APOPTOSIS

In animal studies, a rapid increase in the rate of programmed cell death (apoptosis) of intestinal crypts cells can be observed after exposure to low-dose radiation (1 to 5 cGy). The rate of apoptosis is radiation dose dependent and reaches a plateau at 1 Gy. Radiation exposure also increases expression of the tumor suppressor gene P53 in the stem cell region. The apoptosis induced by radiation is dependent on the presence of P53. Additionally, the rate of spontaneous and radiation-induced apoptosis is significantly increased in animals lacking bcl-2, suggesting a protective effect of bcl-2 against radiation-induced apoptosis.² It is therefore postulated that P53 promotes apoptosis after irradiation and that bcl-2 protects the mucosa. The expression of higher levels of bcl-2 may explain the increased tolerance of the colorectal mucosa to radiation as compared with the small intestine (see following).

ROLE OF CYTOKINES

Ionizing radiation activates the translation of the gene coding for transforming growth factor-β (TGF-β) in the intestines. TGF-β is a potent fibrogenic and proinflammatory cytokine, leading to hyperplasia of connective tissue mast cells and leukocyte migration into the intestinal wall. TGF-β promotes intestinal fibrosis by stimulating the expression of collagen and fibronectin genes and the chemotaxis of fibroblasts. The extracellular matrix of the intestine is also increased as TGF-β inhibits its degradation. The increased expression of TGF-β is especially enhanced in areas with histopathologic changes consistent with radiation damage: areas with mucosal ulceration, mucosal and serosal thickening, inflammatory cell infiltrates, and vascular sclerosis.^3,4 TGF-β exists in three isoforms: TGF-β1, TGF- β2, and TGF- β3. All three isoforms are overexpressed in the early postradiation phase. However, only isoform β1 remains elevated six months after radiation exposure. In the first 2 weeks after radiation, TGF-β1 messenger RNA is increased in epithelial cells, fibroblasts of the submucosa and subserosa, vascular endothelial cells, and smooth muscle cells of the intestinal wall. However, at 26 weeks, the expression of TGF-β1 of epithelial cells returns to baseline level but TGF-β1 expression remains elevated in vascular endothelial cells, fibroblasts, and smooth muscle cells.⁵ Compared with control mouse intestine, the TGF-β1 immunoreactivity or overexpression is substantially increased in areas of radiation-induced acute and late bowel injury.^6,7 In addition, pathologic examination of bowel specimens from patients undergoing surgery for radiation enteropathy showed an increased TGF-β in areas with vascular sclerosis and fibrotic areas of the serosa and muscularis propria as compared with patients who have surgery for other causes.⁸ Neutralizing antibodies to TGF-β and gene therapy using decorin (a natural TGF-β inhibitor) have been shown to suppress or reverse fibrosis in preclinical models.⁹

Epidermal growth factors, interleukins, and tumor necrosis factors are also being investigated for their effects in chronic radiation injury.¹⁰ Another cytokine implicated in the development of radiation injury is connective tissue growth factor (CTGF). The CTGF expression is increased in intestinal radiation fibrosis associated with chronic radiation injury.¹¹ CTGF is found commonly in the extracellular region surrounding the area of active fibrosis or neovascularization. TGF-β1 may induce CTGF, which in turn functions as a mediator of intestinal radiation fibrosis by sustaining the activation of fibrogenesis in the irradiated gastrointestinal tract. Mechanisms underlying the pathogenesis of radiation-induced gastrointestinal damage remain an active area of investigation.

INCIDENCE AND CLINICAL FEATURES

Early and late injury of the esophagus often occurs following irradiation of malignances of the thorax and upper abdomen (e.g., esophageal/gastroesophageal junctional carcinomas and lung carcinomas). The normal esophageal mucosa undergoes continuous renewal or turnover. Acute esophageal side effects are believed to be primarily related to radiation damage to the basal epithelial layer, manifested histologically by vacuolization, resulting in epithelial thinning followed by denudation (Fig. 39-1). These changes manifest clinically as dysphagia, odynophagia, and substernal discomfort, usually occurring within two to three weeks following initiation of radiation therapy. Patients may describe a sudden, sharp, severe chest pain radiating to the back. As treatment progresses, pain may become constant and may not necessarily be related to swallowing. The symptoms may be confused with Candida esophagitis, which may occur in conjunction with radiation esophagitis. Concurrent chemotherapy exacerbates these toxic effects. Endoscopically, mucositis and ulceration may be observed. Perforation and bleeding are rare in the acute phase.¹² After treatment completion, basal proliferation returns and regeneration occurs, usually within three weeks.¹³

Figure 39-1. Acute radiation-induced esophageal injury. Acute esophageal ulceration with abundant fibroblasts is seen. (Hematoxylin and eosin, ×400.)

