Adenocarcinoma of the Esophagus and Gastroesophageal Junction

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Adenocarcinoma of the Esophagus and Gastroesophageal Junction

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1. Adenocarcinoma of the Esophagus and Gastroesophageal Junction Steven R. Alberts, MD MPH Medical Oncology Mayo Clinic Rochester, MN

2. Adenocarcinoma of the Esophagus - An Evolving Story Progressive decline in stomach cancer since early 1900’s Refrigeration of food Decrease in smoked and salted foods

3. Mortality from Stomach and Esophageal Cancer

4. Esophageal and GE Junction Cancers Recent dramatic increase in adenocarcinomas of the esophagus and gastroesophageal junction More rapid increase than melanomas

5. Esophagus and GE Junction In SEER and probably other registries, cancers of the GE junction are coded as gastric cardia. The epidemiology of gastric cardia adenocarcinoma is more similar to those of esophageal adenocarcinomaa than distal stomach. The presentation will focus on esophageal adenocarcinoma, but data on gastric cardia adenocarcinoma will also be presented where relevant. In SEER and probably other registries, cancers of the GE junction are coded as gastric cardia. The epidemiology of gastric cardia adenocarcinoma is more similar to those of esophageal adenocarcinomaa than distal stomach. The presentation will focus on esophageal adenocarcinoma, but data on gastric cardia adenocarcinoma will also be presented where relevant.

6. Occurrence of Esophageal and Gastric Cancer New Cases in 2004 Esophagus 14,250 Men 10,860 Women 3,390 Stomach 22,710 Men 13,640 Women 9,070 One-third of stomach cancers from GE Junction and Cardia Jemal A, et al. CA Cancer J Clin 54:8-29, 2004

7. Pathology - American College of Surgeons National Cancer Database 1973-82 1994 (N=5644) (N=5044) Adenocarcinoma 13% 42% Squamous Cell 79% 52% Yang PC, et al. Cancer 61:612-17, 1988 Daly JM, et al. J Am Coll Surg 190:562-73, 2000

8. The incidence patterns for GCA are similar to EA, but less dramatic. Rates for non-cardia GA are decreasing while rates for GA are increasing. Among white men, rates of non-cardia and cardia GA converge in the mid-1990s. Unlike EA, however, rates for cardia GA show signs of leveling in recent years. The incidence patterns for GCA are similar to EA, but less dramatic. Rates for non-cardia GA are decreasing while rates for GA are increasing. Among white men, rates of non-cardia and cardia GA converge in the mid-1990s. Unlike EA, however, rates for cardia GA show signs of leveling in recent years.

9. EA is the most rapidly increasing cancer among white men in the U.S., rose more than 400% since the early 1970s. Since mid-1990s, the rates of adenocarcinoma surpassed rates of squamous cell cancer as the predominant cancer esopahgeal cancer among white men. Among blacks, squamous cell is still the predominant esophageal cancer type, but rates of EA are rapidly increasing also. The patterns are similar among women - squamous cell is still the predominate cancer among women, but sq cell cancerrates are decresing while EA rates are increasing rapidly If this pattern continues, with time, EA may become the predominant esophageal cancer among white women in the near future. EA is the most rapidly increasing cancer among white men in the U.S., rose more than 400% since the early 1970s. Since mid-1990s, the rates of adenocarcinoma surpassed rates of squamous cell cancer as the predominant cancer esopahgeal cancer among white men. Among blacks, squamous cell is still the predominant esophageal cancer type, but rates of EA are rapidly increasing also. The patterns are similar among women - squamous cell is still the predominate cancer among women, but sq cell cancerrates are decresing while EA rates are increasing rapidly If this pattern continues, with time, EA may become the predominant esophageal cancer among white women in the near future.

10. Esophageal Adenocarcinoma Incidence Trends, Males, Europe The increasing incidence rates of EA appear to be a worldwide phenomenon. Most of the increasing trends are reported in Western Europe, although data are emerging to show increasing patterns in Eastern Europe (such as Slovenia show here). Increases in some Asian countries also have been suggested. The increasing incidence rates of EA appear to be a worldwide phenomenon. Most of the increasing trends are reported in Western Europe, although data are emerging to show increasing patterns in Eastern Europe (such as Slovenia show here). Increases in some Asian countries also have been suggested.

