Updated: Jun 20, 2006
In 1897, 2 years after the discovery of x-rays by Roentgen, radiation-induced intestinal injury was first reported.
Although toxicity was the limiting factor in the early years, advancements in technology made delivering high doses of radiation possible to selective localized tissue targets, resulting in increased efficacy and increased utilization of radiation in the armamentarium of cancer therapy.
Many cancer patients receive some form of radiation as part of their cancer therapy; therefore, radiation-induced injury is likely to be a frequent occurrence despite improvements in radiation technology. Significant efforts have been made to develop methods to decrease or prevent radiation damage and to treat this dreadful complication.
This article focuses specifically on the effects of radiation on the small intestine, the large intestine, and the rectum.
Understanding the basic principles of how radiation affects the intestinal tract at the cellular level is important.
The new accepted unit dose of radiation is the gray (Gy); 1 Gy is equivalent to 100 rads. Although radiation injury can occur at doses of less than 40 Gy, serious injury usually occurs at doses greater than 50 Gy. Minimal tolerance (TD 5/5) is the dose that causes 5% of patients to have radiation injury within 5 years. While maximal tolerance (TD 50/5) is the dose at which 25-50% of patients manifest injury in 5 years. This translates to 45-65 Gy for the small intestine, 45-60 Gy for the colon, and 55-80 Gy for the rectum. The window of safety is narrow or perhaps nonexistent because the doses that cause injury are very close to the doses needed for therapy.
Cells are most sensitive to radiation during the G2 and M stages of mitotic division; therefore, rest periods between radiation sessions are important for the recovery of tissues. The most rapidly dividing cells are the most radiosensitive.
Radiation-induced injury is best described in 2 ways. Acute injury is a function of fractionation of the dose, field size, type of radiation, and frequency of treatment. Acute injury is caused by injury to the mitotically active intestinal crypt cells. On the other hand, chronic radiation injury is caused by injury to the less mitotically active vascular endothelial and connective tissue cells. Chronic injury is a function of the total dose of radiation used. This accounts for the described biphasic radiation injury.
Radiation injury impairs the normal repopulation of surface epithelium with growing new cells from the epithelial crypt cells. Repopulation normally takes place in 5-6 days. This impairment leads to varying degrees of retraction of villous core cells and spreading out of the enlarged villous epithelial cells. The loss of absorptive surface leads to malabsorption manifesting as diarrhea. Depending on the degree of disruption to the mucosal barrier by injury to the surface cells, microulcerations may form. The microulcerations can coalesce to form gross lesions. Intercellular tight junctions are disrupted, permitting the passage of endotoxin-containing particles from the lumen into the plasma.
Impairment to the blood supply by injury to capillary endothelium also contributes to the disruption. Invasion of the mucosa by intestinal microbes and sepsis may occur. Usually, therapeutic doses do not produce these profound consequences, and radiation treatment should be suspended or reduced when symptoms become significant. Crypt mitosis returns to normal within 3 days. Complete histologic recovery takes as long as 6 months. Chronic effects usually manifest after 6-24 months and are caused mostly by obliterative arteritis and thromboses of vessels; the result is ischemia or necrosis.
The combination of acute and chronic radiation injury can result in varying degrees of inflammation, thickening, collagen deposition, and fibrosis of the bowel, as well as impairment of mucosal and motor functions.
Although the exact incidence remains controversial, radiation enteritis is increasing and has been estimated to occur in 2-5% of patients receiving abdominal or pelvic radiotherapy. This incidence is expected to continue increasing.
Some investigators report much higher numbers of radiation enteritis, which may be explained by the extent of radiation field, the technique, and the dosage of radiation used.
The prevalence has been underestimated largely due to lack of clinical recognition and varies from 0.5-37%, depending on the radiation technique.
The cumulative 10-year incidence of moderate injuries is estimated at 8%, and that of severe injuries is estimated at 3%, including bleeding and obstruction, stenosis and fistulization, and malabsorption and peritonitis.
No predilection exists for any racial group.
No sex predilection exists.
No predilection exists for any age group. Because most malignancies occur in older individuals, one expects this entity to be less of a problem in children.