Following recovery from acute injury, late effects such as benign stricture, persistent ulceration and fistula formation may occur months to years following treatment. These effects are believed primarily due to inflammation and scar formation within the esophageal muscle. The connective tissues surrounding the esophagus may also exhibit severe fibrosis over time.¹⁴ Small vessel telangiectasias may be seen endoscopically. Histologic studies of the esophagus in previously irradiated patients have demonstrated epithelial thickening, chronic inflammation, fibrosis of the submucosa and muscularis propria, and (rarely) chronic ulceration. Complete epithelial recovery from radiation effects may take 3 to 24 months.¹⁵ Late effects often manifest as dysphagia due to stricture as well as altered motility due to fibrosis or muscular damage, possibly with accompanying nerve injury. Fistula formation is unusual and radiation dose dependent. Barium swallow examination may show strictures as well as disruption of peristalsis at the level of the irradiated esophagus with repetitive and nonperistaltic waves above and below the irradiated region. Abnormal peristalsis has been reported at 1 to 3 months following treatment completion, whereas most strictures occur 4 to 8 months following treatment completion. Late effects are usually not seen until 3 months following completion of radiation therapy, with a median time to onset of 6 months in some series.^16,17

Development of radiation-related late complications is dose related. The TD_5/5 (i.e., dose at which 5% of patients will develop complications at five years) has been estimated to be 60 Gy when one third of the length of the esophagus is irradiated.¹⁸ Other series have reported complication rates of less than 1% to 30% with doses of approximately 60 Gy, with benign stricture as the primary complication. Seaman and Ackerman treated patients to doses of 60 to 75 Gy, resulting in severe esophagitis and stricture formation in some patients. They concluded that the upper limit of dose tolerance of the esophagus was 60 Gy given at 10 Gy per week.¹⁹ Other studies reported that patients receiving 60 Gy had late complication rates of 1.2% to 18%. With contemporary radiation doses of 50 Gy, late complication rates have been observed in 2% of patients or less.^20,21

Brachytherapy (the temporary insertion of a radioactive source into or adjacent to a tumor) has also been used as a technique for radiation dose escalation in esophageal cancer. Gaspar and colleagues reported the results of a phase I/II study examining the role of brachytherapy in addition to external beam radiation therapy in the treatment of esophageal cancer. The one-year actuarial fistula formation rate was 18%, and the authors recommended caution in the use of this approach, particularly in conjunction with concurrent chemotherapy.²² In contrast, other authors have reported much lower rates of fistula formation with brachytherapy.²³ The length of esophagus being irradiated may not closely correlate with the incidence of esophagitis after radiotherapy.^24,25 However, the intensity of cancer treatment such as use of concurrent chemotherapy with radiation therapy increases the rate of acute esophagitis.²⁶ Maguire and colleagues evaluated 91 patients treated with radiation therapy for non–small cell lung cancer and found that the percent esophageal volume and surface area treated to greater than 50 Gy predicted late esophageal toxicity. Patients who had preexisting gastroesophageal reflux disease and esophageal erosions secondary to tumor were at increased risk for late toxicity. Hyperfractionation (multiple daily radiation treatments) was also associated with increased acute toxicity.²⁷ Singh and associates studied patients with non–small cell lung cancer who received conformal daily radiation therapy with or without concurrent chemotherapy; they found that a maximal esophageal “point” dose of 69 Gy (radiation therapy alone) and 58 Gy (with concurrent chemotherapy) predicted significant toxicity. Twenty-six percent of patients receiving concurrent chemoradiotherapy developed grade 3 or higher esophageal toxicity, whereas only 1.3% of patients who received radiation therapy alone experienced this degree of toxicity.²⁸ Ahn and colleagues found that the most powerful predictor of late esophageal toxicity in 254 patients treated for non–small cell lung cancer was the severity of acute esophageal toxicity. Severe acute toxicity was predicted by the use of twice daily radiation, older age, increasing nodal stage and a variety of dosimetric parameters. The overall incidence of late toxicity was 7%, with a median and maximal time to onset of 5 and 40 months, respectively.²⁹ The Radiation Therapy Oncology Group, using standard radiation therapy techniques, reported grade 3 or higher acute esophageal toxicity in 34% of patients treated with concurrent hyperfractionated radiation therapy and chemotherapy versus 1.3% of patients treated with standard thoracic radiotherapy alone.³⁰ Based on these and other data, it is clear that the addition of concurrent chemotherapy to radiation therapy increases the incidence of esophageal toxicity.

TREATMENT AND PREVENTION

The treatment and prevention of radiation-induced esophagitis have come under increased attention with the use of aggressive combination chemotherapy and radiation therapy regimens. The treatment of acute esophagitis is based on the grade of symptoms experienced by the patient. Treatment interruptions may ease the symptoms of acute esophagitis, but may also compromise the patient’s cancer treatment. Treatment interruption is reserved for severe cases. The management of acute esophagitis usually includes symptomatic management such as topical anesthetics (including viscous lidocaine-based regimens), oral analgesics (including anti-inflammatory agents and narcotics), gastric antisecretory drugs (histamine [H₂] blockers, proton pump inhibitors), promotility agents (such as metoclopramide), and treatment of superimposed infection (candidiasis). Dietary modification, including bland foods as well as pureed or soft foods and soups, can help patients maintain food and liquid intake. Other modifications include avoidance of smoking, alcohol, coffee, spicy or acidic foods or liquids, chips, crackers, fatty foods, and indigestible foods. A study of dietary modifications and pharmacologic prophylaxis for radiation-induced esophagitis reported decreased toxicity and fewer treatment interruptions. It was recommended to drink between meals and to eat six smaller meals per day, consisting of semisolid food, soup, high-calorie supplements, purees, puddings, milk, and soft breads.³¹ Additionally, ingestion of hot or cold foods should be avoided if possible; instead foods and liquids should be at room temperature. In severe cases, feeding tube placement may be required.

