Diagnosis and management of chronic radiation enteritis

Diagnosis and management of chronic radiation enteritis
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INTRODUCTION — Chronic radiation enteritis is a complication of radiation therapy for cancer, most commonly for rectal, prostate and pelvic malignancies. It can affect both the large and small intestine, is often progressive, and may lead to a variety of clinical consequences (such as diarrhea, nausea, weight loss, abdominal pain, intestinal obstruction, and perforation) depending upon the extent of the injury. It usually develops six or more months after radiation therapy (mean approximately 5 years, range two months to as long as 30 years. This contrasts with the timing of acute radiation enteritis (characterized by diarrhea and abdominal pain), which develops during or shortly after radiation therapy and resolves within two to six weeks.

The incidence has not been well defined, in part because of the large number of patients who died or were lost to follow-up in major studies involving radiation therapy, and because of the variability in the field size and dose of radiation. One literature review estimated that the incidence ranged from 1.2 to as high as 15 percent in patients with rectal cancer

This topic review will focus on the diagnosis and management of chronic radiation injury to the small intestines and proximal colon. Issues related to the prevention and treatment of chronic radiation proctitis (usually encountered following treatment of cancers of the rectum, cervix, uterus, prostate, urinary bladder, and testes) are presented separately.

PATHOGENESIS — Chronic radiation enteritis usually develops only after large doses of radiation therapy have been delivered (4500 to 5500 cGY); it is uncommon at lower doses. In addition to the dose of radiation, several other predisposing conditions have been described including:

Older age
Combined chemotherapy
Poor radiation technique
Postoperative radiation; in this setting, bowel loops fixed together by adhesions may prolapse into the pelvis, leading them to receive excessive radiation exposure. Adhesions due to past surgical procedures can have the same effect.
Intestinal injury is believed to be related to oxidative damage caused by the formation of free radicals. The end result is an obliterative endarteritis that leads to intestinal ischemia resulting in stricturing with ulceration and fibrosis and occasionally fistula formation. The physiologic consequences may include altered intestinal transit, reduced bile acid absorption, increased intestinal permeability, bacterial overgrowth and lactose malabsorption The resulting clinical manifestations may include nausea, vomiting, lactose intolerance, obstructive symptoms, diarrhea, weight loss, malnutrition, and bleeding (usually in patients with colonic involvement).

The prominent histopathologic features are those of an occlusive vasculitis with diffuse collagen deposition and fibrosis. The arteriolar walls may show a hyaline ring-like thickening and large foams cells beneath the intima. Mucosal ulceration, necrosis and perforation may develop as the disease progresses. Progressive fibrosis leads to stricturing with dilation of proximal segments. The intestinal segments and their associated serosa appear grossly thickened. Telangiectasias may be seen.

The precise mechanisms leading from oxidative damage to the histologic and morphologic abnormalities described above are incompletely understood. Several theories have been proposed, all of which are probably interrelated:

One model suggests that fibrosis develops from the initial mucosal injury
Another theory suggests that fibrosis develops in connective tissues where radiation has caused a decrease in cell turnover and a low rate of proliferation.
A third model focuses on the cellular responses to vascular damage caused by paracrine mediators. The signals leading to the developing of fibrosis are a topic of intensive ongoing investigation.
One study found that intestinal webs forming after radiation therapy demonstrated an impaired vasodilatory response in vitro to acetylcholine treatment. This microvascular dysfunction may lead to the formation of the abnormal tissue response seen in the wall of the intestine post-radiation therapy.
CLINICAL MANIFESTATIONS — The classical features of radiation enteritis are abdominal pain, nausea, vomiting, and diarrhea. Patients with severe disease may develop intermittent, partial, or complete small bowel obstruction

As noted above, bacterial overgrowth may lead to malabsorption and contribute to the nausea, abdominal pain and diarrhea. Bacterial overgrowth should be suspected in patients with intestinal strictures. Another clue may be the development of new lactose intolerance. Nonspecific symptoms include diarrhea, bloating, excessive gas, borborygmi, and nausea. Most such patients have only subtle laboratory or clinical findings pointing toward the diagnosis; thus a high index of suspicion is required. Rare patients with severe malabsorption may present with a more fulminant clinical and laboratory profile

DIAGNOSIS — The diagnosis is usually established by suggestive radiologic findings in patients with compatible clinical features who have a history of prior radiation exposure. The patient's previous radiation treatment record should be reviewed to determine the total dose and distribution of the radiation field. This may help to determine which intestinal segments may have received excessive radiation exposure, information that can be correlated with the radiologic findings and the clinical presentation.

We usually obtain an abdominal CT scan followed by an upper gastrointestinal series with small bowel follow through in patients with suspected small bowel disease. Additional imaging is reserved for patients in whom the diagnosis remains unclear. We generally perform a colonoscopy in patients with suspected colonic involvement.

Upper gastrointestinal series — An upper gastrointestinal series with small bowel follow-through is a useful initial test for evaluating the extent of disease although it is not as sensitive as enteroclysis.