11. Age-Specific Incidence Rates White Males, SEER, 1995-1999 Like most cancers, incidence rates of EA increase consistently with age (except at the very old age where statistics are harder to interpret – e.g., incomplete diagnosis and reporting). Incidence rates for GCA are similar to those of EA. Of note, rates of EA at every age are higher than rates for esophageal squamous cell cancer. Like most cancers, incidence rates of EA increase consistently with age (except at the very old age where statistics are harder to interpret – e.g., incomplete diagnosis and reporting). Incidence rates for GCA are similar to those of EA. Of note, rates of EA at every age are higher than rates for esophageal squamous cell cancer.

12. Age-Specific Incidence Rates White Females, SEER, 1995-1999 The patterns of age-specific incidence rates among women are similar to those of men, except that among women, squamous cell is still the predominant histologic type. The patterns of age-specific incidence rates among women are similar to those of men, except that among women, squamous cell is still the predominant histologic type.

13. Male to Female Incidence Rate Ratios SEER, 1995-1999 Like most cancers, incidence rates of esophageal and gastric cancers are higher among men than women. However, the male excess of EA is much higher than most other cancers. Male excess of GCA also is high, particularly among whites. Whereas male excess of non-cardia GA is much more moderate than both EA and GCA. Like most cancers, incidence rates of esophageal and gastric cancers are higher among men than women. However, the male excess of EA is much higher than most other cancers. Male excess of GCA also is high, particularly among whites. Whereas male excess of non-cardia GA is much more moderate than both EA and GCA.

14. Esophageal Adenocarcinoma One-year Survival Rates, SEER Much of the improvement in survival occur among patients diagnosed with tumors at localized stage, and some improvement for regional tumors. However, for patients diagnosed with distant tumors, the survival rates have worsened. Much of the improvement in survival occur among patients diagnosed with tumors at localized stage, and some improvement for regional tumors. However, for patients diagnosed with distant tumors, the survival rates have worsened.

15. 5-year survival for patients with esophageal cancer Stage I: 79% Stage IIA: 38% Stage IIB: 27% Stage III: 14% Stage IV: 5%

16. Esophageal Adenocarcinoma Survival Rates, SEER As you well know, survival rates are poor for EA. Less than 50% survive more than 12 months since diagnosis. However, survival rates are improving for each successive 5-year time period for patients diagnosed since the early 1970s. As you well know, survival rates are poor for EA. Less than 50% survive more than 12 months since diagnosis. However, survival rates are improving for each successive 5-year time period for patients diagnosed since the early 1970s.

17. Esophageal Adenocarcinoma Stage at Diagnosis, SEER Indeed, EAs are diagnosed at increasingly earlier stages over time, with the proportion of distant tumors decreasing, while proportion of localized tumors increasing. Much of the overall improvement in survival among EA patients is probably due to an improvement in early detection and diagnosis. Indeed, EAs are diagnosed at increasingly earlier stages over time, with the proportion of distant tumors decreasing, while proportion of localized tumors increasing. Much of the overall improvement in survival among EA patients is probably due to an improvement in early detection and diagnosis.

18. Environmental Risk Factors Esophageal Adenocarcinoma Enviornmental risk factors are broadly defined to include lifestyle factors, dietary practices, height and weight history, medical history, and other exposures. Most of the epidemiologic data on environmental risk factors for EA are case-control studies, where information obtained from cases are compared to healthy controls. Prospective data from cohort studies are uncommon because of the rarity of this cancer. Much of the data that I’ll present today are from a multicenter case-control study in the U.S., including the Fred Hutchinson Cancer Research Center (covering 3 western counties in Washington State), Yale University (covering the State of Connecticut), and Columbia University (covering 15 counties in northern NJ). I’ll supplement data from other studies and from the literature where relevant. Enviornmental risk factors are broadly defined to include lifestyle factors, dietary practices, height and weight history, medical history, and other exposures. Most of the epidemiologic data on environmental risk factors for EA are case-control studies, where information obtained from cases are compared to healthy controls. Prospective data from cohort studies are uncommon because of the rarity of this cancer. Much of the data that I’ll present today are from a multicenter case-control study in the U.S., including the Fred Hutchinson Cancer Research Center (covering 3 western counties in Washington State), Yale University (covering the State of Connecticut), and Columbia University (covering 15 counties in northern NJ). I’ll supplement data from other studies and from the literature where relevant.