Radioprotective chemical agents have been investigated as a means of mitigating radiation-induced normal tissue toxicity. The best-studied of these is amifostine, an organic thiophosphate. This agent is a scavenger of free radicals and serves as an alternative target to nucleic acids for alkylating or platinum agents.³² In one trial, patients treated with chemotherapy and radiation therapy for non–small cell lung cancer were randomized to receive amifostine or no drug. Amifostine did not significantly reduce grade 3 or higher esophagitis in these patients. However, patient self-assessments suggested a significantly lower incidence of acute esophagitis in those who received amifostine.³³ Other trials have demonstrated a protective effect,^34,35 whereas others have not confirmed this.³⁶ Larger, randomized and placebo-controlled trials are needed to determine the ultimate efficacy of amifostine in preventing radiation injury of the esophagus.

The management of late esophageal radiation stricture consists of endoscopic dilatation (often serially), usually resulting in symptomatic improvement. Additionally, long-term use of gastric antisecretory drugs as well as prokinetic agents such as metoclopramide have been recommended to decrease gastroesophageal (GE) reflux effects. Dilatations in advanced stricture can cause esophageal rupture and therefore their use should be approached cautiously. Uncommonly, tube feedings may be required for patients with significant weight loss or for those only able to take in liquids. Surgical intervention may be required for patients who develop perforation or fistula.

Finally, it is important to note that the clinical symptoms associated with late radiation injury are often difficult to distinguish from those caused by recurrent (or new) cancer. Therefore, patients with strictures or ulcerations should also be evaluated to differentiate chronic radiation changes from cancer recurrence.

INCIDENCE AND CLINICAL FEATURES

The stomach may be damaged following irradiation of the upper abdomen for cancer, including esophageal-GE junctional, gastric, and pancreatic carcinomas. Radiation to the stomach in animals using a very high single dose of irradiation results in erosive and ulcerative gastritis. A slightly lower single dose (23 Gy) results in gastric dilatation and gastroparesis, with replacement of the normal gastric mucosa by hyperkeratinized squamous epithelium. With even lower doses, gastric obstruction occurring months after irradiation was observed, with an atrophic gastric mucosa and intestinal metaplasia seen in surviving animals.³⁷

Studies in which serial gastric biopsies were obtained following irradiation of patients for peptic ulcer disease noted coagulation necrosis of chief and parietal cells with mucosal thinning, edema, and chronic inflammatory infiltration.^17,38 In addition, gastric acid production decreased after relatively low doses of gastric irradiation. In the past, radiotherapy had been used to decrease acid production in patients with peptic ulcer disease. Even with a relatively low dose of 18 Gy delivered in 10 fractions, approximately 40% of ulcer patients had a 50% reduction in gastric acid secretion that lasted for a year or more.³⁹

Clinically, radiation-induced gastritis may occur within a week of starting radiotherapy, with microscopic changes including edema, hemorrhage, and exudation. Histologic changes may also include disappearance of cytoplasmic details and granules in parietal and chief cells as early as one week into therapy. Cell damage and subsequent cell death are often seen first in the depths of glands, followed by thinning of the gastric mucosa.⁴⁰ Additional mucosal changes include deepening of the glandular pits and proliferation of cells in the glandular neck. Loss of glandular architecture and thickening of the mucosa can be seen by the third week of radiotherapy. Approximately three weeks after completing radiotherapy, histologic recovery may be seen. Signs of recovery of early radiation injury to the stomach include re-epithelialization and fibrosis.

Symptoms of acute radiation injury of the stomach consist primarily of nausea and vomiting, dyspepsia, anorexia, abdominal pain, and malaise. These are more common with the concurrent administration of chemotherapy. Radiation-induced nausea and vomiting may occur within the first 24 hours following treatment. It is estimated that approximately half of patients receiving upper abdominal radiation will experience emesis within two to three weeks following initiation of irradiation.⁴¹

Late effects of gastric irradiation have been classified into four categories: (1) acute ulceration (occurring shortly after completion of radiation therapy); (2) gastritis with smoothened mucosal folds and mucosal atrophy on endoscopy accompanied by radiographic evidence of antral stenosis (1 to 12 months following irradiation) (see Chapter 51); (3) dyspepsia, consisting of vague gastric symptoms without obvious clinical correlate (6 months to four years following irradiation); and (4) late ulceration (averaging 5 months after irradiation).^17,42 The TD_5/5 for treatment of the entire stomach has been estimated to be 50 Gy. Large studies of upper abdominal irradiation have suggested that prior abdominal surgery as well as using a higher radiation dose per fraction of radiation may increase the risk of late effects.⁴³ Studies from Walter Reed Army Medical Center delivering abdominal radiation using now antiquated techniques in testicular cancer patients have suggested that higher radiation doses lead to an increasing risk of late ulceration and perforation, with ulceration occurring in approximately 6% of patients treated to 45 to 50 Gy, 10% of patients treated to 50 to 60 Gy, and 38% of patients treated to greater than 60 Gy. No ulceration was seen in patients receiving less than 45 Gy. In this series, symptomatic gastritis occurred approximately 2 months following radiation completion, with ulcer formation occurring at a median of 5 months. Six of 233 patients (3%) required surgery for ulcer hemorrhage or pain related to ulcer disease, almost all of whom had received doses of greater than 50 Gy.^17,45 Other studies of patients treated with radiation therapy for Hodgkin’s lymphoma or for testicular, gastric, or cervical cancer have established tolerance limits for gastric irradiation.^43–46 These studies delivered doses of 40 to 60 Gy. Patients who received doses greater than 50 Gy experienced gastric ulceration and gastric ulcer–associated perforation at rates of 15% and 10%, respectively. If indicated, the dose to the entire stomach with conventionally administered radiation therapy is limited to 45 to 50 Gy, with an estimated 5% to 10% risk of severe radiation toxicity. Where appropriate, reduced field boosts can be given to treat to doses up to 55 Gy with acceptable toxicity.