Symptoms can appear early, within hours of the first treatment session; very shortly after therapy; or months to years after the treatment has ended.
Physical examination varies, and findings can be normal or abnormal depending on the presence or absence of an underlying complication.
Although radiation obviously is responsible for radiation-induced intestinal injury, certain predisposing factors increase the risk of radiation injury, as follows:
| Bacterial Overgrowth Syndrome | Intestinal Perforation |
| Colonic Obstruction | Malabsorption |
| Hemorrhoids | Peptic Ulcer Disease |
| Inflammatory Bowel Disease | Proctitis and Anusitis |
Gastrointestinal malignancy
Small bowel obstruction
Diverticular bleed
Ischemic colitis
Histologic changes vary depending on the timing of presentation. Acute changes include hyperemia, edema, and inflammatory cell infiltration of the mucosa, with villous shortening, crypt abscesses, thinning of the mucosa, and ulceration. During the subacute and chronic stages, some mucosal regeneration may occur. The endothelial cells may degenerate, and fibrin plugs may form. Large foam cells beneath the intima are considered pathognomonic for radiation injury. Submucosal fibrosis and obliteration of small blood vessels result in ischemia, which is progressive and irreversible. Ischemia initially involves the mucosa and gradually progresses to involve the submucosa and serosa. Ischemic necrosis and ulceration may lead to fistula formation.
In general, correlation between pathologic and physiologic changes in the intestines is poor.
The treatment of acute injury varies depending on the symptoms, and the treatment of chronic injury varies depending on the location of injury.
Surgical intervention usually is required as a last resort or in the case of complications (eg, perforation, obstruction, abscess drainage, fistulae, local wound infections).
No restriction on activity is necessary.
The treatment of acute injury varies depending on the symptoms, and treatment of chronic injury varies depending on the location of the injury.
Used to treat nausea and vomiting related to acute radiation enteritis.
Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin), and complete body radiotherapy. Also beneficial in reducing the frequency of diarrhea by delaying intestinal transit.
8 mg PO tid
Not established
Although potential exists for cytochrome P-450 inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) to change half-life and clearance of ondansetron, dosage adjustment usually is not required
Documented hypersensitivity
B - Usually safe but benefits must outweigh the risks.
To be administered for prevention of nausea and vomiting, not for rescue of nausea and vomiting; use cautiously so that it does not mask progressive ileus; caution in breastfeeding women
Used to treat diarrhea associated with acute radiation enterocolitis.
Acts on intestinal muscles to inhibit peristalsis and slow intestinal motility. Prolongs movement of electrolytes and fluid through bowel and increases viscosity and loss of fluids and electrolytes.
4 mg PO initially, then 2 mg after each loose stool up to 16 mg/d
<2 years: Not recommended
2-5 years: 1 mg PO tid
6-8 years: 2 mg PO bid
8-12 years: 2 mg PO tid
Phenothiazines, TCAs, and CNS depressants may increase toxicity
Documented hypersensitivity; diarrhea resulting from infections; pseudomembranous colitis
B - Usually safe but benefits must outweigh the risks.
Discontinue use or switch to diphenoxylate if no clinical improvement occurs in 48 h; consider interrupting radiation; because primarily metabolized in liver, monitor for CNS toxicity in patients with hepatic insufficiency; do not use if high fever or blood in stool coincides with diarrhea
Drug combination that consists of diphenoxylate, which is a constipating meperidine congener and a subtherapeutic dose of atropine to discourage misuse. Inhibits excessive GI propulsion and motility.
20 mg/d of diphenoxylate PO qid; decrease dose when controlled
<2 years: Not recommended
>2 years: 0.3-0.4 mg/kg PO divided qid
May delay metabolism of drugs in liver; CNS depressants, MAOIs, and antimuscarinic agents may increase the toxicity of this drug combination
Documented hypersensitivity; narrow-angle glaucoma; hepatic insufficiency or obstructive jaundice; diarrhea associated with pseudomembranous enterocolitis or enterotoxin-producing bacteria
C - Safety for use during pregnancy has not been established.