20. Cigarette Smoking U.S. Multicenter study Smoking Status OR 95% CI Never smoker 1.0 Current smoker 2.2 (1.4-3.3) Ex-smoker 2.0 (1.4-2.9) Pack-years of Smoking <14 1.4 (0.8-2.2) 14-31 1.6 (1.0-2.6) 32-54 2.9 (1.8-4.5) >54 2.8 (1.8-4.4) Cigarette smoking has been shown to increase the risk of EA in many studies. In the U.S. multicenter study, risk about doubled among smokers. This risk is intermediate between smoking-related risks for esophageal squamous cell carcinoma and distal stomach cancer. There is also a dose-response in risk with amount and duration of smoking. Here we show that risks increased with pack-years of smoking. Of note, risk for current and former smokers are similar. Cigarette smoking has been shown to increase the risk of EA in many studies. In the U.S. multicenter study, risk about doubled among smokers. This risk is intermediate between smoking-related risks for esophageal squamous cell carcinoma and distal stomach cancer. There is also a dose-response in risk with amount and duration of smoking. Here we show that risks increased with pack-years of smoking. Of note, risk for current and former smokers are similar.

21. Smoking Cessation Years Stopped OR (95% CI) <11 2.7 (1.6-4.4) 11-20 2.3 (1.4-3.8) 21-30 1.9 (1.1-3.2) >30 1.2 (0.7-2.2) When risks were examined in relation to years after smoking cessation, the two-fold risk persisted even among those who quit smoking for 20-30 years. It was only among those who quit for more than 30 years a significant drop in risk was observed. When risks were examined in relation to years after smoking cessation, the two-fold risk persisted even among those who quit smoking for 20-30 years. It was only among those who quit for more than 30 years a significant drop in risk was observed.

22. Since the first Surgeon General report came out in 1966, the anti-smoking sentiment in this country has increased over time. Since the first Surgeon General report came out in 1966, the anti-smoking sentiment in this country has increased over time.

23. Indeed, the prevalence of cigarette smoking in the U.S. has declined substantially since the mid-1960s. So it is unlikely that smoking has contributed to the recent increase in EA incidence. However, since the risk among former smokers are not reduced even decades after smoking cessation, it’s possible that the increases in smoking until the mid-1960s have contributed to some of the early increases in EA. Indeed, the prevalence of cigarette smoking in the U.S. has declined substantially since the mid-1960s. So it is unlikely that smoking has contributed to the recent increase in EA incidence. However, since the risk among former smokers are not reduced even decades after smoking cessation, it’s possible that the increases in smoking until the mid-1960s have contributed to some of the early increases in EA.

25. Usual Adult Body Mass Index U.S. Multicenter Study BMI Quartiles OR 95% CI I – Low 1.0 II 1.3 (0.8-2.2) III 2.0 (1.3-3.3) IV – High 2.9 (1.8-4.7) We also examined body mass index as a potential risk factor and found that risk increased consistently with increasing BMI, rising to 3-fold in the highest quartile. We also examined body mass index as a potential risk factor and found that risk increased consistently with increasing BMI, rising to 3-fold in the highest quartile.

26. By now, everybody probably knows that obesity is increasing in this country. As documented here by our evolving stature. By now, everybody probably knows that obesity is increasing in this country. As documented here by our evolving stature.

27. The increasing prevalence of obesity in this country is well-known, nearly doubling between 1960 and 1994, with faster increases among whites than blacks. However, the prevalence of obesity is highest among African American women and lowest among white men. Therefore, obesity per se does not explain the gender and racial patterns in esophageal adenocarcinoma. The increasing prevalence of obesity in this country is well-known, nearly doubling between 1960 and 1994, with faster increases among whites than blacks. However, the prevalence of obesity is highest among African American women and lowest among white men. Therefore, obesity per se does not explain the gender and racial patterns in esophageal adenocarcinoma.

