Gastrointestinal toxicity of radiation therapy

Gastrointestinal toxicity can occur following irradiation of thoracic, abdominal, or pelvic malignancies if gastrointestinal structures are located within the radiation therapy (RT) field. Dr Sudeshen Naidoo explains further.

The incidence and severity of RT side effects depend upon the site, volume of tissue exposed, and treatment schedule, including total dose, dose per fraction, and type of radiation. Other risk factors for radiation-induced GI toxicity include the use of concomitant chemotherapy.

1. Oesophagitis

Normal oesophageal mucosa undergoes continuous cell turnover and renewal. Acute radiation oesophagitis is primarily due to effects on the basal epithelial layer. This causes a thinning  of the mucosa, which can progress to denudation (stripping). The late effects are believed to be due to inflammation and scar formation within the oesophageal musculature.

Clinical manifestations

Acute effects: Dysphagia (difficulty in swallowing), odynophagia (pain on swallowing), and substernal discomfort. Symptoms usually occur within 2 to 3 weeks of initiation of RT. Patients may describe a sudden, sharp, severe chest pain radiating to the back.

Late effects: Occur within 3 months of completion of RT, with a median time to onset of 6 months.^1,2 Patients often present with dysphagia secondary to stricture or altered motility caused by fibrosis/muscular damage or nerve injury or odynophagia due to chronic ulceration. Rarely patients may develop a tracheoesophageal fistula (an abnormal connection) and present with dyspnoea (difficult or laboured breathing) secondary to aspiration pneumonia.

Management

It is managed symptomatically. Although interruption of RT is occasionally necessary because of severe symptoms; this approach may compromise treatment efficacy and should be avoided whenever possible.

• Topical anaesthetics, analgesics and antisecretory therapy (proton pump inhibitors, H2 receptor blockers).
• Dietary modification (bland, pureed, or soft foods, soups) to help a patient maintain adequate caloric and liquid intake.³ Eating more frequent, smaller meals and avoiding foods that are very hot or very cold. Avoidance of smoking, alcohol, coffee, spicy or acidic foods or liquids, chips, crackers, and fatty and indigestible foods.
• High-dose steroids assist with decreasing inflammation.

2. Gastritis

Irradiation of the stomach can cause early and/or delayed toxicity. Low doses of RT can cause a decrease in gastric acid production, coagulation necrosis   of chief and parietal cells, mucosal thinning, oedema, and chronic inflammatory infiltration.^2,4 Acute ulceration results from desquamation and erosion of the damaged mucosa.

Risk factors include radiation dose  and use of concurrent chemo.

Clinical manifestations

Acute: Nausea and vomiting may occur within 24 hours after the start of treatment. Approximately one-half of patients receiving upper abdominal irradiation will experience vomiting within 2 to 3 weeks of the start of treatment.⁵

Other early effects include dyspepsia, anorexia, abdominal pain, and malaise. Symptoms generally resolve within 1 to 2 weeks following completion of RT. These symptoms may be accompanied by development of acute ulceration, occurring shortly after completion of RT.⁶ 

Late: Patients may present with abdominal pain. These symptoms may be due to non-ulcer dyspepsia, late gastric ulceration (which usually occurs 5 months after irradiation), or antral stenosis (which can occur 1 to 12 months after irradiation).

Management

Nausea and vomiting are generally managed with antiemetics. Patients with abdominal pain and dyspepsia should be treated with antisecretory medications, including a proton pump inhibitor. These may be helpful on a long-term basis to avoid late ulceration. Patients with severe pain may require narcotic and non-narcotic analgesics as needed. High-dose steroids decrease inflammation and assists with nausea and vomiting.

3. Enteritis

RT can cause an acute injury to the small and large intestines which develops during or shortly after treatment. The initial toxicity generally resolves within a matter of weeks, but chronic changes can develop months or years after therapy. The gastrointestinal epithelium has a high proliferative rate, making it susceptible to injury from both radiation and chemotherapy.

Clinical manifestations

Acute: Symptoms include diarrhoea, abdominal pain, nausea and vomiting, anorexia, and malaise. Radiation-induced diarrhoea often appears during the third week of treatment, with reports of frequency ranging from 20 to 70%. The symptoms subside as the acute pathologic effects resolve, and typically disappear 2 to 6 weeks after the completion of RT.⁷

Late: These typically manifest 8 to 12 months after RT, although toxicity may not appear until years later in some cases. ^2,8 

Management

Dietary modification: there does not appear to be a clear-cut diet that reliably alleviates all symptoms of chronic radiation enteritis. However, patients should be instructed to avoid foods that are high in fibre, such as fruits, vegetables and whole grains. A high-fibre diet may worsen diarrhoea and urgency.⁹ Patients with lactose intolerance should be advised to restrict but not eliminate dietary lactose.

Antidiarrheal agents

Antidiarrheal agents can help improve diarrhoea, although they should not be used in patients with suspected small or large bowel obstruction.

4. Proctitis

Radiation proctitis is usually encountered following treatment of cancers of the anus, rectum, cervix, uterus, prostate, urinary bladder, and testes. Defined as epithelial damage to the rectum due to radiation that is associated with minimal or no inflammation.

