Radiation injuries to the small and large bowel
Radiation therapy is an important treatment modality for malignancies of the cervix, uterus, prostate, bladder, testes and rectum. Although radiation therapy is generally well tolerated, a small percentage of patients will suffer significant radiation-induced damage. The complication rates following radiation therapy range from 0.5 to 36%, depending on the bias of the reports. The incidence of clinically significant radiation-related complications is about 5–20%. Many of the more serious injuries occur in the gastrointestinal tract, with damage to the small bowel, colon and rectum. Tolerance of normal tissues to radiation is dependent on the organ involved and the total radiation doses delivered.
Ionising radiation generates free radicals from intracellular water, which in turn affect DNA synthesis. Cells with a high proliferation rate tend to be more susceptible to radiation injury. The gastrointestinal tract is second only to the kidneys in radiosensitivity. While the small bowel is more radiosensitive than the large bowel, it is injured less frequently because of its mobility within the peritoneal cavity. Because of its relative fixity, the terminal ileum is the most commonly injured segment of the small bowel. Acute changes are inflammatory and chronic changes are sclerotic and fibrotic.
Acute radiation damage may occur within hours to days after radiation. Early radiation injuries result in oedematous, thickened and hyperaemic mucosa. Superficial ulceration or necrosis may be present. In the small bowel the villi become blunted, and in both the small and large bowel the crypts become shortened. The submucosa may show bizarre and enlarged fibroblasts with cytological atypia and is replaced with a hyalin-type substance. Infiltration by leucocytes is seen throughout the full thickness of the bowel wall. Spasm and thrombosis may affect arterioles. Hyalin thickening of the artery wall occurs (Flow chart of radiation injury to bowel.).
Chronic radiation damage is frequently progressive. Late injuries are characterised by fibrosis. Unlike acute damage, which mainly involves the mucosa, chronic damage represents involvement of the entire bowel wall. The bowel appears pale and shortened. The mesentery is thickened and shortened. Loops of small bowel may be fused with obliterative fibrous adhesions, often called a ‘frozen pelvis’ or ‘frozen abdomen’. Long strictures affecting the bowel are present. Ulcers within the bowel wall develop and may progress to a fistula or perforation. Incidence of severe delayed toxicity among women treated for cervical cancer is 10% at 20 years. Up to 10% of chronic persistent radiation enteropathy will die from the disease. Microscopic features include thrombosis, obliterative endarteritis, submucosal fibrosis and hyalinisation, and lymphatic and venous ectasia. The ganglion cells in the rectum may degenerate, affecting sphincter function, rectal compliance, contractability and continence.
The incidence and severity of intestional radiation toxicity depends on dose, volume of bowel irradiated, fractionisation schedule, use of concomitant chemotherapy, co-morbidity and duration of follow-up.
Cumulative total dosage of radiation delivered to the tissues
Cumulative total dosage of radiation delivered to the tissues is an important determinant of subsequent radiation damage. Toxicity has been quantified as the minimum tolerance dose (TD 5/5) and maximum tolerance dose (TD 50/5). TD 5/5 is defined as that dosage that leads to the development of clinical damage in up to 5% of patients within 5 years, and TD 50/5 indicates the dosage that produces radiation-related complications in up to 50% of patients within 5 years. When the total radiation dose is less than 3000 cGy intestinal injury is rare; the injury rate increases to 36% among patients receiving 7000 cGy.
Rate of delivery of radiation
Normal cells are more tolerant of frequent dosing of radiation than malignant cells because the latter do not self-repair as well as normal cells. External beam radiation uses doses less than 200 cGy per day. With intracavitary radiation the dosing is particularly crucial; dosage rates greater than 60 cGy per hour are associated with a higher incidence of visceral injuries.
Techniques of radiation delivery
Exposure of the small bowel to radiation can be decreased by careful positioning of the patient during radiotherapy, by distending the bladder and by using multiple fixed or rotational fields. Whenever possible, intracavitary irradiation is used because it also limits the extent of radiation exposure of normal tumours. Surgical manoeuvres during laparotomy may also minimise adhesion of the small bowel in the pelvis (see under ‘Prevention’).
Cardiovascular diseases and diabetes potentiate radiation-induced vascular injury (obliterative endarteritis). Concurrent chemotherapy, such as adriamycin and 5-fluorouracil, enhances radiation-induced cell injury.