As in the esophagus, combining chemotherapy with radiation therapy decreases the tolerance of the gastric mucosa to radiation therapy. 5-Fluorouracil (5-FU) is the most common chemotherapy agent delivered concurrently with radiation therapy in the management of gastrointestinal tumors. This agent can be given in an adjuvant or neoadjuvant setting or as “definitive” therapy for gastroesophageal junction, gastric, pancreatic and biliary cancers. 5-FU is a radiation sensitizer, but has historically been given safely with radiation therapy at doses of 45 to 50 Gy without substantial increases in toxicity. Newer systemic agents have been shown to increase acute gastric toxicity when delivered with radiotherapy, including taxanes, gemcitabine, and epidermal growth factor inhibitors. These regimens remain the subject of investigation in the treatment of abdominal malignancies.

TREATMENT AND PREVENTION

Acute symptoms of gastric radiation in toxicity are treated with antiemetics (5-hydroxytryptamine-3 [5-HT₃] antagonists, phenothiazines, metoclopramide, glucocorticoids, benzodiazepines, antihistamines, or anticholinergics), as well as consumption of a light meal prior to delivery of radiation therapy. Randomized trials of prophylactic 5-HT₃ inhibitors have shown efficacy compared with placebo in preventing radiation-induced nausea and vomiting.⁴⁷ A randomized trial of 211 patients receiving upper abdominal radiation compared the 5-HT₃ inhibitor ondansetron given twice daily, with or without dexamethasone delivered daily for the first five fractions of treatment. Patients receiving dexamethasone showed a trend toward improved complete control of nausea (50% versus 38%) and significant improvement in complete control over emesis. The authors concluded that the addition of dexamethasone resulted in modest improvement in protection against radiation-induced emesis.⁴⁸ Narcotic and non-narcotic agents are often used for pain. Additionally, it is generally recommended that patients be placed on antacid medications, including proton pump inhibitors. Careful nutritional support along with antiemetic therapy is essential for patients undergoing radiotherapy to the abdomen. Acute symptoms generally resolve within one to two weeks following completion of radiation therapy.

Late gastritis-related symptoms are often treated with antacids (H₂ antagonists, proton pump inhibitors, sucralfate, and so on). These may be used on a long-term basis to avoid late ulceration. With more severe complications of bleeding, ulceration, gastric outlet obstruction, fistula formation, or perforation, patients may require endoscopic therapeutic approaches or rarely surgical intervention with partial gastrectomy.

INCIDENCE AND CLINICAL FEATURES

The epithelium of the gastrointestinal tract has a high proliferative rate, making it susceptible to radiation- and chemotherapy-induced mucositis. The intestinal lining is normally replaced every three to five days, reflecting this high cellular turnover rate. Irradiation of intestinal mucosa primarily affects the clonogenic intestinal stem cells within the crypts of Lieberkühn (cells that provide, via self-replication and eventual maturation, replacement cells in the intestinal villi). Stem cell damage, either as a primary result of radiation damage or as a result of radiation-induced microvascular damage, leads to a decrease in cellular reserves for the intestinal villi, resulting in mucosal denudement, shortened villi, and decreased absorptive area, with associated intestinal inflammation and edema. Histologic changes are seen within hours of irradiation. Within two to four weeks, an infiltration of leukocytes with crypt abscess (microabscess) formation can be seen (Fig. 39-2). Ulceration may also occur. This acute injury can result in impaired absorption of fats, carbohydrates, proteins, bile salts, and vitamin B₁₂, with associated loss of water, electrolytes, and protein. Additionally, impaired ileal bile salt absorption increases loads of conjugated bile salts entering the colon, which are in turn deconjugated by colonic bacteria, resulting in intraluminal water retention with resultant diarrhea. Furthermore, impaired digestion of lactose may occur following radiation, leading to increased bacterial fermentation with associated flatulence, distention, and diarrhea, possibly accompanied by bacterial overgrowth. There is also evidence of acutely altered gut motility following radiation therapy.⁵⁰

Figure 39-2. Microabscesses and radiation-related fibroblasts. Submucosal reaction shows large, bizarre radiation fibroblasts that have both cytomegaly and nucleomegaly. Smooth muscle cells also have reactive changes. Microabscesses composed of excess neutrophils infiltrate the stroma. (Hematoxylin and eosin, ×400.)

(Courtesy Dr. Robin Amirkahn, Dallas, Tex.)