28. Obesity may increase the risk of esophageal adenocarcinoma through increased gastroesophageal reflux resulting from increased abdominal pressure. Men, in particular, tend to have central obesity with most of the weight carried in the abdominal area, and therefore increased addominal pressure, whereas women tend to carry more of their weight in the hip and thigh. In our study, the increased risk of esophageal adenocarcinoma among obese individuals was seen regardless of reflux symptoms. Thus, other mechanisms may be involved in linking obesity to this tumor. Intra-abdominal obesity also has a stronger link to insulin resistence and increased levels of IgF-1(insulin-like growth factor), which has been linked to elevated risks of several cancers.Obesity may increase the risk of esophageal adenocarcinoma through increased gastroesophageal reflux resulting from increased abdominal pressure. Men, in particular, tend to have central obesity with most of the weight carried in the abdominal area, and therefore increased addominal pressure, whereas women tend to carry more of their weight in the hip and thigh. In our study, the increased risk of esophageal adenocarcinoma among obese individuals was seen regardless of reflux symptoms. Thus, other mechanisms may be involved in linking obesity to this tumor. Intra-abdominal obesity also has a stronger link to insulin resistence and increased levels of IgF-1(insulin-like growth factor), which has been linked to elevated risks of several cancers.

29. Waist-to-Hip Ratio and Intermediate Markers in Barrett’s Esophagus Percent with Intermediate Markers Waist-to-hip ratio 4N Aneuploidy 9pLOH 17pLOH Quartile I 5 5 49 18 II 8 7 48 15 III 11 12 58 18 Quartile IV 14 17 67 29 Data on intra-abdominal obesity and risk of EA are limited. However, the Seattle group (Tom Vaughan, Brian Reid) has looked at waist-to-hip ratio in relation to intermediate markers in BE. The proportion of BE patients with cytometric abnormalities (increase 4N and anueploidy cells) and loss of heterocygocity in 9p and 17p increased with increasing levels of W-to-H rations, an indicator of increased intro-abdominal obesity. Interestingly, in this study, BMI per se was not related to risk, suggesting that differences in obesity between men and women may have contributed to some extent the gender difference in incidence of EA. Data on intra-abdominal obesity and risk of EA are limited. However, the Seattle group (Tom Vaughan, Brian Reid) has looked at waist-to-hip ratio in relation to intermediate markers in BE. The proportion of BE patients with cytometric abnormalities (increase 4N and anueploidy cells) and loss of heterocygocity in 9p and 17p increased with increasing levels of W-to-H rations, an indicator of increased intro-abdominal obesity. Interestingly, in this study, BMI per se was not related to risk, suggesting that differences in obesity between men and women may have contributed to some extent the gender difference in incidence of EA.

31. Gastroesophageal Reflux Southern California Kaiser Study Reflux OR 95% CI No 1.0 Yes 2.1 (1.2-3.6) Duration (Years) 1-5 1.2 (0.5-3.0) >5 2.7 (1.5-4.9) Back in the early 1990s when we first noticed the rapid increases in esophageal adenocarcinoma incidence, little was known about the underlying etiology of this cancer. A leading hypothesis at the time was that the increasing use of medications to treat gastrointestinal diseases promoted reflux and increased the risk of this cancer. To test this hypothesis, we studied records of members of the Southern California Kaiser Foundation Health Plan. We found that a history of gastroesophageal reflux disease was the risk factor, not the medications used. Patients with a history of reflux-related conditions had double the risk compared to those with no such history. The risk was mainly confined to those who had these conditions for 5 or more years. The risks were similar whether the patients used medications for treatment of reflux. Back in the early 1990s when we first noticed the rapid increases in esophageal adenocarcinoma incidence, little was known about the underlying etiology of this cancer. A leading hypothesis at the time was that the increasing use of medications to treat gastrointestinal diseases promoted reflux and increased the risk of this cancer. To test this hypothesis, we studied records of members of the Southern California Kaiser Foundation Health Plan. We found that a history of gastroesophageal reflux disease was the risk factor, not the medications used. Patients with a history of reflux-related conditions had double the risk compared to those with no such history. The risk was mainly confined to those who had these conditions for 5 or more years. The risks were similar whether the patients used medications for treatment of reflux.

