Understanding the Link Between Gastroesophageal Reflux and Esophageal Adenocarcinoma

Over recent decades, the incidence of adenocarcinoma of the esophagus and gastric cardia has increased steadily in the United States and Western Europe [1–4]. Among these malignancies, esophageal adenocarcinoma has shown the most pronounced increase in incidence [1–5].

The reasons for this trend remain unclear, although several established risk factors are known to contribute to disease development [6].

Histologically, the two most common types of esophageal cancer are squamous cell carcinoma and adenocarcinoma. While squamous cell carcinoma has historically been the predominant subtype, its incidence has declined in recent years. In contrast, the incidence of adenocarcinoma has risen rapidly.

In economically developed countries, including Lithuania, gastroesophageal reflux disease (GERD) remains one of the most important risk factors for esophageal adenocarcinoma. As the prevalence of GERD continues to increase, the number of patients developing esophageal adenocarcinoma is also likely to rise.

According to 2012 statistics, esophageal cancer ranked as the eighth most common cancer worldwide, with approximately 456,000 new cases diagnosed each year [22].

Appropriate surveillance, diagnosis, and treatment of patients with GERD may help reduce the incidence of esophageal adenocarcinoma. Regular esophagogastroduodenoscopy with biopsy is essential for the early detection of high-grade dysplasia or early-stage cancer, allowing timely radical treatment.

In addition, patients with clinical symptoms of GERD or evidence of active esophagitis should receive continuous treatment with proton pump inhibitors at effective therapeutic doses [7].

Clinical Study Evaluating Reflux as a Risk Factor for Esophageal Cancer

Because epidemiological evidence regarding the role of gastroesophageal reflux in the development of adenocarcinoma was limited, a large population-based clinical study was conducted in Sweden to evaluate the risk factors for adenocarcinoma of the esophagus and gastric cardia and to determine the extent to which reflux symptoms contribute to the risk of developing cancer at these sites.

The study included Swedish residents younger than 80 years of age.

A total of 618 patients with adenocarcinoma of the esophagus or gastric cardia and 820 individuals in the control group were interviewed.

Among the enrolled participants, 451 patients with esophageal or cardia adenocarcinoma met the study eligibility criteria, representing 85% of all adenocarcinoma cases identified during the study period. Of the remaining participants, 73% met the eligibility criteria for inclusion in the control group or the squamous cell carcinoma comparison group.

The characteristics of the study population are presented in Table 1.

Table 1. Characteristics of the Study Participants

Abbreviations:
EAC – esophageal adenocarcinoma; GCA – gastric cardia adenocarcinoma; ESCC – esophageal squamous cell carcinoma.

¹ Current or former smoker: smoked cigarettes, cigars, or a pipe for at least 2 years before the interview.
² Heavy alcohol consumption: more than 70 g of alcohol per week.
³ Low educational attainment: fewer than seven years of formal education.
⁴ Twenty-eight (2%) individuals in the control group could not be contacted by mail or telephone.

Esophageal Adenocarcinoma

The incidence of esophageal adenocarcinoma was almost eight times higher among patients who experienced heartburn, acid regurgitation, or both symptoms at least once a week than among individuals without these complaints (Table 2). Nocturnal reflux increased the risk approximately elevenfold.

To further evaluate the association between gastroesophageal reflux and esophageal adenocarcinoma, reflux symptoms were graded using a severity score: heartburn alone (1 point), regurgitation alone (1 point), heartburn with regurgitation (1.5 points), nocturnal symptoms (yes = 2 points; no = 0 points), and symptom frequency (once weekly = 0 points; 2–6 times per week = 1 point; 7–15 times per week = 2 points; more than 15 times per week = 3 points) (Table 3).

Patients with a symptom score of 4.5 or higher—representing heartburn with regurgitation, nocturnal symptoms, and symptom recurrence two to six times per week—had a 20-fold higher risk of developing esophageal adenocarcinoma than individuals without reflux symptoms.

The risk of esophageal adenocarcinoma also increased with symptom duration. Among patients whose symptoms had persisted for more than 20 years and whose symptom score was at least 4.5, the adjusted odds ratio for esophageal adenocarcinoma was 43.5 (95% CI, 18.3–103.5) compared with healthy individuals (Table 3).