Patients with acute radiation enteritis experience diarrhea, abdominal cramping or pain, nausea and vomiting, anorexia, and malaise. Radiation-induced diarrhea often appears during the third week of a fractionated radiation course, with reported rates of 20% to 70%.⁵¹ Acute radiation enteropathy with diarrhea may be seen in some patients after delivery of doses of 18 to 22 Gy using conventional fractionation, and in most patients receiving doses of 40 Gy. The symptoms and pathologic findings typically subside and spontaneously disappear two to six weeks following completion of radiation therapy.⁵² However, growing evidence suggests that patients who develop acute small intestine toxicity may be at higher risk for chronic effects.⁵³

Histologic changes of chronic toxicity to the small intestine include progressive occlusive vasculopathy with foam cell invasion of the intima and hyaline thickening of the arteriolar walls, as well as collagen deposition and fibrosis, often in the submucosal layer of the bowel wall. The small bowel becomes thickened with development of telangiectasias, whereas the vessel walls of small arterioles are obliterated, causing ischemia (Fig. 39-3).⁵⁴ As the vasculopathy progresses, mucosal ulceration, necrosis, and occasionally perforation of the intestinal wall can be seen, resulting in fistula and abscess formation. Lymphatic damage results in constriction of the lymphatic channels, which contributes to mucosal edema and inflammation.⁵⁵ Histologically, the mucosa atrophies, with atypical hyperplastic glands and intestinal wall fibrosis (Fig. 39-4).¹⁵ As the ulcers heal, there can be fibrosis with narrowing of the intestinal lumen with subsequent stricture formation and even obstruction with dilatation of the proximal bowel. Bacterial overgrowth may be an indirect complication arising from stasis in a dilated loop of bowel proximal to the stricture. Although the affected segments of intestine and serosa appear thickened with areas of telangiectasias,⁵⁶ it should be noted that even if the gut appears normal, patients can still be at risk of spontaneous perforation.⁵⁷

Figure 39-3. Submucosal arteriole in chronic radiation enteropathy. Radiation-induced changes include thickening of vessel walls and subintimal hydropic change and fibrosis. Vessel wall thickening results in luminal narrowing/occlusion and subsequent tissue ischemia. (Hematoxylin and eosin, ×200.)

(Courtesy Dr. Robin Amirkahn, Dallas, Tex.)

Figure 39-4. Small intestinal submucosal fibrosis following radiation therapy. The patient presented with small intestinal obstruction due to this stricture. (Hematoxylin and eosin, ×40.)

(Courtesy Dr. Robin Amirkahn, Dallas, Tex.)

Chronic radiation enteritis can cause significant morbidity. This complication tends to be progressive, with an onset at least 6 months after radiotherapy. Late radiation injury to the small intestine occurs at a median of 8 to 12 months following radiation therapy, though it can appear years later.¹⁷ There are numerous clinical manifestations of the chronic phase of radiation enteritis (Table 39-1). These include malabsorption and diarrhea, with more rapid transit times occurring in the affected bowel. Rarely, chronic malnutrition may develop, resulting in anemia and hypoalbuminemia. There can be bleeding from ulceration and pain and bloating from strictures, as well as fevers from abscess. Fibrosis and vasculitis of the bowel may lead to dysmotility, stricture, and malabsorption.^58,59 Malabsorption and other complications may require surgical intervention and parenteral alimentation (discussed in Chapters 4 and 5 and following). Patients with severe chronic radiation enteritis have a poor long-term prognosis with a mortality rate of approximately 10%.^60–66 The overall incidence of chronic radiation enteritis has not been precisely defined. Retrospective series suggest an incidence of 5% to 15%; however, these studies often include a large number of patients who were lost to follow-up or died between the end of radiation therapy and the completion of the study. A review of randomized trials of adjuvant radiation therapy for rectal cancer shows severe long-term complications as low as 1.2% and as high as 15%.⁶⁷ In older series of radiotherapy for abdominal cancers, symptoms of chronic bowel dysfunction were present in many patients, although such symptoms are often multifactorial and influenced by other treatment modalities including surgery and chemotherapy.^68,69 However, it appears that advances in radiation therapy treatment techniques have reduced chronic small intestinal toxicity rates.

Table 39-1 Clinical Complications of Chronic Radiation Enteritis or Proctitis*

* From Girvent M, Carlson GL, Anderson I, et al: Intestinal failure after surgery for complicated radiation enteritis. Ann R Coll Surg Engl 2000; 82:198.

Certain factors have been found to predispose patients to radiation toxicity to the small intestine. Women, older patients, and thin patients may have a larger amount of small bowel in the pelvic cul-de-sac, which can increase the probability of radiation injury in the treatment of pelvic malignancies.⁷⁰ Patients with a history of pelvic inflammatory disease or endometriosis also appear to be at higher risk of radiation complications.^71,72 Patients who have had previous abdominal surgery can develop adhesions that decrease the mobility of the small bowel, thereby allowing it to be consistently exposed to fractionated radiation therapy.^73,74 In addition, patients with prior pelvic surgery may have an increase in the amount of small bowel within the pelvis, allowing increased exposure during pelvic irradiation. In a series published by Eifel and associates, the risk of small bowel complications was significantly higher in women who had undergone a previous laparotomy.⁷⁵ With modern treatment approaches (allowing direct visualization of the volume of bowel in treatment field) and use of improved treatment techniques (discussed later), as well as a shift toward neoadjuvant approaches, this risk factor may not be as relevant as in prior years. Patients with diabetes, hypertension, and cardiovascular disease also have an increased risk of pre-existing vascular damage or occlusion.⁷⁶ These comorbid conditions are compounded by the pathologic changes of chronic radiation injury, which include vasculopathy and ischemia, predisposing these patients to radiation-related small bowel toxicity. Patients with collagen vascular disease and inflammatory bowel disease also have a higher risk of acute as well as chronic radiation-induced injury. Patients with these diseases may have pathologic changes which include transmural fibrosis, collagen deposition, and inflammatory infiltration of the mucosa. The late effects induced by radiation therapy to the small bowel are likely additive to these preexisting changes, and studies have shown that these patients have a lower gastrointestinal tolerance to radiation therapy.^77–79 Patients whose inflammatory bowel disease or nonmalignant systemic disease is quiescent or well controlled appear to fare better than patients with active disease.