32. Use of Medications Southern California Kaiser Study Medications OR 95% CI No 1.0 Anticholinergics only 0.8 (0.4-1.5) H2 antagonists only 0.7 (0.3-1.6) Both 0.5 (0.1-1.4) In contrast, we found that risk of esophageal adenocarcinoma was not related to the use of H2 antagonists or anticholinergic medications for treatment of reflux diseases. These data suggest that reflux disease per se is the risk factor for EA. Note that a few case-control studies based on interviews have reported associations with these medications. However, it is very difficult to disentangle the underlying cause from its treatment in cancer risk in interview-based studies because of recall bias for these closely related exposures. In contrast, we found that risk of esophageal adenocarcinoma was not related to the use of H2 antagonists or anticholinergic medications for treatment of reflux diseases. These data suggest that reflux disease per se is the risk factor for EA. Note that a few case-control studies based on interviews have reported associations with these medications. However, it is very difficult to disentangle the underlying cause from its treatment in cancer risk in interview-based studies because of recall bias for these closely related exposures.

33. Gastroesophageal Reflux U.S. Multi-Center Study Reflux symptoms (times/year) OR 95% CI Never 1.0 1-2 0.5 (0.2-1.0) 3-12 1.2 (0.6-2.2) 13-104 2.0 (1.2-3.2) 105-364 3.4 (1.9-6.1) >364 5.5 (3.2-9.3) The finding of reflux was later confirmed in the U.S. multicenter study, as well as a Swedish nation-wide study that was published in the New Engl J Med. In our study, we found that risk of EA increased with frequency of reflux, to more than five-fold for patients with daily symptoms of reflux. The finding of reflux was later confirmed in the U.S. multicenter study, as well as a Swedish nation-wide study that was published in the New Engl J Med. In our study, we found that risk of EA increased with frequency of reflux, to more than five-fold for patients with daily symptoms of reflux.

34. BMI, Reflux Symptoms, and Risk of Esophageal Adenocarcinoma Reflux Symptoms BMI Quartile No Yes I 1.0 1.0 II 2.0 2.0 III 4.4* 3.3* IV 7.6* 8.8* * p<0.05 To reiterate our finding that there are independent effects of BMI and reflux symptoms on EA risk, the Swedish study also found that regardless of reflux symptoms, risk increased with BMI levels. To reiterate our finding that there are independent effects of BMI and reflux symptoms on EA risk, the Swedish study also found that regardless of reflux symptoms, risk increased with BMI levels.

35. Data on the trends for reflux disease are limited. My colleagues at DCEG looked at the hospitalization rates for reflux disease among male veterans in this country. As shown here, the rapid increases of incidence rates of reflux disease parallel those for esophageal adenocarcinoma. The rates for reflux are higher among whites than blacks, which may explain to some extent the white excess of EA.Data on the trends for reflux disease are limited. My colleagues at DCEG looked at the hospitalization rates for reflux disease among male veterans in this country. As shown here, the rapid increases of incidence rates of reflux disease parallel those for esophageal adenocarcinoma. The rates for reflux are higher among whites than blacks, which may explain to some extent the white excess of EA.

36. Progression of Esophageal Adenocarcinoma Gastroesophageal Reflux Disease Metaplasia/Barrett’s Esophagus Low Grade Dysplasia High Grade Dysplasia Adenocarcinoma It is generally accepted that reflux-related EA develop through a spectrum of histologic and genomic changes from gastroesophageal reflux disease to cancer. As a result of the chronic mucosal injury associated with gastroesophageal reflux disease, approximately 10-20% of patients will develop metaplastic layers called Barrett’s esophagus. It is believed that most EAs arise from Barrett’s esophagus, but it is unclear what proportion of patients with Barrett’s esophagus will progress to cancer over time. The risk of adenocarcinoma in patients with Barrett’s esophagus, particularly those with high grade dysplasia, has been estimated to be 30-125 times that of age-matched controls. It is generally accepted that reflux-related EA develop through a spectrum of histologic and genomic changes from gastroesophageal reflux disease to cancer. As a result of the chronic mucosal injury associated with gastroesophageal reflux disease, approximately 10-20% of patients will develop metaplastic layers called Barrett’s esophagus. It is believed that most EAs arise from Barrett’s esophagus, but it is unclear what proportion of patients with Barrett’s esophagus will progress to cancer over time. The risk of adenocarcinoma in patients with Barrett’s esophagus, particularly those with high grade dysplasia, has been estimated to be 30-125 times that of age-matched controls.

