Summary Of Evidence

Significance

Evidence Of Benefit

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SUMMARY OF EVIDENCE

Squamous cell carcinoma:

Squamous cell cancer of the esophagus is strongly and independently associated with tobacco and alcohol abuse.[1]

Levels of Evidence for preceding statement: 3aii,4

Evidence obtained from well-designed and conducted cohort or case-control studies, preferably from more than one center or research group that have a cancer incidence endpoint.

Ecologic and descriptive studies (e.g., international patterns studies, migration studies, time series)

The relative risk associated with tobacco use is 2.4, and the population attributable risk is 54.2% (95% confidence interval (CI), 3.0-76.2).[1] Retrospective cohort studies adjusted for tobacco use have shown a two- to sevenfold increase in risk of esophageal cancer in alcoholics, compared with rates for the general population.[2] Case-control studies have also suggested a significantly increased risk of cancer of the esophagus associated with alcohol abuse.

Level of Evidence for preceding statement: 3

Evidence obtained from well-designed and conducted cohort or case-control studies, preferably from more than one center or research group

Diets high in vegetables and fruits are associated with a decreased risk of esophageal cancer.[1]

Level of Evidence for preceding statement: 3

Evidence obtained from well-designed and conducted cohort or case-control studies, preferably from more than one center or research group

High intake of vitamin C and high intake of carotenoids possibly decrease the risk of esophageal cancer.[1]

Level of Evidence for preceding statement: 3

Evidence obtained from well-designed and conducted cohort or case-control studies, preferably from more than one center or research group

A significant dose-response relationship has been reported in South America between the amount of mate (a hot, aromatic beverage with stimulant properties like tea or coffee) drunk each day and the risk of esophageal cancer, with an odds ratio (OR) ranging between 1.5 and 12.2.[3] The very high temperature at which this beverage is consumed appears to be important. Level of Evidence for preceding statement: 3

Evidence obtained from well-designed and conducted cohort or case-control studies, preferably from more than one center or research group

Epidemiologic studies have found that regular aspirin use (persons who used aspirin 16/month or more for at least 1 year) was associated with a decreased risk of death from esophageal cancer, and occasional use of aspirin was associated with a 90% decreased risk of developing esophageal cancer. [4,5]

Levels of evidence for preceding statement: 3ai, 3aii, 4ai, 4aii

3ai, 3aii: Evidence obtained from well-designed and conducted cohort or case-control studies, preferably from more than one cancer or research group, that have cancer mortality and cancer incidence endpoints

4ai, 4aii: Ecologic and descriptive studies (eg., international patterns studies, migration studies, time series) that have cancer mortality and cancer incidence endpoints

Adenocarcinoma of the esophagus:

A strong association exists between gastroesophageal reflux disease (GERD) and adenocarcinoma.[6] Long-standing GERD is associated with the development of Barrett's esophagus, a condition in which an abnormal intestinal type epithelium replaces the stratified squamous epithelium that normally lines the distal esophagus.

It is unknown whether elimination of gastroesophageal reflux by surgical or medical means will reduce the risk of esophageal adenocarcinoma.[7]

Level of Evidence for preceding statement: 4

Ecologic and descriptive studies (e.g., international patterns studies, migration studies, time series)

References:

1. Siemiatycki J, Krewski D, Franco E, et al.: Associations between cigarette smoking and each of 21 types of cancer: a multi-site case-control study. International Journal of Epidemiology 24(3): 504-514, 1995.
2. Oesophagus. In: World Cancer Research Fund in association with American Institute for Cancer Research: Food, Nutrition and the Prevention of Cancer: a Global Perspective. Washington, DC: American Institute for Cancer Research, 1997, pp 118-129.
3. De Stefani E, Munoz N, Esteve J, et al.: Mate drinking, alcohol, tobacco, diet, and esophageal cancer in Uruguay. Cancer Research 50(2): 426-431, 1990.
4. Funkhouser EM, Sharp GB: Aspirin and reduced risk of esophageal carcinoma. Cancer 76(7): 1116-1119, 1995.
5. Thun MJ, Namboodiri MM, Calle EE, et al.: Aspirin use and risk of fatal cancer. Cancer Research 53(6): 1322-1327, 1993.
6. Lagergren J, Bergstrom R, Lindgren A, et al.: Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. New England Journal of Medicine 340(11): 825-831, 1999.
7. Spechler SJ, Goyal RK: The columnar-lined esophagus, intestinal metaplasia, and Norman Barrett. Gastroenterology 110(2): 614-621, 1996.