Studies have also addressed the effect of radiation dose on occurrence of small bowel toxicity. Volume of the treatment field, volume of irradiated small bowel, total radiation dose, fraction size, treatment time, and treatment technique all influence small bowel tolerance. The TD_5/5 for small volumes of small bowel has been estimated to be 50 Gy. Patients can generally receive 45 to 50 Gy in 1.8 to 2 Gy daily fractions to a pelvic field without a significant rate of toxicity.⁸⁰ For postoperative patients, radiation to 45 to 50 Gy in five weeks is associated with an approximate 5% incidence of small bowel obstruction requiring surgery, whereas at doses greater than 50 Gy, the incidence rises to as high as 25% to 50%.⁷⁰ Doses greater than 2 Gy per fraction in the postoperative setting also increase the risk of toxicity.⁸¹ At radiation doses of 70 Gy or greater, the incidence of toxicity rises precipitously.⁸² A study of different treatment techniques to minimize the effect of pelvic radiation on the small bowel showed that irradiating smaller volumes of bowel yielded less toxicity.⁸³ In addition, treating patients in the prone position with external compression and bladder distention decreased side effects, likely from exclusion of portions of the small bowel from the radiation field. Another study treating postoperative patients with pelvic radiation therapy noted less small bowel toxicity by placing patients in the decubitus position.⁸⁴ Studies have also analyzed dose-volume parameters associated with acute small bowel toxicity in patients undergoing treatment with 5-FU–based chemoradiation therapy for rectal cancer.^85,86 These found strong correlations between acute toxicity and the amount of small bowel irradiated at each dose level analyzed. Another analysis evaluating rectal cancer patients treated preoperatively with chemoradiotherapy also showed a strong correlation between the occurrence of severe diarrhea and irradiated small bowel volume, surmising that limiting the volume of small bowel receiving greater than 15 Gy may significantly improve treatment tolerance.⁸⁷ These and other studies imply that attention to detail in radiation planning with the use of modern treatment techniques are important considerations in patient treatment.

The combination of radiation and chemotherapy (e.g., 5-FU) increases the risk of small bowel toxicity. In a randomized trial delivering 40 to 48 Gy using parallel, opposed fields to patients with rectal cancer, the incidence of severe small bowel complications was significantly higher in patients who received chemotherapy and radiation therapy than in patients who received radiation therapy alone. There were two treatment-related deaths (4%) in the combination therapy arm.^88,89 In other trials in which multiple field radiation techniques were used, bolus 5-FU and radiation therapy showed no increase in chronic toxicity when chemotherapy and radiation therapy were combined. There was, however, a mild increase in acute diarrhea symptoms.^83,90 The use of continuous infusional 5-FU as opposed to bolus 5-FU combined with radiation therapy also has been studied. Continuous 5-FU with radiation to 50.4 Gy in 1.8-Gy fractions was associated with more acute diarrhea, but no significant increase in chronic or severe small bowel toxicity as compared with bolus 5-FU therapy.⁹¹ Capecitabine, a prodrug that is converted to 5-FU in the tumor, also appears to enhance acute diarrhea rates when combined with radiation therapy.⁹² Although the addition of concurrent chemotherapy increases the acute toxicity of external radiotherapy (e.g., diarrhea, bowel frequency, cramping), its contribution to late bowel toxicity is poorly defined.¹⁷

There is investigation in integration of novel chemotherapeutic and “targeted” agents with radiation therapy in the neoadjuvant therapy of gastrointestinal cancers. Data from phase I and phase II trials using novel agents such as oxaliplatin, irinotecan, and epidermal growth factor receptor inhibitors suggest that the addition of these agents may significantly increase grades 3 and 4 gastrointestinal toxicity rates relative to conventional neoadjuvant chemoradiotherapy regimens, further emphasizing the importance of careful radiation planning to maximize normal tissue sparing in these patients.^93–95

Diagnosis of chronic enteropathy is often a clinical one. The cause of symptoms can be variable from patient to patient. Therefore, individualization of diagnostic and therapeutic approaches is indicated. General diagnostic evaluation procedures and therapeutic options are displayed in Tables 39-2 and 39-3. Consultation with the treating radiation oncologist should be requested if the clinical presentation is consistent with radiation enteritis. Review of the patient’s previous radiation treatment record will reveal the total dose, fractionation, volume of treatment, and other radiation parameters. Analysis of the treatment plan may show areas of high dose, especially if the patient had an intracavitary implant or brachytherapy. Lesions encountered at endoscopy or x-ray studies are usually localized in the area of high dose. Ulceration of the mucosa, thickening of jejunal folds, and thickening of the intestinal loops are radiologic signs that suggest radiation damage to the small bowel (Fig. 39-5). Faster intestinal transit and reduced bile acid and lactose absorption are observed in patients with chronic radiation enteritis.⁹⁶ These effects may be improved after the administration of loperamide. Antibiotics are indicated if there is small bowel bacterial overgrowth syndrome (see Chapter 102).^97,98

Table 39-2 Pathophysiologic Features of Patients with Late Radiation Enteropathy

From Hauer-Jensen M, Wang J, Denham J. Bowel injury: Current and evolving management strategies. Semin Radiat Oncol 2003; 13:357-371.