Previous laparotomy with adhesion formation and pelvic inflammatory disease predispose to radiation injury because of the relative fixation of the bowel in the pelvis.
Early injuries or reactions usually occur within the first 3 months of therapy. These injuries usually result in mucositis. About 50% of patients develop early reactive symptoms after radiation therapy to the abdomen or pelvis, usually within 6 weeks of the first treatment. The symptoms are usually transient and readily amenable to conservative therapy. In some patients, the symptoms are severe enough to warrant temporary cessation of radiation therapy. Rarely, an early injury is severe enough to cause necrosis and perforation of the bowel.
Late complications typically develop 6–36 months after completion of therapy, although some cases develop many years later. The underlying pathophysiology of chronic radiation injury is obliterative endarteritis and ischaemic fibrosis. Late effects may be the continuation of early reactions but more commonly they arise de novo. The incidence of late complications following abdominal and pelvic radiation range from 1 to 17%; overall, about 1–5% of patients will require surgery for these delayed effects and 10% may die from chronic persistent complications.
The clinical presentation of chronic radiation injury varies with the segment of bowel affected.The symptoms may be hard to distinguish from those of recurrent cancer.
The most common symptoms include colicky abdominal pain, bloody diarrhoea, steatorrhoea or weight loss. More acute presentations include obstruction, perforation, fistula or bleeding. Extensive disease may lead to malnutrition from malabsorption and bowel obstruction.
Enteroclysis is more reliable than barium small bowel series in defining changes and extent of radiation enteritis. Suggestive radiological findings include mural thickening, thickened valvulae conniventes, strictures, separation of bowel loops secondary to oedema and/or fibrosis and fixation of small bowel loops within the pelvis. Fistulae, internal or enterocutaneous, may also be present. Small bowel ischaemia, when present, manifests as ‘thumbprinting’ nodular-filling defects. Radiological changes may be difficult to distinguish from neoplastic invasion. Most radiation injuries appear in the terminal ileum, while recurrent malignancy may affect the duodenum and jejunum.
Acute toxicity is best treated with anti-diarrhoeal, antiemetic, and spasmolytic agents.
A low-residue diet and a diet low in fats and lactose are helpful. In more severe cases, an elemental diet may improve diarrhoea while maintaining nutrition.
Antispasmodics, anticholinergics and opiates can improve symptoms of pain and diarrhoea by reducing motility. Oral antibiotics may improve diarrhoea in patients with bacterial colonisation of the small bowel. Enteric-coated acetylsalicylic acid (ASA) may improve symptoms, possibly because of its anti-inflammatory effects. If the bile salt absorption is abnormal, cholestyramine can decrease diarrhoea. However, cholestyramine should not be given concurrently with other drugs because it binds other oral medications. Occasionally synthetic somastatin analogues can be tried for resistant diarrhoea.
Total parenteral nutrition
Bowel rest and total parenteral nutrition (TPN) may be used for severe symptomatic disease and malnutrition and for enterocutaneous fistulas, although spontaneous closure is uncommon. Total parenteral nutrition is also invaluable in preparing the malnourished patient for surgery.
Indications for surgery include bowel obstruction, perforation, abscess, fistula unresponsive to TPN, intractable bleeding or diarrhoea, and occasionally malabsorption. Surgery is associated with a high operative morbidity (65%) and mortality (40%), with poor nutritional status, delayed wound healing and high risk for wound dehiscence and fistula. Clinical judgement on timing and type of operation is critical. Surgical decision-making is sometimes influenced by uncertainty about recurrent malignancy (Treatment options for chronic radiation enteritis and rectal disease.).
Patients should be carefully evaluated pre-operatively for the extent of radiation damage, unless emergency surgery is required. This includes a careful review of the patient's general medical condition and correction of any fluid and electrolyte abnormalities. A decompressive nasogastric tube is inserted if the patient is obstructed. Broad-spectrum antibiotics that cover Gram-negative organisms and anaerobes are prescribed if there is active sepsis. Preliminary treatment with TPN should be considered in patients who are malnourished. Appropriate bowel cleansing programs are initiated.