38. Potential Dietary Risk Factors Factor Risk Fruits & vegetables* Dietary fiber Antioxidants Total fat Reflux-inducing foods -- Heterocyclic amines -- A few studies also have examined diet in relation to risk of EA. The most consistent findings are a reduced risk with high intake of fresh fruits and vegetables. Related to this finding, some studies also reported decreased risks with high intake of dietary fiber and antioxidants, which are mostly derived from plant sources. A few studies, including our multicenter study, reported an increased risk with high fat intake, but the findings are less consistent than that for fruits and vegetables. A few studies also have looked at certain foods that may promote reflux, including fat and other items such as chocolate, mint, onions, coffee, etc., but generally have found no consistent associations. Heterocyclic amines, carcinogens occur during high temperature cooking of meat, such as barbecue, also have been hypothesized, but generally were not associated with risk. A few studies also have examined diet in relation to risk of EA. The most consistent findings are a reduced risk with high intake of fresh fruits and vegetables. Related to this finding, some studies also reported decreased risks with high intake of dietary fiber and antioxidants, which are mostly derived from plant sources. A few studies, including our multicenter study, reported an increased risk with high fat intake, but the findings are less consistent than that for fruits and vegetables. A few studies also have looked at certain foods that may promote reflux, including fat and other items such as chocolate, mint, onions, coffee, etc., but generally have found no consistent associations. Heterocyclic amines, carcinogens occur during high temperature cooking of meat, such as barbecue, also have been hypothesized, but generally were not associated with risk.

39. Population Attributable Risks U.S. Multicenter Study Risk Factor PAR (95% CI) Smoking: ever 40 (26-56) BMI: upper 3 quartiles 41 (24-61) Reflux symptoms 30 (20-42) Fruits & vegetables 15 (6 -35) (<2 times/day) All factors combined 79 (67-87) In our population-based mutlicenter study in the U.S., we estimated that about 80% of EA can be attributed to a combination of these four well-established risk factors, namely, smoking, excess BMI, having a history of gastroesophageal reflux disease, and less than recommended intake of fresh fruits and vegetables. In terms of cancer prevention, reduction of one of these risk factors, particularly smoking, obesity, or reflux disease, will contributing substantially in lowering the incidence of this cancer. In our population-based mutlicenter study in the U.S., we estimated that about 80% of EA can be attributed to a combination of these four well-established risk factors, namely, smoking, excess BMI, having a history of gastroesophageal reflux disease, and less than recommended intake of fresh fruits and vegetables. In terms of cancer prevention, reduction of one of these risk factors, particularly smoking, obesity, or reflux disease, will contributing substantially in lowering the incidence of this cancer.

41. Helicobacter pylori and cagA Status U.S. Multicenter Study H. pylori status OR 95% CI Negative 1.0 Positive 0.7 0.4-1.1 cagA status Negative 1.0 0.5-1.7 Positive 0.4 0.2-0.8 In addition to the well-established risk factors, evidence is accumulating for two other factors that may reduce the risk of EA. We found an inverse association between EA and carriage of Helicobacter pylori, a stomach bacterium that has previously been linked to gastric cancer and peptic ulcer. The reduction in risk was most prominent for those who carried the more virulent cagA positive strain of H. pylori. The finding has now been confirmed in the nationwide Swedish study. This observation has also been seen in studies of Barrett’s esophagus and reflux disease. The mechanisms by which H. pylori may reduce the risk of EA is unclear. It has been suggested that colonization of H. pylori in the gastric mucosa reduces the secretion of gastric acid and its subsequent reflux to the lower esophagus. In addition to the well-established risk factors, evidence is accumulating for two other factors that may reduce the risk of EA. We found an inverse association between EA and carriage of Helicobacter pylori, a stomach bacterium that has previously been linked to gastric cancer and peptic ulcer. The reduction in risk was most prominent for those who carried the more virulent cagA positive strain of H. pylori. The finding has now been confirmed in the nationwide Swedish study. This observation has also been seen in studies of Barrett’s esophagus and reflux disease. The mechanisms by which H. pylori may reduce the risk of EA is unclear. It has been suggested that colonization of H. pylori in the gastric mucosa reduces the secretion of gastric acid and its subsequent reflux to the lower esophagus.