Table 39-3 Therapeutic Options for Patients with Late Radiation Enteropathy

From Hauer-Jensen M, Wang J, Denham J. Bowel injury: Current and evolving management strategies. Semin Radiat Oncol 2003; 13:357-371.

Figure 39-5. Radiographic evidence of radiation injury of the intestine. A, In early injury, edema may cause separation of intestinal loops, lead to thickening and straightening of mucosal folds, and impart a spiked appearance (arrows) to the small bowel mucosa. B, Severe radiologic abnormalities of the rectosigmoid colon are evident when this barium enema examination was performed 2 months after the patient underwent radiation therapy for cervical carcinoma. Subacute radiation injury of the colon may present radiologically as edematous, occasionally ulcerated mucosa, with asymmetrical areas of narrowing suggestive of Crohn’s colitis or recurrent tumor (arrows). C, Late radiation change in the colon with stricture formation (arrow) after a cumulative dose of approximately 55 Gy (5500 cGy).

TREATMENT AND PREVENTION

The management of acute radiation small bowel toxicity should be based on the severity of symptoms. Most cases of acute radiation enteritis are self-limited, requiring only supportive treatment. Diarrhea, nausea, vomiting, and abdominal cramping are treated symptomatically. Antidiarrhea medications such as loperamide, diphenoxylate with atropine, anticholinergic agents, and opiates can be used. Antiemetic agents may also be effective. A low-fat, lactose-free diet also may improve symptoms. A study of oral sulcralfate in patients receiving pelvic irradiation showed a decrease in frequency and improvement in consistency of bowel movements. In this study, not only were acute symptoms improved, but also chronic symptoms a year after completion of radiation seemed to be improved.⁹⁹ Cholestyramine to treat diarrhea from bile acid malabsorption has shown some benefit,¹⁰⁰ and treatment with anti-inflammatory agents has decreased some symptoms.¹⁰¹ Intractable diarrhea during the combined-modality treatment may require hospital admission for administration of parenteral fluids and electrolytes. Patients who are refractory to conventional antidiarrhea medications may benefit from administration of a synthetic somatostatin analog such as octreotide.

The management of chronic radiation enteritis remains a major challenge because of the progressive evolution of the pathophysiology, including obstructive endarteritis and fibrosis. In addition, there is variation in clinical manifestations of patients with chronic radiation enteropathy. The treatment should be as conservative as possible because of the diffuse nature of the process and the high morbidity associated with surgery. However, surgical intervention is indicated in intestinal obstruction, perforation, fistulas, and severe bleeding (discussed following).

Chronic effects of diarrhea are managed symptomatically with low-residue diet. Fiber supplementation (e.g., Metamucil, Citrucel) has shown benefit in some cases. In the rare setting of malnutrition related to chronic radiation injury, total parenteral nutrition (TPN) can improve clinical outcome, and methylprednisolone may add to the effects of TPN.⁷² However, the five-year survival rate for patients undergoing TPN ranges from 36% to 54%.^62,102 It has been estimated that overall mortality rates associated with chronic radiation enteropathy are approximately 10%.¹⁰³

Endoscopic techniques are sometimes required for diagnosis of bleeding small intestinal ulcers. Newer endoscopic techniques, including double-balloon enteroscopy and capsule endoscopy may help facilitate this diagnosis. Additionally, the double-balloon enteroscope method may allow therapeutic intervention in certain situations, including coagulation of small bowel telangiectasias. Significant bleeding refractory to endoscopic intervention may be managed surgically.

Small bowel obstruction is generally managed conservatively with bowel rest and tube decompression. If the obstruction is severe or chronic, bowel resection or lysis of adhesions may be required, although the need for surgery is relatively uncommon. It is difficult to perform surgery for chronic radiation enteritis because of the diffuse fibrosis and alterations in the intestine and mesentery. The risk of anastomotic leak is high if the anastomosis is performed using irradiated bowel.¹⁰³ The risk of leak can be lowered if at least one limb of the anastomosis is previously unirradiated.¹⁰⁴ However, it may be difficult to distinguish between the area of normal tissue and the irradiated portion of the intestines by gross examination during surgery, even when the fresh tissue is sent for frozen section. Another method the surgeon can use to circumvent this technical difficulty is to create the anastomosis with unirradiated colon. The accuracy in localizing injured bowel may be improved by intraoperative endoscopic examination, which can detect radiation-induced mucosal injury.¹⁰⁵

Limited resection of the diseased intestine is the goal, but if the lesion is too diffuse, a bypass procedure may be attempted. If feasible, resection of the affected bowel results in a superior outcome than an enteric bypass procedure. However, extensive surgical resection of the diseased intestines may lead to short bowel syndrome (see Chapter 103) and increase the need for total parenteral nutrition. Because of the progressive evolution of the fibrosis, the patient may require additional surgery. Surgical bypass of the injured bowel may be associated with a blind loop syndrome, and the patient still may be at risk for perforation, bleeding, abscess, and fistulas due to the persistence of the affected bowel. Bypass procedures should be performed when resection is not possible or as a temporary management before resection at a later date. Surgery should be performed by an experienced team familiar with the management of radiation enteritis. Perforations and fistulae are best managed surgically. It should be noted that many patients with chronic small bowel radiation toxicity are nutritionally depleted and are more susceptible to anastomotic leakage and dehiscence after surgery. The postoperative mortality of these patients may be significant and must be taken into consideration before a decision to proceed with surgery is made.