SIGNIFICANCE

Incidence and Mortality

Two histological types account for the majority of malignant esophageal neoplasms, i.e., adenocarcinoma and squamous carcinoma. The epidemiology of these types varies markedly. In the 1960s, squamous cell cancers comprised over 90% of all esophageal tumors. The incidence of esophageal adenocarcinomas has risen markedly over the past 2 decades, such that it is now more prevalent than squamous cell cancer in the United States and Western Europe, with most tumors located in the distal esophagus.[2] Although the overall incidence of squamous cell carcinoma of the esophagus is declining, this histologic type remains 6 times more likely to occur in black males than in white males.[1] Incidence rates generally increase with age in all racial/ethnic groups. In black men, however, the incidence rate for the 55 to 69 year age group is close to that of whites in the 70 and over age group. In black women, aged 55 to 69 years, the incidence rate is slightly higher than that of white women in the 70 years and older age group.

Risk Factors

An interesting hypothesis relates the rise in the incidence of esophageal adenocarcinoma to a declining prevalence of Helicobacter pylori infection in Western countries. Reports have suggested that gastric infection with H. pylori may protect the esophagus from GERD and its complications.[5] According to this theory, H. pylori infections that cause pangastritis also cause a decrease in gastric acid production that protects against GERD.[6] Patients whose duodenal ulcers were treated successfully with antibiotics developed reflux esophagitis twice as often as those in whom infection persisted.[7] Other factors that have been suggested to explain the increased risk of esophageal adenocarcinoma include obesity [8] and use of medications, such as anticholinergics, that can predispose to GERD by relaxing the lower esophageal sphincter.[9]

GERD is a risk factor for esophageal adenocarcinoma because long-standing GERD is associated with Barrett's esophagus, the condition in which an abnormal intestinal epithelium replaces the stratified squamous epithelium that normally lines the distal esophagus.[10] The intestinal-type epithelium of Barrett's esophagus has a characteristic endoscopic appearance that differs from squamous epithelium.[11] Dysplasia in Barrett's epithelium represents a neoplastic alteration of the columnar epithelium that may progress to invasive adenocarcinoma.[12]

References:

1. American Cancer Society: Cancer Facts and Figures-2002. Atlanta, Ga: American Cancer Society, 2002.
2. Blot WJ, McLaughlin JK: The changing epidemiology of esophageal cancer. Seminars in Oncology 26(5 suppl 15): 2-8, 1999.
3. Siemiatycki J, Krewski D, Franco E, et al.: Associations between cigarette smoking and each of 21 types of cancer: a multi-site case-control study. International Journal of Epidemiology 24(3): 504-514, 1995.
4. Lagergren J, Bergstrom R, Lindgren A, et al.: Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. New England Journal of Medicine 340(11): 825-831, 1999.
5. O'Connor HJ: Helicobacter pylori and gastro-oesophageal reflux disease-clinical implications and management. Alimentary Pharmacology and Therapeutics 13(2): 117-127, 1999.
6. Graham DY, Yamaoka Y: H. pylori and cagA: relationships with gastric cancer, duodenal ulcer, and reflux esophagitis and its complications. Helicobacter 3(3): 145-151, 1998.
7. Labenz J, Blum AL, Bayerdorffer E, et al.: Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology 112(5): 1442-1447, 1997.
8. Lagergren J, Bergstrom R, Nyren O: Association between body mass and adenocarcinoma of the esophagus and gastric cardia. Annals of Internal Medicine 130(11): 883-890, 1999.
9. Lagergren J, Bergstrom R, Adami HO, et al.: Association between medications that relax the lower esophageal sphincter and risk for esophageal adenocarcinoma. Annals of Internal Medicine 133(3): 165-175, 2000.
10. Spechler SJ, Goyal RK: The columnar-lined esophagus, intestinal metaplasia, and Norman Barrett. Gastroenterology 110(2): 614-621, 1996.
11. Van Dam J, Brugge WR: Endoscopy of the upper gastrointestinal tract. New England Journal of Medicine 341(23): 1738-1748, 1999.
12. Reid BJ, Blount PL, Rubin CE, et al.: Flow-cytometric and histological progression to malignancy in Barrett's esophagus: prospective endoscopic surveillance of a cohort. Gastroenterology 102(4 pt 1): 1212-1219, 1992.

