Prevention of Esophageal Cancer

Summary Type: Prevention
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about factors that may influence the risk of developing esophageal cancer and about research aimed at the prevention of this disease.

Prevention of Esophageal Cancer

Summary of Evidence

Note: Separate PDQ summaries on Screening for Esophageal Cancer, Esophageal Cancer Treatment, and Levels of Evidence for Cancer Screening and Prevention Studies are also available.

Squamous Cell Carcinoma

Avoidance of tobacco and alcohol

Based on solid evidence, avoidance of tobacco and alcohol would decrease the risk of squamous cell cancer.^1,

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 twofold 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.

Description of the Evidence
• Study Design : Evidence obtained from cohort or case-control studies.
• Internal Validity : Fair.
• Consistency : Multiple studies.
• Magnitude of Effects on Health Outcomes : Large positive benefit.
• External Validity : Fair.

Dietary factors

Based on fair evidence, diets high in cruciferous (cabbage, broccoli, cauliflower) and green and yellow vegetables and fruits are associated with a decreased risk of esophageal cancer.^3,4,

Description of the Evidence
• Study Design : Evidence obtained from cohort or case-control studies.
• Internal Validity : Fair.
• Consistency : Multiple studies.
• Direction and Magnitude of Effect : Small positive.
• External Validity : Fair.

Aspirin and nonsteroidal anti-inflammatory drug use

Based on fair evidence, epidemiologic studies have found that aspirin or nonsteroidal anti-inflammatory drug (NSAID) use is associated with decreased risk of developing or dying from esophageal cancer (odds ratio [OR] = 0.57; 95% CI, 0.47–0.71).^5,

Description of the Evidence
• Study Design : Evidence obtained from cohort or case-control studies.
• Internal Validity : Fair.
• Consistency : Good.
• Magnitude of Effects on Health Outcomes : Large positive.
• External Validity : Fair.

Based on solid evidence, harms of NSAID use include upper gastrointestinal bleeding and serious cardiovascular events such as myocardial infarction, heart failure, hemorrhagic stroke, and renal impairment.

Description of the Evidence
• Study Design : Evidence obtained from randomized controlled trials.
• Internal Validity : Good.
• Consistency : Good.
• Magnitude of Effects on Health Outcomes : Increased risk, small magnitude.
• External Validity : Good.

Helicobacter pylori infection and gastric atrophy

Based on fair evidence, serum CagA antibodies and gastric atrophy are associated with an increased risk of esophageal squamous cell carcinoma (OR = 2.1; 95% CI, 1.1–4.0 and OR = 4.3; 95% CI, 1.9–9.6, respectively).^6,

Description of the Evidence
• Study Design : Evidence obtained from cohort or case-control studies.
• Internal Validity : Fair.
• Consistency : Large study.
• Magnitude of Effects on Health outcomes : Unknown magnitude.
• External Validity : Fair.

Adenocarcinoma of the Esophagus

Gastroesophageal reflux/Barrett’s esophagus

Based on fair evidence, an association exists between gastroesophageal reflux disease (GERD) and adenocarcinoma.^7,8 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.^8,9,

Description of the Evidence
• Study Design : Ecologic and descriptive studies.
• Internal Validity : Fair.
• Consistency : Good–multiple studies.
• Magnitude of Effects on Health Outcomes : Unknown.
• External Validity : Fair.

Aspirin and nonsteroidal anti-inflammatory drug use

Based on fair evidence, epidemiologic studies have found that aspirin or NSAID use is associated with decreased risk of developing or dying from esophageal cancer (OR = 0.57; 95% CI, 0.47–0.71).^5,

Description of the Evidence
• Study Design : Evidence obtained from cohort or case-control studies.
• Internal Validity : Fair.
• Consistency : Good.
• Magnitude of Effects on Health Outcomes : Positive; unknown magnitude.
• External Validity : Fair.

Based on solid evidence, harms of NSAID use include upper gastrointestinal bleeding and serious cardiovascular events such as myocardial infarction, heart failure, hemorrhagic stroke, and renal impairment.