Clinical manifestations 

Symptoms include diarrhoea, mucus discharge, urgency, tenesmus, and, uncommonly, bleeding. Patients with chronic radiation proctitis have similar symptoms as patients with acute radiation proctitis, but bleeding is usually more severe.

Management

In patients with acute radiation proctitis, treatment is supportive (e.g. hydration and antidiarrheals as needed).

In patients with persistent or severe bleeding due to chronic radiation proctitis, we suggest an initial trial of sucralfate enemas.

5. Anal toxicity

The anal canal is typically spared from significant radiation exposure except when RT is used to treat anal, low rectal, or gynaecologic cancers. In these settings, the acute toxicity includes diarrhoea caused by exposure of the rectum to irradiation. Damage to the anus itself can cause mucosal oedema and friability, which can progress to desquamation or ulceration. These changes may be exacerbated by diarrhoea.

Clinical manifestations

Acute: A perianal skin reaction that ranges from minimal skin changes to moist desquamation and erythema. Pain typically accompanies worsening desquamation in the perianal skin region, and inflammation of the anal canal and distal rectum can also cause pain, bleeding, and tenesmus.

Late: Can appear months to years after completion of therapy. The most common late complication is anorectal ulceration. Anal strictures (stenosis) or anorectal fistulas may also occur.^10,11,12,13 Patients usually present with anal pain and anal incontinence.

Management

Is supportive and includes proper skin care, dietary modification in patients with faecal incontinence, pain medications, and corticosteroid suppositories. The acute RT side effects are generally self-limited and usually resolve within weeks after the end of therapy. However, treatment interruptions may be required if toxicity is severe.^14,15,16

Sphincter dilation is the standard treatment for anal strictures or stenosis. Rare patients may require a colostomy if symptoms are severe.

MEET OUR EXPERT – Dr Sudeshen Naidoo

Dr Sudeshen Naidoo is a radiation oncologist, a director at de Muelenaere Oncology (Ahmed Kathrada Cancer Institute and Sandton Oncology) and the radiation oncology advisor for The Ministerial Advisory Committee on Cancer Care and Prevention in South Africa.

REFERENCES

1. O’Rourke IC, Tiver K, Bull C, et al. Swallowing performance after radiation therapy for carcinoma of the esophagus. Cancer 1988; 61:2022.
2. Coia LR, Myerson RJ, Tepper JE. Late effects of radiation therapy on the gastrointestinal tract. Int J Radiat Oncol Biol Phys 1995; 31:1213.
3. Sasso FS, Sasso G, Marsiglia HR, et al. Pharmacological and dietary prophylaxis and treatment of acute actinic esophagitis during mediastinal radiotherapy. Dig Dis Sci 2001; 46:746.
4. Goldgraber MB, Rubin CE, Palmer WL, et al. The early gastric response to irradiation; a serial biopsy study. Gastroenterology 1954; 27:1.
5. Henriksson R, Bergström P, Franzén L, et al. Aspects on reducing gastrointestinal adverse effects associated with radiotherapy. Acta Oncol 1999; 38:159.
6. Sell A, Jensen TS. Acute gastric ulcers induced by radiation. Acta Radiol Ther Phys Biol 1966; 4:289.
7. Hauer-Jensen M. Late radiation injury of the small intestine. Clinical, pathophysiologic and radiobiologic aspects. A review. Acta Oncol 1990; 29:401.
8. Kwitko AO, Pieterse AS, Hecker R, et al. Chronic radiation injury to the intestine: a clinico-pathological study. Aust N Z J Med 1982; 12:272.
9. Sek S. Chronic radiation enteritis: womens food tolerances after radiation treatment for gynaecological cancer. J Am Diet Assoc 2000; 100:941
10. Mitchell SE, Mendenhall WM, Zlotecki RA, Carroll RR. Squamous cell carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2001; 49:1007.
11. Flam MS, John MJ, Mowry PA, et al. Definitive combined modality therapy of carcinoma of the anus. A report of 30 cases including results of salvage therapy in patients with residual disease. Dis Colon Rectum 1987; 30:495.
12. Gabriele AM, Rovea P, Sola B, et al. Radiation therapy and chemotherapy in the conservative treatment of carcinoma of the anal canal: survival and late morbidity in a series of 25 patients. Anticancer Res 1997; 17:653.
13. Peiffert D, Bey P, Pernot M, et al. Conservative treatment by irradiation of epidermoid cancers of the anal canal: prognostic factors of tumoral control and complications. Int J Radiat Oncol Biol Phys 1997; 37:313.
14. Levitsky J, Hong JJ, Jani AB, Ehrenpreis ED. Oral vitamin a therapy for a patient with a severely symptomatic postradiation anal ulceration: report of a case. Dis Colon Rectum 2003; 46:679.
15. Salama JK, Mell LK, Schomas DA, et al. Concurrent chemotherapy and intensity-modulated radiation therapy for anal canal cancer patients: a multicenter experience. J Clin Oncol 2007; 25:4581.
16. Flam M, John M, Pajak TF, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol 1996; 14:2527.