AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

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.

Pathophysiology

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.

Frequency

United States

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.

Mortality/Morbidity

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.

Race

No predilection exists for any racial group.

Sex

No sex predilection exists.

Age

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.

CLINICAL

Section 3 of 11  

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History

Symptoms can appear early, within hours of the first treatment session; very shortly after therapy; or months to years after the treatment has ended.

• Early presentation: In most situations, patients experience acute symptoms 2-3 weeks into the treatment. Symptoms usually resolve in 2-6 months. Symptoms tend to be self limited and mild in severity, requiring predominantly symptomatic therapy. The correlation between the severity of mucosal damage and the severity of symptoms appears to be poor. Symptoms include the following:
• • Anorexia
  • Nausea - More frequent with upper abdominal radiation
  • Vomiting - More frequent with upper abdominal radiation
  • Abdominal cramps - Consequence usually of small intestinal involvement
  • Diarrhea - More often observed as a consequence of pelvic irradiation
  • Tenesmus and mucoid rectal discharge - As a result of rectal involvement
  • Rectal bleeding - As a result of rectal involvement
• Late presentation - Symptoms generally are insidious and develop months to years after therapy has ended. Many patients with chronic radiation enteritis may not have a prior history of acute radiation injury.
• • Colicky abdominal pain - Most common late symptom, due to partial small bowel obstruction
  • Nausea and vomiting - Consequences of small bowel obstruction
  • Chronic watery diarrhea and/or steatorrhea - Consequence of multiple factors, including malabsorption, bile acid-mediated diarrhea, bacterial overgrowth, impaired motility, and development of fistulas
  • Feculent vaginal discharge or pneumaturia - Consequence of fistula development
  • Tenesmus, mucoid rectal discharge, rectal bleeding, constipation, and decrease in stool caliber - Consequences of rectal involvement
  • Massive intestinal bleeding - Occurs rarely
  • Acute onset of abdominal pain and toxemia - Rare occurrences, consequences of a free perforation

Physical

Physical examination varies, and findings can be normal or abnormal depending on the presence or absence of an underlying complication.

• Weight loss and malnutrition - Consequences of malabsorption
• Generalized and conjunctival pallor - Consequence of anemia
• Abdominal tenderness
• Peritoneal signs - Results of a free perforation
• Palpable mass on abdominal examination - Possible consequence of an inflammatory response
• Hyperactive bowel sounds, tinkling, rushes, and audible borborygmi - Possible consequences of bowel obstruction
• Rectal tenderness and bleeding - Occasional consequences of rectal involvement

Causes

Although radiation obviously is responsible for radiation-induced intestinal injury, certain predisposing factors increase the risk of radiation injury, as follows:

• Previous surgery causes the development of adhesions that tend to fix the intestines, which may be unable to be involved in the radiation field.
• Patients with hypertension, diabetes mellitus, and generalized atherosclerosis are at an increased risk for vascular occlusive disease.
• Thin, elderly, and female individuals may have more small intestine lying in the pelvis and may be subject to more radiation exposure.
• Hypoxic cells are less sensitive to radiation injury. Administering hyperbaric oxygen (HBO) at the time of radiation to increase tumor cell destruction also can increase damage to the healthy cells.
• Certain chemotherapeutic agents (eg, Adriamycin, methotrexate, 5-fluorouracil, bleomycin) increase sensitivity to radiation.
• Based on limited uncontrolled retrospective data, patients with underlying inflammatory bowel disease may be at a higher risk for severe toxicity.

DIFFERENTIALS

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Other Problems to be Considered

Gastrointestinal malignancy
Small bowel obstruction
Diverticular bleed
Ischemic colitis

WORKUP

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Lab Studies

• Complete blood count to look for anemia due to acute or chronic bleeding, as well as malabsorption
• Complete metabolic panel to look for azotemia, electrolyte abnormalities, and nutrition parameters secondary to vomiting and malabsorption
• Stool studies for enteric pathogens and fat to rule out any infectious causes of diarrhea and steatorrhea

Imaging Studies

• Plain abdominal radiographs - Flat and upright
• • These radiographs usually are nonspecific.
  • During the early phase, radiographs may show findings consistent with an ileus.
  • Results also may show dilated loops with air fluid levels in the event of a bowel obstruction.
  • Thumb printing may be due to mucosal edema.
• Barium contrast studies of the small intestine and colon
• • Barium studies are better than plain radiographs because they provide better mucosal detail and document the presence of fistulae.
  • Usual findings include separation of loops, narrowed fixed loops with poor distension, absent haustral markings, diffuse mucosal ulceration, or a single ulcer. The single ulcer usually is located on the anterior wall of the rectum.
• CT scan of the abdomen and pelvis
• Excellent study to confirm bowel obstruction and its possible location
• Can rule out the possibility of abscess
• May help in further delineation of fistulae