Barrett's esophagus is a characteristic, although not obligatory, precursor lesion in the development of esophageal adenocarcinoma [12,13]. Patients with Barrett's esophagus have a 30–60-fold higher risk of developing adenocarcinoma than the general population [14–16].

However, because long-standing and severe reflux symptoms markedly increased the risk of esophageal adenocarcinoma regardless of whether Barrett's esophagus was present, reflux itself is believed to be the principal factor driving this carcinogenic process rather than Barrett's esophagus alone.

The mechanism by which gastroesophageal reflux increases the risk of esophageal adenocarcinoma in the absence of Barrett's esophagus remains unclear. Possible sites of origin include the submucosal glands or ectopic gastric epithelial cells. Chronic mucosal irritation and inflammation are recognized carcinogenic stimuli [8,9]. Animal studies have also demonstrated that bile reflux is an additional risk factor for the development of esophageal adenocarcinoma [10,11].

Gastric Cardia Adenocarcinoma

Reflux symptoms are also associated with an increased risk of gastric cardia adenocarcinoma, although the association is less pronounced than that observed for esophageal adenocarcinoma (Table 2).

Among patients with severe reflux symptoms, the risk of cardia adenocarcinoma was approximately twofold higher than among individuals without reflux symptoms.

The risk increased with both the duration and severity of reflux symptoms, although less markedly than for esophageal adenocarcinoma. Patients with very severe or long-standing symptoms had an odds ratio of approximately 3 for developing gastric cardia adenocarcinoma (Table 3). For those with both severe symptoms and prolonged symptom duration, the adjusted odds ratio increased to 4.4 (95% CI, 1.7–11.0).

Table 2. Reflux Symptoms Present Five or More Years Before the Interview and the Risk of Esophageal Adenocarcinoma, Gastric Cardia Adenocarcinoma, and Esophageal Squamous Cell Carcinoma*

Abbreviations: EAC – esophageal adenocarcinoma; GCA – gastric cardia adenocarcinoma; ESCC – esophageal squamous cell carcinoma; OR – odds ratio; CI – confidence interval.

* Multivariable logistic regression analysis adjusted for age, sex, socioeconomic status, body mass index, tobacco smoking, alcohol consumption, fruit and vegetable intake, occupational physical activity, and leisure-time physical activity.

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Table 3. Duration and Frequency of Reflux Symptoms Five or More Years Before the Interview*

Abbreviations: EAC – esophageal adenocarcinoma; GCA – gastric cardia adenocarcinoma; ESCC – esophageal squamous cell carcinoma; OR – odds ratio; CI – confidence interval.

* Multivariable logistic regression analysis adjusted for age, sex, socioeconomic status, body mass index, tobacco smoking, alcohol consumption, fruit and vegetable intake, occupational physical activity, and leisure-time physical activity.

¹ Reflux symptom score: heartburn = 1 point; regurgitation = 1 point; heartburn plus regurgitation = 1.5 points; nocturnal symptoms: no = 0, yes = 2 points; symptom frequency: once/week = 0 points, 2–6 times/week = 1 point, 7–15 times/week = 2 points, >15 times/week = 3 points.

Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma is one of the two major histological types of esophageal cancer.

Several conditions are recognized as precancerous lesions associated with an increased risk of developing esophageal squamous cell carcinoma:

• Esophageal strictures resulting from corrosive injury or radiation-induced esophagitis in younger individuals, with cancer typically developing several decades later.
• Esophageal achalasia, in which carcinoma tends to arise in the dilated, food-retaining segment of the esophagus.
• Cancer of the pharynx or larynx, as patients with these malignancies have a higher incidence of esophageal squamous cell carcinoma than the general population.
• Plummer–Vinson syndrome, characterized by chronic iron-deficiency anemia accompanied by glossitis and dysphagia.

Because these conditions are relatively uncommon, routine surveillance with repeated esophagogastroscopy in these patient groups is unlikely to have a substantial impact on the overall incidence of esophageal squamous cell carcinoma.

Unlike esophageal adenocarcinoma, esophageal squamous cell carcinoma is not associated with the frequency, severity, or duration of gastroesophageal reflux symptoms. Among patients with severe reflux symptoms, the odds ratio for developing esophageal squamous cell carcinoma was 1.1 (95% confidence interval [CI], 0.7–1.9) compared with individuals who reported no reflux symptoms (Table 2).