EVIDENCE OF BENEFIT

A prospective, placebo-controlled, esophagus chemoprevention study randomized 610 high-risk Chinese subjects.[2] Subjects were from 35 to 64 years old and received either placebo or combined low-dose retinol (15 mg or 50,000 IU) plus riboflavin (200 mg) and zinc gluconate (50 mg) for 13.5 months. Standard histological evaluations (including 2 endoscopic biopsies) were made of 93% of all entered subjects. Micronuclei from esophageal cells were obtained before therapy began and after the 13.5 months of treatment. Serum levels of vitamin A, beta-carotene, riboflavin, and zinc were obtained at 0, 2, and 13.5 months.

The second report of this study presented micronuclei frequency results.[3] A statistically significant reduction occurred in the mean percentage of micronucleated esophageal cells in the active-treatment group compared to the placebo group. The pattern of cell proliferation, another potential intermediate endpoint marker, also improved.[4]

Two NCI-sponsored phase III trials of combinations of multiple vitamins and minerals have been reported. Both were conducted in a high-risk area of China (Linxian). In one, a complex modified factorial design was used to study 4 different vitamin/mineral combinations administered for 5 years at doses 1 to 2 times the U.S. RDA to 29,584 subjects.[5] The combination of beta-carotene, alpha-tocopherol, and selenium was associated with a nonstatistically significant 4% reduction in the esophageal cancer mortality rate. The other trial included only higher-risk subjects with esophageal dysplasia [6] and had a 2-arm design (26 vitamins and minerals, including beta-carotene, alpha-tocopherol, and selenium, at 2-3 times the U.S. recommended daily allowances (RDA) in 1 arm versus placebo in the other). This 6-year intervention was associated with a nonsignificant change: a 16% reduction in the esophageal cancer mortality rate. Similar studies have not been conducted in the United States.

Aspirin and Nonsteroidal Anti-Inflammatory Drugs

References:

1. Oesophagus. In: World Cancer Research Fund in association with American Institute for Cancer Research: Food, Nutrition and the Prevention of Cancer: a Global Perspective. Washington, DC: American Institute for Cancer Research, 1997, pp 118-129.
2. Munoz N, Wahrendorf J, Bang LJ, et al.: No effect of riboflavine, retinol, and zinc on prevalence of precancerous lesions of oesophagus. Randomised double-blind intervention study in high-risk population of China. Lancet 2(8447): 111-114, 1985.
3. Munoz N, Hayashi M, Bang LJ, et al.: Effect of riboflavin, retinol, and zinc on micronuclei of buccal mucosa and of esophagus: a randomized double-blind intervention study in China. Journal of the National Cancer Institute 79(4): 687-691, 1987.
4. Yang GC, Lipkin M, Yang K, et al.: Proliferation of esophageal epithelial cells among residents of Linxian, People's Republic of China. Journal of the National Cancer Institute 79(6): 1241-1246, 1987.
5. 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. Journal of the National Cancer Institute 85(18): 1483-1492, 1993.
6. Li JY, Taylor PR, Li B, et al.: Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. Journal of the National Cancer Institute 85(18): 1492-1498, 1993.
7. Thun MJ, Namboodiri MM, Calle EE, et al.: Aspirin use and risk of fatal cancer. Cancer Research 53(6): 1322-1327, 1993.
8. Funkhouser EM, Sharp GB: Aspirin and reduced risk of esophageal carcinoma. Cancer 76(7): 1116-1119, 1995.

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