Procedures

• Colonoscopy
• • Endoscopy has the advantage over radiologic studies. Biopsies may reveal classic histologic changes consistent with radiation injury. Endoscopic therapy also can be provided in the same setting, as necessary.
  • Endoscopic findings vary depending on the timing of the procedure (ie, acute setting versus chronic setting).
  • Colonoscopy may be dangerous depending on the stage of irritation and injury of the colon. Colonoscopy needs to be performed cautiously in the acute setting.
• Acute setting
• • Initial changes reveal a friable edematous mucosa.
  • Later changes reveal duskiness, edema, and inflammation.
  • Ulceration is infrequent but may occur later as the cumulative dose of radiation increases. In this case, the results would show necrotic mucosa with patchy areas of superficial ulceration.
• Chronic setting
• • Fibrosis of the bowel wall may appear as smooth and symmetric strictures.
  • The mucosa may appear granular, friable, edematous, and pale, with prominent submucosal telangiectatic vasculature.
• Small bowel capsule endoscopy: This can potentially detect strictures or a source of bleeding in the small bowel in difficult to diagnose cases.

Histologic Findings

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.

TREATMENT

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Medical Care

The treatment of acute injury varies depending on the symptoms, and the treatment of chronic injury varies depending on the location of injury.

• For symptom control, consider antidiarrheals, bile-sequestering agents, antiemetics, 5-aminosalicylic acid (5-ASA) moieties, and sucralfate. Simple iron supplementation may suffice in some individuals with low-grade bleeding leading to mild anemia.
• Consider topical steroids and sucralfate enemas if symptoms are related to rectal involvement. 5-ASA enemas have not been found to be very helpful.
• Consider formalin instillation of the rectum and therapeutic endoscopic interventions (eg, ablation with argon, Nd:YAG laser, bipolar circumactive probe [BICAP], argon plasma coagulator).
• HBO therapy may be considered in intractable radiation proctitis before surgical intervention.

Surgical Care

Surgical intervention usually is required as a last resort or in the case of complications (eg, perforation, obstruction, abscess drainage, fistulae, local wound infections).

• The surgical approach should be as conservative as possible.
• Abdominopelvic operations are best avoided in patients who received high-dose radiation to the pelvis. Resection of the rectum carries an operative morbidity rate of 12-65% and a mortality rate of 0-13%.
• Resection of the diseased bowel can be difficult because identifying the affected loops at laparotomy may be difficult. Doppler viewing of the bowel and intraoperative frozen sections have not been helpful.
• An intestinal bypass procedure may be necessary depending on surgical findings and technical difficulties. Although resection has been shown to cause a higher incidence of leakage and mortality than bypass, diseased bowel left behind also can cause more bleeding and can result in perforation and fistulization.
• Several techniques have been described for resection with primary anastomosis or secondary anastomosis with diversion colostomy or ileostomy.
• When at least 1 end of a primary anastomosis is healthy bowel, reports exist that leakage is reduced significantly.
• Dilation of strictures may be required. Perforation risk is significant if the strictures are long.
• Rectovaginal fistulae may close spontaneously or after diversion colostomy. Other fistulae usually require surgical repair.
• Presacral sympathectomy has been used for severe pain.

Consultations

• A team approach is extremely important to treat these patients. The team may include a radiation oncologist, a medical oncologist, a gastroenterologist, a nutritionist, and, possibly, a surgeon.
• The services of a pain specialist may be necessary if the pain is intractable and severe.
• Also, the services of a physician experienced with HBO therapy may be necessary if this modality is considered in intractable proctitis.

Diet

• Based on animal studies, a low-fat diet is recommended, with the intention of decreasing pancreatic and biliary secretions to decrease radiation damage. A low-fat, low-residue, and lactose-free diet has been tried with some suggested success. Elimination of insoluble fiber from the diet with substitution of soluble fiber has been tried.
• Findings from animal studies suggest that glutamine-supplemented diets (eg, polymeric, elemental) may be protective against radiation injury.
• Consider an elemental diet or the use of total parenteral nutrition as the clinical situation demands. A recent Italian retrospective study in patients with mechanical bowel obstruction due to chronic radiation enteritis showed that initial treatment with bowel rest and home parenteral nutrition was superior to initial surgical intervention in long-term survival and nutrition autonomy.

Activity

No restriction on activity is necessary.

MEDICATION

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The treatment of acute injury varies depending on the symptoms, and treatment of chronic injury varies depending on the location of the injury.

Drug Category: Antiemetics

Used to treat nausea and vomiting related to acute radiation enteritis.

Drug Category: Antidiarrheals

Used to treat diarrhea associated with acute radiation enterocolitis.

Drug Category: Topical corticosteroids

Used to treat symptoms related to radiation proctitis.

Drug Category: Topical formalin therapies

Used for intractable bleeding from radiation proctitis.