Clinically Proven Effects of Omeprazole

As discussed above, gastroesophageal reflux plays a significant role in the development of esophageal adenocarcinoma. Patients with severe reflux symptoms therefore require treatment with effective doses of antisecretory medications.

Histamine H₂-receptor antagonists suppress acid secretion by blocking histamine receptors on the surface of gastric parietal cells. Omeprazole, in contrast, inhibits the final step of gastric acid production within the parietal cell itself [17].

Omeprazole selectively suppresses gastric acid secretion by irreversibly inhibiting the H⁺/K⁺-ATPase proton pump located on the secretory membrane of gastric parietal cells, thereby blocking the final stage of hydrogen ion secretion into the stomach. It inhibits both basal and stimulated gastric acid secretion without affecting acetylcholine or histamine receptors.

Following oral administration, omeprazole begins to act within approximately one hour, reaches its maximum effect after about two hours, and produces dose-dependent suppression of gastric acid secretion lasting for more than 24 hours. Maximum therapeutic effectiveness is achieved after approximately four days of continuous treatment [18].

A clinical study conducted in Gothenburg evaluated the effects of different doses of omeprazole on gastric acid secretion.

Two hours after administration, the maximum gastric acid output decreased by 51 ± 9% following a 20 mg dose and by 86 ± 4% following a 40 mg dose.

After 24 hours, acid secretion remained suppressed by 26 ± 12% and 48 ± 9%, respectively (Figure).

With repeated administration of 20 mg, gastric acid suppression on the third and fourth days was no longer significantly different from placebo. In contrast, treatment with 40 mg continued to produce clinically relevant acid suppression on days 3 and 4 (34 ± 7% and 18 ± 4%, respectively).

Omeprazole has also been evaluated in patients with peptic esophagitis.

In one clinical study, 63 patients received either 20 mg or 40 mg of omeprazole (n = 31) or placebo (n = 32). After four weeks of treatment, 81% of patients receiving omeprazole showed both clinical and endoscopic improvement compared with only 6% of patients receiving placebo (p < 0.0001).

Comparison of the two omeprazole doses demonstrated significantly better therapeutic outcomes with 40 mg daily than with 20 mg daily after four weeks of treatment.

In another clinical trial involving 165 patients with erosive or ulcerative esophagitis, patients initially received 20 mg of omeprazole. Subsequently, 159 participants were randomly assigned to one of three maintenance regimens:

• ranitidine 150 mg twice daily;
• omeprazole 20 mg once daily;
• omeprazole 20 mg only on weekends (Friday, Saturday, and Sunday).

Patients were followed for up to 12 months or until relapse occurred.

Neither ranitidine nor weekend-only omeprazole therapy maintained long-term remission.

Among patients receiving 20 mg of omeprazole daily, remission was maintained in 89% after 12 months, compared with 25% of those treated with ranitidine and 32% of those receiving weekend-only omeprazole.

All three treatment regimens were well tolerated [19].

Following successful short-term therapy, discontinuation of treatment carries a high risk of relapse, with approximately 80% of patients relapsing within six months [20]. Consequently, long-term maintenance therapy is often required to achieve sustained remission.

The 2013 GERD treatment guidelines concluded that an 8-week course of proton pump inhibitor therapy is highly effective for erosive esophagitis and recommended this approach based on high-quality evidence [21].

Given the strong evidence linking gastroesophageal reflux with the development of esophageal adenocarcinoma, patients with severe reflux symptoms are recommended to receive omeprazole 40 mg once daily. Once-daily administration rapidly and effectively suppresses both daytime and nocturnal gastric acid secretion [18].

Summary

• Epidemiological studies demonstrate that both the incidence and mortality of esophageal and gastric cardia adenocarcinoma have increased in recent years.
• Gastroesophageal reflux significantly increases the risk of both esophageal and gastric cardia adenocarcinoma, with risk rising according to the severity and duration of reflux symptoms.
• Because the association between reflux and esophageal adenocarcinoma has been clearly demonstrated in clinical studies, patients with severe reflux symptoms should receive effective treatment with proton pump inhibitors.
• Clinical trial data show that long-term treatment with omeprazole is effective in maintaining long-term remission of esophagitis.

Prepared by Dr. D. Kasperavičiūtė

Source: Lithuanian Doctor's Journal