42. As shown in this schematic drawing by our colleague, Marty Blaser, the incidence and prevalence of H. pylori carriage have progressively declined during this century in relation to improving living conditions and increased use of antibiotics, particularly among children. In contrast, the incidence of gastroesophageal reflux, then Barrett’s esophagus, and subsequently esophageal adenocarcinoma has rapidly increased in western countries. As shown in this schematic drawing by our colleague, Marty Blaser, the incidence and prevalence of H. pylori carriage have progressively declined during this century in relation to improving living conditions and increased use of antibiotics, particularly among children. In contrast, the incidence of gastroesophageal reflux, then Barrett’s esophagus, and subsequently esophageal adenocarcinoma has rapidly increased in western countries.

44. Use of Nonseroidal Anti-Inflammatory Drugs (NSAID) Barrett’s Esophagus NSAID Aneu- Use EA 4N ploidy 9pLOH 17pLOH Never 1.0 1.0 1.0 1.0 1.0 Former 0.4 1.1 0.2 0.9 0.7 Current 0.4* 0.6 0.6 1.1 0.3* A protective role of aspirin and other NSAIDs for some cancers, particularly colorectal cancer, have been well established. In our study, we found reduced risk of EA among both former and current users of NSAIDs. In the Barrett’s esophagus study from Seattle that we mentioned earlier, NSAID users also have reduced risk of cytometric abnormalities and LOH in 17p. There is also increasing evidence from laboratory studies and animal models to support this hypothesis, but epidemiologic evidence is still limited. A protective role of aspirin and other NSAIDs for some cancers, particularly colorectal cancer, have been well established. In our study, we found reduced risk of EA among both former and current users of NSAIDs. In the Barrett’s esophagus study from Seattle that we mentioned earlier, NSAID users also have reduced risk of cytometric abnormalities and LOH in 17p. There is also increasing evidence from laboratory studies and animal models to support this hypothesis, but epidemiologic evidence is still limited.

45. Summary Environmental Risk Factors Population Cancer Risk Factor Trend Trend Reflux disease Overweight Smoking H. Pylori Fruits/vegetables NSAID Use In summary, of the six factors that we discussed, several could have contributed to the rising incidence of EA, particularly the rapid increases in reflux disease and obesity in this country. Smoking prevalence has declined, but the increases in smoking up to the mid-1960s could have contributed to some of the early increase in EA. If the inverse association with H. pyloir proven to be causal, the decline in H. pylori carriage in this country also could have contributed to the increasing EA trends. Intake of fruits and vegetables and NSAID use have increased in this country over time. Since both factors are inversely related to EA risk, the increasing trends of these factors should reduce the incidence of EA. These factors therefore are unlikely to have contributed substantially to the increasing trends of EA. In summary, of the six factors that we discussed, several could have contributed to the rising incidence of EA, particularly the rapid increases in reflux disease and obesity in this country. Smoking prevalence has declined, but the increases in smoking up to the mid-1960s could have contributed to some of the early increase in EA. If the inverse association with H. pyloir proven to be causal, the decline in H. pylori carriage in this country also could have contributed to the increasing EA trends. Intake of fruits and vegetables and NSAID use have increased in this country over time. Since both factors are inversely related to EA risk, the increasing trends of these factors should reduce the incidence of EA. These factors therefore are unlikely to have contributed substantially to the increasing trends of EA.

46. Summary Potential opportunity for prevention and early intervention Managing obesity Smoking cessation Monitoring patients with reflux Improving diet Use of risk modifying agents in high-risk populations

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