Surgical treatment: Resection versus bypass
Major controversy surrounds surgical treatment, by resection or bypass, of the abnormal bowel. The argument against resection with primary anastomosis is the concern about the viability of bowel ends and that dissection around adhesions increases the risk of later fistula formation. However, bypassing an irradiated segment leaves behind a diseased portion of bowel that is prone to perforation, sepsis, fistula formation and development of a blind-loop syndrome.
An individualised approach with regard to the choice of treatment is desirable. Resection is preferable if only a short segment of small bowel is diseased or if ileocolic anastomosis to normal colon can be performed. The caecum and right colon are frequently in the radiation field and are not ideal sites for anastomosis. The transverse colon is generally preferred for the ileocolic anastomosis. In patients with extensive disease and considerable adhesions in the pelvis, a bypass procedure without resection is prudent. Anastomosis or stoma formation should be constructed in non-irradiated bowel whenever possible. Lysis of adhesions should be undertaken with great caution. Careless adhesion lysis is associated with ischaemia or inadvertent enterotomies. These may lead to fistula formation or perforation.
Management of fistulas in the presence of radiation enteritis poses special problems. The radiation damage is generally severe and the fistula is unlikely to close with bowel rest and TPN. Surgery is complicated and often difficult.
Colonic and rectal injuries
Patients with radiation damage to the colon and rectum usually present with bleeding, urgency, diarrhoea, tenesmus, constipation from stricture, anal and pelvic floor pain and faecal incontinence. A digital examination may reveal an anorectal stenosis, and a bimanual examination can detect a frozen pelvis. Proctosigmoidoscopy may reveal oedematous and pale rectal mucosa with petechial haemorrhages. Colonoscopy defines the extent and distribution of radiation damage. With radiation damage to the rectosigmoid region, barium enema studies reveal shortening and narrowing of the rectosigmoid region, with loss of the normal curvature. With chronic cases, the rectum may appear rigid and narrowed. Multiple strictures may be present.
Ulcerations may appear, especially on the anterior rectal wall following irradiation for cervical or prostatic cancer. The ulcers probably result from ischaemia and thrombosis of small mucosal vessels. Biopsies may be required to rule out malignancy, but these must be performed with care or a rectal perforation can result. Frequently, the rectal ulcers are extremely painful. With progression of disease, perforation and fistulisation may develop. Erosions may lead to massive haemorrhage. Fibrosis leads to strictures with obstructive symptoms.
Low-residue diet and stool softeners minimise damage to the rectal mucosa. Salazopyrine and prednisolone can help some patients. For radiation proctitis, 5-ASA or steroid enemas are helpful and short chain fatty acids and butyrate enemas have been tried more recently. Belladonna and opiate suppositories may improve rectal pain. Gentle dilatation may be useful for treating low rectal strictures. Troublesome haemorrhage sometimes occurs. For acute bleeding from proctitis, an adrenaline enema with 50 mL 1 : 100 000 solution is effective. For recurrent bleeding, endoscopic argon plasma coagulation or laser ablation of the petechiae or telangiectasias is useful, although repeated applications are necessary. In refractory cases, gentle topical application of formalin solution has shown some promise.
Most colorectal radiation injuries do not require surgery. If obstruction, perforation, fistula, persistent bleeding, intractable pain or severe faecal incontinence develops, surgery should be considered, especially if there are no other co-morbid factors.
Surgical options include a diverting stoma (colostomy or ileostomy), and resection and, rarely, anastomosis. Diversion alone may ameliorate pain or ulceration in the distal large bowel. Its efficacy for bleeding is less predictable. A healthy loop of bowel should be adequately exteriorised to form the stoma.
With severe rectal disease, especially in younger patients, formal resection may be preferred. Conventional anterior resection with a low colorectal anastomosis is associated with high operative risks and significant anastomotic leaks. This should be attempted only if the colon and rectum have received less than 4000–4500 cGy, and a protective ileostomy or colostomy is generally performed. Mucosal proctectomy and coloanal sleeve anastomosis between a wellvascularised, non-irradiated proximal colon and the anal canal has met with some success, although this is a major surgery.
Technological advances in radiation oncology have allowed a more focused delivery of radiation to the areas of interest while sparing normal adjacent tissues unnecessary radiation. Fractionating radiation doses, altering the size of the radiated field and use of various positioning techniques, such as the prone position and bladder distension, have helped to minimise small bowel exposure. Several surgical techniques have been developed following proctectomy to exclude the small bowel from the pelvis before irradiation.
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