Description of the Evidence
• Study Design : Evidence obtained from randomized controlled trials.
• Internal Validity : Good.
• Consistency : Good.
• Magnitude of Effects on Health Outcomes : Increased risk, small magnitude.
• External Validity : Good.

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. Int J Epidemiol 24 (3): 504-14, 1995.

² Oesophagus. In: World Cancer Research Fund., American Institute for Cancer Research.: Food, Nutrition and the Prevention of Cancer: A Global Perspective. Washington, DC: The Institute, 1997, pp 118-129.

³ Chainani-Wu N: Diet and oral, pharyngeal, and esophageal cancer. Nutr Cancer 44 (2): 104-26, 2002.

⁴ Boeing H, Dietrich T, Hoffmann K, et al.: Intake of fruits and vegetables and risk of cancer of the upper aero-digestive tract: the prospective EPIC-study. Cancer Causes Control 17 (7): 957-69, 2006.

⁵ Corley DA, Kerlikowske K, Verma R, et al.: Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis. Gastroenterology 124 (1): 47-56, 2003.

⁶ Ye W, Held M, Lagergren J, et al.: Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. J Natl Cancer Inst 96 (5): 388-96, 2004.

⁷ Lagergren J, Bergström R, Lindgren A, et al.: Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 340 (11): 825-31, 1999.

⁸ Fitzgerald RC: Molecular basis of Barrett's oesophagus and oesophageal adenocarcinoma. Gut 55 (12): 1810-20, 2006.

⁹ Spechler SJ, Goyal RK: The columnar-lined esophagus, intestinal metaplasia, and Norman Barrett. Gastroenterology 110 (2): 614-21, 1996.

Significance

Incidence and Mortality

Annually, it is estimated that 15,560 Americans will be diagnosed with esophageal cancer and 13,940 will die of this malignancy. Of the new cases, it is estimated that 12,130 will occur in men and 3,430 will occur in women.^1,

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 six times more likely to occur in black males than in white males.³ Incidence rates generally increase with age in all racial/ethnic groups. In black men, however, the incidence rate for those aged 55 to 69 years is close to that of whites aged 70 years and older. In black women, aged 55 to 69 years, the incidence rate is slightly higher than that of white women aged 70 years and older.

Risk Factors

While risk factors for squamous cell carcinoma of the esophagus have been identified (such as tobacco use, alcoholism, malnutrition, and infection with human papillomavirus),⁴ the risk factors associated with esophageal adenocarcinoma are less well defined. The most important epidemiological difference between squamous cell cancer and adenocarcinoma, however, is the strong association between gastroesophageal reflux disease (GERD) and adenocarcinoma. The results of a population-based case-controlled study suggest that symptomatic gastroesophageal reflux is a risk factor for esophageal adenocarcinoma. The frequency, severity, and duration of reflux symptoms were positively associated with increased risk of esophageal adenocarcinoma.^5,

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.⁶ According to this theory, H. pylori infections that cause pangastritis also cause a decrease in gastric acid production that protects against GERD.⁷ Patients whose duodenal ulcers were treated successfully with antibiotics developed reflux esophagitis twice as often as those in whom infection persisted.⁸ Other factors that have been suggested to explain the increased risk of esophageal adenocarcinoma include obesity ⁹ and use of medications, such as anticholinergics that can predispose to GERD by relaxing the lower esophageal sphincter.^10,

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.¹¹ The intestinal-type epithelium of Barrett’s esophagus has a characteristic endoscopic appearance that differs from squamous epithelium.¹² Dysplasia in Barrett’s epithelium represents a neoplastic alteration of the columnar epithelium that may progress to invasive adenocarcinoma.^13,

¹ American Cancer Society.: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online. Last accessed March 5, 2007.

² Holmes RS, Vaughan TL: Epidemiology and pathogenesis of esophageal cancer. Semin Radiat Oncol 17 (1): 2-9, 2007.

³ Devesa SS, Blot WJ, Fraumeni JF Jr: Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 83 (10): 2049-53, 1998.

⁴ 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. Int J Epidemiol 24 (3): 504-14, 1995.

⁵ Lagergren J, Bergström R, Lindgren A, et al.: Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 340 (11): 825-31, 1999.