FOLLOW-UP

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Deterrence/Prevention:

• Prevention is the single most important element in dealing with intestinal radiation injury.
• Although pretreatment calculation of the dose is important, sensitive probes have been replaced by computer calculations. Three-dimensional treatment-planning techniques have been employed and have been shown to be more accurate and safer.
• A small decrease in radiation (as small as 10%) with an increase in the duration may reduce adverse effects significantly without affecting the total radiation dose.
• Pretreatment barium contrast studies to determine how much of the small intestine is in the pelvis might be a guide in custom shielding.
• Filling the urinary bladder may push the small bowel away from the pelvis.
• Body positioning in the prone position, decubitus, or the Trendelenburg position may be helpful. A special table with a central cavity, which allows the bowel loops to drop away from the target tissue, has been described.
• Pharmacologic therapy
• • A number of promising innovative pharmacologic therapies are being studied. Unfortunately, most of the data are from animal studies, and trials in humans are lacking. These agents include antioxidants in the form of vitamin E and vitamin E-like compounds, as well as the lazaroids (ie, 21-amino steroids) and more recently octreotide.
  • Although nonsteroidal anti-inflammatory drugs have shown some promise in animal studies, the results with a prostaglandin analogue, misoprostol, have been less than satisfactory.
  • Other emerging therapies include intravenous and intra-arterial vasopressin, epidermal growth factor, growth hormone, and nitric oxide (NO) inhibitors.
  • Sucralfate therapy in doses varying from 1 g every 4-6 hours during treatment and for another 3-4 weeks thereafter has been shown effective during pelvic irradiation. However, a recent study showed that oral sucralfate was not effective in preventing late rectal injury in patients with prostate cancer.
  • The Food and Drug Administration (FDA) recently approved the use of IV amifostine (Ethyol) as a radioprotectant agent. Administered as a daily dose, amifostine is to be used in the prevention of radiation-induced xerostomia in the postoperative setting. Its efficacy in the prevention of radiation intestinal injuries has yet to be established. Concern about tumor protection appears to be unwarranted. Adverse effects, such as nausea and hypotension, the need for daily injections, and cost concerns may limit its wide acceptance.
• The most important aspect is prevention; therefore, a number of innovative prophylactic surgical therapies have been proposed, and include the following:
• • Biodegradable mesh slings
  • Sodium chloride–filled tissue expanders
  • Inflatable prosthesis
  • Abdominopelvic omentopexy
  • Suturing the bladder to the sacrum

Complications:

• Small or large bowel obstruction
• Small or large bowel bleeding
• Fistulae - Rectovaginal, enterovesical, rectovesical, or enterocolic
• Malabsorption, electrolyte abnormalities, and dehydration
• Perforation
• Urethral stenosis
• Cystitis

Prognosis:

• The natural history of radiation enteritis is hard to ascertain due to the lack of follow-up information in these patients. Often, these patients succumb to their original malignancy. Reports exist that 50% of patients with radiation-induced enteritis who survived more than 3 months after surgery and who were observed for as long as 12 years did well, while the remainder had persistent symptoms, developed complications, or both. The 5-year survival rate for the entire group was 40%.
• In terms of radiation proctitis, Gilinsky et al (1983) developed the following classification system based on outcome:
• • Group I is comprised of 44% of patients with the most favorable outcome; 70% achieved resolution in 18 months, 5% required surgery, and 15% died from complications.
  • Group II is comprised of 36% of patients with a less favorable outcome and 25% mortality rate.
  • Group III is comprised of 20% of patients with intractable bleeding, all of whom required surgery. The overall mortality rate was 41%.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure by endoscopists to exercise extreme caution, especially in acute severe injury and stricture dilation
• Failure to use surgical intervention with great caution and as a last resort: Patients should be well informed of the risks and the potential adverse short-term and long-term outcomes, which can be devastating.
• Failure to use all available modalities to try to prevent or minimize radiation-induced injury
• Failure to investigate patients with GI symptoms on the presumption that these symptoms are a consequence of radiation damage. A recent prospective study of 265 patients showed that more than one half had more than one GI diagnosis contributing to their symptoms. Significant neoplasia was found in at least 12% of patients and one third of all diagnoses were unrelated to prior radiation therapy.

MULTIMEDIA

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Media file 1:  Intestinal radiation injury. Characteristic mucosal changes observed in radiation proctitis with multiple telangiectasias.
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Media file 2:  Intestinal radiation injury. Friability and oozing of blood from atrophic-appearing mucosa due to radiation.
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Media file 3:  Intestinal radiation injury. Appearance of mucosa after therapy with bipolar circumactive probe (BICAP) probe.
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Media file 4:  This slide illustrates disorderly crypts, fibrosis of lamina propria, and vascular dilatation, all of which are characteristic of colonic injury due to radiation. (This slide was provided courtesy of Ronald Burns, MD, Palmetto Richland Memorial Hospital, Columbia, SC.)
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Media file 5:  A deep rectal ulcer from prostate cancer radiation years ago. Patient presented with significant rectal bleeding.
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Media file 6:  After 6 months of treatment with daily Canasa (5-ASA) suppositories
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Media file 7:  Retroflexed view of the same radiation induced ulcer after 6 months of treatment
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REFERENCES

Section 11 of 11

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Article Last Updated: Jun 20, 2006