case of esophageal cancer in the United States.174 According to a study using a simulated computer model, the cost of periodic endoscopy of 50-year-old men with Barrett’s esophagus and dysplasia was $10,440 per year of life saved.170 However, screening endoscopy of patients without dysplasia every 5 years cost an additional $596,000 per year of life saved. Therefore, it may be reasonably cost-effective to screen 50-year-old men with

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GERD for Barrett’s esophagus and to do follow-up endoscopy only in patients with dysplasia. The current guidelines from the American College of Gastroenterology call for endoscopy every 2 to 3 years in patients with Barrett’s esophagus without dysplasia, repeated endoscopy after 6 and 12 months for patients with low-grade dysplasia, and intensive endoscopic surveillance every 3 months or esophagectomy for high-grade dysplasia.156 In Japan, where gastric cancer accounts for 18% of cancer-related deaths,34 annual screening with a double-contrast barium technique and endoscopy is recommended for persons over the age of 40 years. With mass screening, about half of gastric tumors are being detected at an early stage in asymptomatic individuals and the mortality rate from gastric cancer has more than halved since the early 1970s.44 An intervention trial in China is underway which involves a comprehensive approach to gastric cancer prevention including H pylori eradication and nutritional supplements, as well as aggressive screening with double contrast x-ray and endoscopic examinations. In the first 4 years after intervention, the relative risk of overall mortality with intervention for high-risk groups was 0.51 (95% CI, 0.35 to 0.74).175 This study suggests that targeting high-risk populations for aggressive screening and prevention may decrease gastric cancer mortality. COX Inhibitors Induction of cyclooxygenase-2 (COX-2) may play a role in tumor development. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are thought to inhibit cancer cell growth primarily through the inhibition of COX-2. Most of the interest in NSAIDs as a chemopreventive agent has focused on colorectal cancer. However, evidence is mounting that COX-2 inhibitors may also be beneficial in the prevention of upper GI malignancies. Exposures to polycyclic aromatic hydrocarbons found in cigarette smoke, alcohol use, acid conditions, and H pylori infection all induce COX-2 expression.176-178 As demonstrated by immunohistochemistry, increasing levels of COX-2 are present in the progression of Barrett’s esophagus to dysplasia and adenocarcinoma,179 as well as the progression from atrophic gastritis to intestinal metaplasia and adenocarcinoma in the stomach.180 In a rat model of Barrett’s esophagus, treatment

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with COX-2 inhibitors reduced the relative risk of developing esophageal cancer by 45%.181 In a large population-based, case-control study, current aspirin users compared to never users were at a decreased risk of esophageal squamous cell carcinoma (OR, 0.49; 95% CI, 0.28 to 0.87), esophageal adenocarcinoma (OR, 0.37; 95% CI, 0.24 to 0.58), and noncardia gastric adenocarcinoma (OR, 0.46; 95% CI, 0.31 to 0.68).182 A recent meta-analysis that pooled data from two cohort and seven case-control studies on aspirin/ NSAIDs and esophageal cancer found a protective effect for any use for esophageal squamous cell carcinoma (OR, 0.58; 95% CI, 0.43 to 0.78) and adenocarcinoma (OR, 0.67; 95% CI, 0.51 to 0.87).183 Randomized trials using NSAIDs in the prevention of esophageal cancer are ongoing. Perhaps, treatment of Barrett’s esophagus might entail a combination of antireflux medications and NSAIDs.184 CONCLUSIONS

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