⁶ O'Connor HJ: Review article: Helicobacter pylori and gastro-oesophageal reflux disease-clinical implications and management. Aliment Pharmacol Ther 13 (2): 117-27, 1999.

⁷ Graham DY, Yamaoka Y: H. pylori and cagA: relationships with gastric cancer, duodenal ulcer, and reflux esophagitis and its complications. Helicobacter 3 (3): 145-51, 1998.

⁸ Labenz J, Blum AL, Bayerdörffer E, et al.: Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology 112 (5): 1442-7, 1997.

⁹ Lagergren J: Controversies surrounding body mass, reflux, and risk of oesophageal adenocarcinoma. Lancet Oncol 7 (4): 347-9, 2006.

¹⁰ Lagergren J, Bergström R, Adami HO, et al.: Association between medications that relax the lower esophageal sphincter and risk for esophageal adenocarcinoma. Ann Intern Med 133 (3): 165-75, 2000.

¹¹ Spechler SJ, Goyal RK: The columnar-lined esophagus, intestinal metaplasia, and Norman Barrett. Gastroenterology 110 (2): 614-21, 1996.

¹² Van Dam J, Brugge WR: Endoscopy of the upper gastrointestinal tract. N Engl J Med 341 (23): 1738-48, 1999.

¹³ Reid BJ, Blount PL, Rabinovitch PS: Biomarkers in Barrett's esophagus. Gastrointest Endosc Clin N Am 13 (2): 369-97, 2003.

Evidence of Benefit

Tobacco, Alcohol, and Dietary Factors

In the United States, squamous cell carcinoma of the esophagus is strongly associated with tobacco and alcohol abuse. The risk declines with smoking cessation. In China, esophageal cancer is associated with deficiencies of nutrients such as retinol, riboflavin, alpha-carotene and beta-carotene, alpha-tocopherol, ascorbate, and zinc, and with exposure to specific carcinogens (e.g., N-nitroso compounds).^1,

Chemoprevention

A prospective, placebo-controlled, esophagus chemoprevention study randomly assigned 610 high-risk Chinese subjects.² Subjects ranged in age from 35 to 64 years 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 two 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 with 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 four different vitamin/mineral combinations administered for 5 years at doses 1 to 2 times the U.S. recommended daily allowances (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 two-arm design (26 vitamins and minerals, including beta carotene, alpha-tocopherol, and selenium, at 2 to 3 times the U.S. RDA in one 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

A systematic review and meta-analysis of the association of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) with esophageal cancer identified two cohort and seven case-control studies published between 1980 and 2001.⁷ Pooled results show a protective association between aspirin/NSAID use and esophageal cancer (odds ratio [OR] = 0.57; 95% confidence interval [CI], 0.47–0.71). Association with aspirin use was statistically significant (OR = 0.50; 95% CI, 0.38–0.66); association with NSAIDs was of borderline significance (OR = 0.75; 95% CI, 0.54–1.0). Aspirin/NSAID use was associated with lower risk of both adenocarcinoma (OR = 0.67; 95% CI, 0.51–0.87) and squamous cell carcinoma (OR = 0.58; 95% CI, 0.43–0.78).

¹ Oesophagus. In: World Cancer Research Fund., American Institute for Cancer Research.: Food, Nutrition and the Prevention of Cancer: A Global Perspective. Washington, DC: The Institute, 1997, pp 118-129.

² Muñoz 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): 111-4, 1985.

³ Muñoz 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. J Natl Cancer Inst 79 (4): 687-91, 1987.

⁴ Yang GC, Lipkin M, Yang K, et al.: Proliferation of esophageal epithelial cells among residents of Linxian, People's Republic of China. J Natl Cancer Inst 79 (6): 1241-6, 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. J Natl Cancer Inst 85 (18): 1483-92, 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. J Natl Cancer Inst 85 (18): 1492-8, 1993.

⁷ Corley DA, Kerlikowske K, Verma R, et al.: Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis. Gastroenterology 124 (1): 47-56, 2003.

Changes To This Summary (04/20/2007)

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