Summary of Evidence

Note: Separate PDQ summaries on Esophageal Cancer Screening , 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 pyloriinfection 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 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 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.

Ablation of Barrett Esophagus With Dysplasia

A randomized controlled trial has found that radiofrequency ablation of Barrett esophagus with severe dysplasia may lead to eradication of both dysplasia and intestinal metaplasia, and a reduced risk of disease progression.[10]

• Study Design: Evidence obtained from a randomized controlled trial.
• Internal Validity: Good.
• Consistency: Single study.
• Magnitude of Effects on Health Outcomes: Impact on cancer mortality not known.
• External Validity: Good.

Based on solid evidence, harms of radiofrequency ablation include esophageal stricture and requirement for dilatation, and upper gastrointestinal hemorrhage, but at low rates. It is possible that overdiagnosis and overtreatment of Barrett esophagus, particularly without severe dysplasia, could lead to a substantial number of harms.

• Study Design: Evidence obtained from a randomized controlled trial.
• Internal Validity: Good.
• Consistency: Single study.
• Magnitude of Effects on Health Outcomes: The low rates of esophageal stricture and requirement for dilatation and upper gastrointestinal hemorrhage may be an understatement of the risks if this practice is widely adopted by less experienced physicians.
• External Validity: Patients representative of a subset of people with dysplasia, particularly severe dysplasia; physicians may not be representative of practicing physicians since this is a new technology and requires specialized knowledge.

References:

Significance

Incidence and Mortality

In 2012, it is estimated that 17,460 Americans will be diagnosed with esophageal cancer and 15,070 will die of this malignancy. Of the new cases, it is estimated that 13,950 will occur in men and 3,510 will occur in women. [1]

Two histological types account for the majority of malignant esophageal neoplasms: 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 for 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 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 esophagus has a characteristic endoscopic appearance that differs from squamous epithelium.[12] Dysplasia in Barrett epithelium represents a neoplastic alteration of the columnar epithelium that may progress to invasive adenocarcinoma.[13]

References:

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 National Cancer Institute-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 one to two 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 two to three 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).

Radiofrequency Ablation in Dysplastic Barrett Esophagus

A randomized controlled trial [8] assessed whether, among persons with Barrett esophagus and dysplasia, radiofrequency ablation (vs. sham ablation) could eradicate dysplastic Barrett esophagus and decrease the rate of neoplastic progression. Among persons with low-grade dysplasia, eradication of dysplasia occurred in 90.5% of the treatment group compared to 22.7% in the control group; in the high-grade dysplasia group, rates were 81.0% compared to 19.0%. Additionally, 77.4% of persons in the ablation group had complete eradication of intestinal metaplasia, compared to 2.3% in the control group. Persons in the ablation group had less disease progression, and although cancer was not a primary outcome because expected numbers were small, there were fewer cancers in the ablation group (1.2% vs. 9.3%; P = .045). The complication rate was relatively low; among 84 treated persons, there was one upper gastrointestinal hemorrhage and five strictures that were easily treated.[8]

This study suggests that treatment of Barrett with dysplasia may ablate Barrett esophagus and prevent disease progression, but the study provides only weak evidence (indeed, it was not designed to answer) about whether treatment reduces the outcome of esophageal cancer. Evidence from the study suggests that ablation does not simply coagulate and hide dangerous cells under the surface of the esophagus (those cells could later evolve to cancer). A question entirely separate from this study is whether patients should or should not be screened for Barrett esophagus (this study focused on treatment of persons with Barrett who had been identified as having dysplasia). Furthermore, the study does not discuss the net benefits and harms of an overall program of screening (e.g., of screening persons with gastroesophageal reflux disease (GERD) or certain GERD symptoms) and the surveillance of persons with Barrett. The potential for overdiagnosis and overtreatment may be considerable, if physicians used results of this study to treat persons with Barrett esophagus and no dysplasia.

References:

Changes to This Summary (01 / 23 / 2012)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Significance

Updated statistics with estimated new cases and deaths for 2012 (cited American Cancer Society as reference 1).

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about esophageal cancer prevention. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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National Cancer Institute: PDQ® Esophageal Cancer Prevention. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/prevention/esophageal/HealthProfessional. Accessed <MM/DD/YYYY>.

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Last Revised: 2012-01-23