Radiation Esophagitis

Etiology

Radiation esophagitis is inflammation, edema, erythema, and erosion of the mucosal surface of the esophagus caused by radiation therapy to nearby or related structures that cause cell damage, produce proinflammatory cytokines and lead to the development of free-oxygen radical species related to radiation therapy.

Epidemiology

Radiation esophagitis is an adverse effect for patients undergoing radiation cancer therapy, usually for lung, breast, and other thoracic cancers due to its proximity. Symptomatic radiation esophagitis, however, is a rare complication of radiation therapy affecting the minority of patients undergoing treatment. In addition, genetics have been thought to play an important role in a patient who develops radiation esophagitis, with some research correlating single-nucleotide polymorphisms of transforming growth factor b-1 with severe radiation esophagitis.[4][5]

Certain risk factors may predispose patients to a high risk of developing radiation esophagitis. These include White race, age greater than 70, female sex, poor initial performance status, low body mass index, gastroesophageal reflux disease, and dysphagia.

Pathophysiology

Radiation therapy leads to mucosal damage, production of pro-inflammatory cytokines, and eventually cell death which leads to ulcerations of the esophageal mucosal lining. Radiation therapy causes cell DNA damage, leading to stress-related, pro-inflammatory cytokine production through various signaling pathways and ultimately causing mucosal damage and irritation. If severe, ulcerations of the mucosal wall can occur.

Histopathology

Endoscopy in the acute setting may reveal erythema, erosion, mucosal soughing, ulcerations, and hemorrhage. In the chronic setting, fibrosis, atypia, and chronic inflammatory changes may be seen.

Effects of radiation esophagitis predominately involve the basal cells of the squamous epithelium. Within 48 hours of radiation therapy, apoptotic bodies are seen. Within a few weeks, the submucosal layers of the esophagus become involved with mucosal gland degeneration, endothelial swelling, and capillary dilation creating erythema. Within one month, cytological atypia is described as having irregular nuclear membranes and abnormal smudge nuclei with loss of detail with prominent nuclei. In addition, the cytoplasm will reveal a bubble appearance, pleomorphism, cytomegaly, and hyperchromic nuclei with other common findings including parakeratosis and mucosal atrophy.

In chronic esophagitis, fibroblasts and inflammatory cells infiltrate the muscle wall, leading to edema, and thickening of the submucosa, leading to fibrosis and stricture formation.

History and Physical

Patients that develop radiation esophagitis may have a history of poor initial performance status, low body mass index, gastroesophageal reflux disease, and dysphagia. In addition, patients with esophageal infiltrated tumors or late-stage cancer have an increased risk of radiation esophagitis.

When examining a patient with a history of cancer with radiation therapy, it is always important to ask about symptoms of the recurrent disease, i.e., weight loss, worsening respiratory status, dysphagia, or hoarseness. Clinicians should evaluate the oral mucosa extensively, looking for signs of thrush or lesions, evaluate for lymphadenopathy, and perform a thorough respiratory exam.

Common symptoms include dysphagia, nausea, anorexia, and odynophagia.

Evaluation

Radiation esophagitis can be classified as acute or late. Acute radiation esophagitis develops less than 3 months after therapy whereas late occurrences develop greater than 3 months after therapy. However, most cases of acute radiation esophagitis develop within 2 to 3 weeks post initial treatment and 6 months for late development. Symptoms may be cumulative but are typically self-limiting. In severe cases, dysmotility, perforations, fistula, and strictures can develop.[6][7]

The diagnosis is typically made clinically in these patients; however, if there is a concern for more serious complications, further diagnostics may be needed. A barium swallow should be used to evaluate for esophageal strictures or impaired peristaltic waves and dysmotility. Chest and abdomen computed tomography (CT) may be used to evaluate for fistula and characterization of strictures. Upper endoscopy may be used to evaluate for ulcerations and biopsy if needed.

Treatment / Management

Treatment is supportive care with adequate hydration and nutrition intake. Amifostine, an organic triphosphate, has been studied and shown to act as a radioprotector. It is thought that this medication acts as an antioxidant to neutralize the free-oxygen radicals produced during ionizing radiation. A study performed to look at the effects of amifostine in patients with advanced non-small-cell lung cancer showed improvement of swallowing dysfunction but no effect on reducing rates of esophagitis in severe cases. Another potential radioprotectant, glutamine, has been associated with reduced rates of esophagitis. A small prospective study in non-small cell lung cancer patients showed 49% reported no esophagitis when treated prophylactically with glutamine powder. Nonsteroidal anti-inflammatory drugs (NSAIDs) and other drugs have been studied but have not proven effective.[8][9][10](B2)

Dietary modification in the form of soft, bland diets is typically used along with the removal of irritant foods such as alcohol, spicy foods, and very hot or cold foods. Frequent, small meals also help. Nutritional support may be needed, using supplements, intravenous hydration, electrolyte correction, and total parenteral nutrition. Analgesia is typically needed, using topical or systemic methods. Prophylactic antifungal therapy is indicated due to the increased risk of thrush.[11][12](B2)

If a stricture is present, then dilatation may be required. However, complications like aspiration and perforation are also potential problems.

There are reports of the use of stents to relieve long strictures.

Differential Diagnosis

Radiation esophagitis may develop in the acute stage of therapy or the chronic stage of therapy. Patients with severe esophagitis are at a higher risk of developing long-term complications, and clinicians must be able to recognize severe life-threatening complications such as ulcerations, perforations, fistula, and strictures. Additionally, cytomegalovirus (CMV) esophagitis must be ruled out in these patients.

Staging

Grading of Radiation Esophagitis

• 0 - No symptoms
• 1 - Mild fibrosis and difficulty with swallowing solids
• 2 - Dysphagia-dilatation may be required
• 3 - Severe fibrosis, only able to swallow liquids, dilatation is necessary
• 4 - Necrosis, perforation, or fistula formation

Prognosis

Radiation esophagitis symptoms may be cumulative but they are typically self-limiting. There is no cure, but symptoms typically regress 2 to 4 weeks after the completion of radiation treatment.

Complications

Although radiation esophagitis is relatively benign and self-limiting, in severe cases, it can cause ulcerations, esophageal perforations, tracheoesophageal fistula, stricture development. Severe cases have been associated with genetic factors and polymorphisms.