Enteroclysis — Enteroclysis involves the instillation of contrast material (usually administered through a nasoenteric tube) into the small bowel using a pump (making it considerably less comfortable than a standard small bowel follow-through). It provides more detailed visualization of the small bowel compared with a standard upper gastrointestinal series. Suggestive findings include submucosal thickening, single or multiple stenoses, adhesions, and sinus or fistula formation. Its sensitivity and specificity for radiation enteritis have not been well-defined.

CT scan — Computed tomography may show thickening of bowel segments, but the findings are nonspecific. CT may be helpful in narrowing the differential diagnosis, particularly in distinguishing strictures due to radiation enteritis from those arising from abdominal metastases or a local recurrence

CT enteroclysis (in which a CT is performed after instilling contrast into the intestine using a nasoenteric tube) produces superior bowel opacification compared with conventional CT, and may therefore be useful for identifying low-grade or intermittent obstruction (reported sensitivity and specificity of approximately 88 and 82 percent, respectively). However, the technique is still used only in a few specialized centers. Similarly, other improvements in CT imaging of the small bowel (such as three-dimensional imaging) will likely also have a role in diagnosis of radiation enteritis but are not yet widely available

Magnetic resonance enteroclysis — Magnetic resonance enteroclysis permits visualization of the small bowel using similar principles as described above for CT enteroclysis. Initial studies suggest the results are comparable to (and possibly more sensitive than) CT enteroclysis. However, only small numbers of patients have been studied and the technique is not yet widely available.

Enteroscopy — Enteroscopy (peroral endoscopy of the small bowel using specialized endoscopes) has a limited role in the diagnosis of radiation enteritis although it may help to narrow the differential diagnosis. Enteroclysis can be performed following enteroscopy by leaving a tube inserted in the intestine upon withdrawal of the enteroscope.

Capsule endoscopy — There is no published experience with capsule endoscopy specifically for diagnosing radiation enteritis, although there is some clinical experience. However, it should probably not be performed in patients in whom there is a strong clinical suspicion for radiation enteritis because the capsule may become lodged in a strictured segment, requiring surgical removal.

Colonoscopy — Colonoscopy is helpful in evaluating colonic involvement and can also visualize the terminal ileum. Mucosal features consistent with radiation injury include pallor with friability and telangiectasias, which can be multiple, large, and serpiginous; these changes tend to be continuous. Although mucosal biopsies are not diagnostic, they can help to exclude other causes of proctitis such as infection or inflammatory bowel disease.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of chronic radiation enteritis is broad. Other diagnostic possibilities include post-surgical adhesions, malabsorption syndromes, abdominal metastases, lymphoma, Crohn's disease, infectious, ischemic or ulcerative colitis, and intestinal pseudo-obstruction.

MEDICAL MANAGEMENT — Prevention is the key to avoiding chronic radiation enteritis. Once established, treatment should be as conservative as possible focusing on relief of symptoms. Experience with specific medical treatments has been derived largely from small clinical trials and case series. Approaches used to treat small bowel disease will be summarized below while specific treatments aimed at radiation proctitis are discussed separately.

Dietary recommendations — There does not appear to be a clear-cut diet that reliably alleviates symptoms. A high fiber diet should probably not be recommended specifically since it may worsen diarrhea and urgency. Some patients may develop lactose intolerance, which may be due to bacterial overgrowth, and may improve following antibiotic treatment (see below). Others may require avoidance of lactose. Enteral formulas supplemented with glutamine may have a benefit but studies are limited

Antidiarrheal agents — Judicious use of antidiarrheal agents (such as loperamide) can help improve diarrhea, although it should not be used in patients with suspected small or large bowel obstruction. The efficacy of loperamide was evaluated in a crossover trial involving 18 patients with diarrhea due to radiation enteritis who were randomly assigned to loperamide or placebo for 14 days separated by a 14 day washout period. Loperamide was associated with a significant reduction in the frequency of bowel movements, slower intestinal transit, and improvement in the absorption of bile acids.

Antibiotics — Antibiotics may reduce symptoms in patients in whom bacterial overgrowth has developed. Specific testing for bacterial overgrowth is preferable to empiric therapy. A major drawback to empiric therapy is that treatment may require more than one antibiotic, and repeated and sometimes cyclic treatment. Because antibiotics may be associated with adverse effects, some of which may mimic symptoms of bacterial overgrowth (such as diarrhea and abdominal discomfort), establishing a firm diagnosis is important. This can usually be accomplished with a breath test.

5-ASA drugs — A case report (published nearly three decades ago) suggested a possible benefit from sulfasalazine with or without oral prednisone. There is no large published experience with either of these drugs. Discordant results have been obtained from controlled clinical trials evaluating mesalazine or sulfasalazine in the prevention of acute radiation enteritis

Hyperbaric oxygen — HBO has been used for treatment of refractory foot ulcers in diabetes and in other conditions [39]. The theoretical benefit of hyperbaric oxygen therapy (HBO) may be via inhibition of bacterial growth [40], preservation of marginally perfused tissue, and inhibition of toxin production [41].