In young children, dehydration may influence variability of response and predispose patient to delayed diphenoxylate intoxication; caution in ulcerative colitis; decrease in intestinal motility may be detrimental to patients with diarrhea resulting from Shigella species, Salmonella species, and toxigenic strains of Escherichia coli; overdosage may result in severe respiratory depression and coma (if this occurs, a pure narcotic antagonist, such as naloxone, should be used)
Forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts. Decreases diarrhea by preventing bile salt malabsorption.
4-12 g PO qd
Not established
Inhibits absorption of numerous drugs, including warfarin, thyroid hormone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, and penicillin G
Documented hypersensitivity
C - Safety for use during pregnancy has not been established.
Caution in constipation and phenylketonuria
An aluminum-hydroxide complex of sulfated sucrose, which forms a protective barrier at the site of ulceration due to radiation. Binds bile acids and helps to treat diarrhea from secondary bile acid malabsorption. Effective when administered PO as a prophylactic agent in preventing acute and chronic radiation injury. Studies using enemas for treatment of radiation proctitis have shown promising short-term results. No dosing standards exist, and doses used in studies vary from 1 g PO q4-6h during treatment and for another 3-4 wk thereafter.
1 g PO q4-6h
3 g in 15 mL susp enema qd
Not established
May decrease effects of ketoconazole, ciprofloxacin, tetracycline, phenytoin, warfarin, quinidine, theophylline, and norfloxacin
Documented hypersensitivity
B - Usually safe but benefits must outweigh the risks.
Caution in renal failure and conditions that impair excretion of absorbed aluminum
Used to treat symptoms related to radiation proctitis.
Retention enema. An adrenocorticosteroid derivative suitable for application to skin or external mucous membranes. Has mineralocorticoid and glucocorticoid effects resulting in anti-inflammatory activity. Used for its anti-inflammatory properties and effective in radiation proctitis.
1 enema PR qhs
Not established
None reported
Documented hypersensitivity; viral, fungal, or tubercular skin infections
C - Safety for use during pregnancy has not been established.
Prolonged use, applying over large surface areas, and application of potent steroids may increase systemic absorption of corticosteroids and may cause Cushing syndrome, reversible HPA axis suppression, hyperglycemia, and glycosuria
Used for intractable bleeding from radiation proctitis.
Direct mucosal contact allows rectal bleeding to cease.
Mix 200 mL of 10% buffered formalin with 300 mL of water; used in 50-mL aliquots administered through a rigid proctoscope under local anesthesia; rectal mucosa is treated for 30 sec with each aliquot and irrigated with sodium chloride solution between aliquots
Not established
None reported
Documented hypersensitivity; fistulae or deep ulcers
C - Safety for use during pregnancy has not been established.
Anal canal ulceration and fissuring can occur but may be avoided by using a rigid proctoscope
Deterrence/Prevention:
Complications:
Prognosis:
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radiation enteropathy, radiation enteritis, radiation colitis, radiation proctitis, radiation-induced intestinal toxicity, radiation-induced injury
Rajeev Vasudeva, MD, FACG, Clinical Professor of Medicine, Consultants in Gastroenterology, University of South Carolina School of Medicine
Rajeev Vasudeva, MD, FACG is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, and South Carolina Medical Association
Disclosure: Nothing to disclose.
Anil Minocha, MD, FACP, FACG, Clinical Professor, School of Pharmacy, Professor of Medicine, Director of Digestive Diseases, Medical Director of Nutrition Support, Medical Director of Gastrointestinal Endoscopy, Internal Medicine Department, University of Mississippi Medical Center
Anil Minocha, MD, FACP, FACG is a member of the following medical societies: American Academy of Clinical Toxicology, American Association for the Study of Liver Diseases, American College of Forensic Examiners, American College of Gastroenterology, American College of Physicians, American Federation for Clinical Research, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.
Douglas M Heuman, MD, FACP, Director of Hepatology, McGuire Veterans Affairs Medical Center, Professor, Department of Internal Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine
Douglas M Heuman, MD, FACP is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Physicians, and American Gastroenterological Association
Disclosure: Nothing to disclose.
Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.
Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.
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