A benefit in chronic radiation enteritis was suggested in a case report of a patient in whom 20 treatments over a one month period brought about objective improvements in symptoms and absorption of D-xylose. However, this anecdote did not give the results of long-term follow-up. Other reports have also suggested a benefit for patients with chronic radiation proctitis.

The equipment needed for hyperbaric oxygen treatment is expensive and not widely available. Thus, at the present time, it is not a practical means of treating chronic radiation enteritis outside of centers specializing in this approach, particularly since its effectiveness has not been well-studied.

Parenteral nutrition — A mainstay of the medical therapy of severe chronic radiation enteritis has been total parenteral nutrition (TPN), the success of which is similar for other intestinal disorders requiring TPN. One of the largest series included 54 patients who required home TPN mostly because of intestinal obstruction (27 patients), short bowel syndrome (17 patients), malabsorption (five patients), fistula formation (three patients), and dysmotility (two patients). TPN was initiated a median of 20 months after radiation therapy and was administered for a median of 20 months. Cumulative 5-year survival was 64 percent. Most early deaths were due to recurrent cancer. Similar survival estimates were reached in other series .

SURGERY — As noted above, surgery for radiation enteritis should be avoided if possible because of several inherent difficulties in operating on patients with chronic radiation injury

Diffuse fibrosis and adhesions between bowel loops can make resection technically challenging.
The risk of a leak is high when creating an anastomosis between irradiated tissues. Furthermore, it can be difficult to distinguish healthy tissue for irradiated tissue by gross inspection alone; intraoperative endoscopy may be helpful in this setting, but experienced is limited.
Extensive resection may be required, potentially leading to short bowel syndrome.
Despite attempts at conservative management, approximately one-third of patients progress to the point where surgery is required. Most surgical series of patients treated for radiation enteritis are small; the most common indications for surgery have been persistent ileus, intestinal fistulization, and massive adhesions. Surgical mortality rates are as high as 10 to 22 percent and many patients require more than one laparotomy

An illustrative series focused on 109 patients who underwent surgery during a 10 year period. Five patients died postoperatively (all of whom had undergone resection) while 33 (30 percent) had postoperative complications. Complications were more likely in patients who underwent emergency surgery. Repeat surgery was required in 40 percent of patients during a 40 month follow-up period. Overall survival in patients without a cancer recurrence was 85 percent at year one, and 69 percent at year five.

Strictureplasty may offer a less invasive approach to the management of strictures, but experience is limited. The role of small bowel transplantation in this setting is still being determined; its role, if any, will probably be only in children

SUMMARY AND RECOMMENDATIONS — Chronic radiation enteritis may lead to a variety of clinical consequences (such as diarrhea, nausea, weight loss, abdominal pain, intestinal obstruction and perforation) depending upon the extent of the injury. It usually develops six or more months after radiation therapy (mean approximately 5 years, range two months to as long as 30 years).

The diagnosis is usually established by suggestive radiologic findings in patients with compatible clinical features who have a history of prior radiation exposure. The patient's previous radiation treatment record should be reviewed to determine the total dose and distribution of the radiation field. This may help to determine which intestinal segments may have received excessive radiation exposure, information that can be correlated with the radiologic findings and the clinical presentation. We usually obtain an abdominal CT scan and an upper gastrointestinal series with small bowel follow-through. Further testing with an enteroclysis (standard, CT, or MRI depending upon local expertise) can be performed if the above is unrevealing and clinical suspicion remains.

Management should be conservative, addressing the predominant symptoms.

Patients with diarrhea, abdominal pain, nausea or bloating should undergo breath testing for bacterial overgrowth and treated with antibiotics if bacterial overgrowth is confirmed. Avoidance of lactose may benefit other patients while antidiarrheal agents (such as loperamide) may also be helpful. Loperamide should be avoided in patients with obstructive symptoms.
Patients with intermittent obstructive symptoms may benefit from a low residue diet, although dietary tolerance is variable. Radiologic evaluation may help to identify the strictured segment, information which may be critical should strictureplasty or surgery be ultimately required. The narrowed segment may not always be visible with an upper gastrointestinal series, particularly in patients with intermittent symptoms. Such patients may require enteroclysis as described above.
Despite conservative measures, surgery will be required in approximately 30 percent of patients. This is usually due to persistent ileus, intestinal fistulization, and massive adhesions.
Prognosis is variable since the disease is progressive. Early mortality is usually due to cancer recurrence. Five-year survival is approximately 70 percent in those without cancer recurrence, although many patients continue to have troubling digestive symptoms for the remainder of their lives.

Intensive, ongoing research on mechanisms related to fibrogenesis may eventually produce effective means to prevent or reverse disease progression once it has been established. However, at the present time, prevention during radiation therapy is central to reducing the risk of developing chronic radiation enteritis.