A recent approach to treatment of chronic radiation enteritis is the application of hyperbaric oxygen.^106,107 The rationale for hyperbaric oxygen is the creation of an oxygen gradient in hypoxic tissue that stimulates the formation of new blood vessels. Neoangiogenesis improves the blood supply and decreases the ischemia and necrosis responsible for severe complications. In a retrospective study of 36 patients with severe radiation enteritis refractory to medical management, improvement of clinical symptoms was reported in two thirds of the patients treated with hyperbaric oxygen.¹⁰⁸ Hyperbaric oxygen may be helpful in management of bleeding due to chronic radiation enteritis in patients who are not controlled with conservative measures such as formalin and laser therapy.^109,110 A large clinical series of 65 consecutive patients with chronic radiation enteritis (rectal and small bowel), primarily manifested as chronic bleeding, were treated with hyperbaric oxygen. Response rates for rectal and more proximal sites were 65% and 73%. The response rate for bleeding was 70% and for other symptoms (pain, diarrhea, weight loss, fistula, and obstruction) was 58%. The authors concluded that hyperbaric oxygen therapy resulted in healing or clinically significant improvement in two thirds of patients with chronic radiation enteritis.¹¹¹ The optimal application of hyperbaric oxygen treatments in chronic enteritis remains a topic of ongoing investigation.

Because chronic radiation enteritis is complex and rarely curable, prevention is key and measures to decrease its incidence are imperative. Pancreatic enzymes can exacerbate acute intestinal radiation toxicity,¹¹³ and reducing pancreatic secretion with a synthetic somatostatin receptor analog such as octreotide may reduce early and delayed radiation enteritis in animal studies.¹¹⁴ One of the major risk factors for injury is previous abdominopelvic surgery, which leads to the prolapse of the small intestines into the pelvis, exposing them to more radiation. Anticipation for the need of radiation and chemotherapy before or after surgery requires close collaboration among surgical, radiation, and medical oncologists. If gross residual tumor is found unexpectedly at surgery, outlining the tumor bed with surgical clips to facilitate postoperative treatment planning and surgical techniques to keep the small intestine outside the pelvis (e.g., omentoplasty or polyglycolic mesh) may significantly decrease the rate of complications (see following).

Postoperative bowel adhesions may also increase the volume of bowel irradiated compared with normal small intestine, which is usually mobile and can move out of the radiation field. If radiation therapy is anticipated after surgery, attempts should be made at the time of surgery to displace the bowel outside the radiation field.¹¹⁵ One simple technique is the surgical placement of a polyglycolic, biodegradable mesh that moves the intestines out of the pelvis.^116,117 This procedure has minimal morbidity and it does not significantly increase operating time. It also does not require a second operation to remove the mesh because it is absorbed three to four months after surgery. Magnetic resonance imaging (MRI) can be used after surgery to verify the position of the mesh, the small bowel, and eventual disappearance of the mesh. A reduction of 50% of the volume of the small bowel exposed to the radiation has been demonstrated with placement of a mesh during surgery, allowing a higher dose of radiation to be given postoperatively where indicated.^118,119 Other techniques such as pelvic reconstruction, omentoplasty, and transposition of the colon may also significantly decrease the volume of bowel exposed to radiation therapy.^119–122

Radiation therapy technique is critical in reducing the rate of complications. The use of only anterior and posterior fields for pelvic radiation should be avoided if possible because of the high dose and large volume of bowel irradiated. A higher rate of operative mortality was reported in trials using this technique preoperatively for rectal cancers.^123,124 As discussed, the toxicity of radiation therapy correlates with the volume of small bowel irradiated.¹²⁵ In many patients, treatment in the prone position with a special “belly board” allows the displacement of the small intestines out of the radiation field.^126,127 Patients should be instructed to maintain a full bladder during the radiation session, which further displaces the intestines out of the pelvis.⁷⁴ Three-dimensional treatment planning optimizes the treatment technique by facilitating more accurate dose distributions. A three-dimensional treatment algorithm ensures the sparing of excessive radiation dose to normal tissues by the judicious use of multiple fields to the target volume from multiple geometries.¹²⁸ In gynecologic brachytherapy, appropriate packing to displace the rectum and bladder away from the radioactive sources will decrease the risk of complications. In addition, newer treatment techniques such as intensity-modulated radiotherapy (IMRT) use sophisticated planning techniques to avoid critical structures (discussed following). Preventive therapeutic strategies also include investigation of antioxidants, free-radical scavengers and other cytoprotectant agents, cytokine modification, enterotrophic (growth-promoting) strategies, novel anti-inflammatory agents, modulators of intraluminal contents, modulators of endothelial dysfunction, as well neuroimmunomodulators to prevent this complication.¹⁰³

Treatment of radiation enteritis is often only partially successful. Management is patient specific and should be as conservative as possible because of the relentless progression of the disease. Further understanding of the mechanism of fibrosis and the interaction of the molecular events controlling apoptosis and fibrosis may assist in the identification of the patient at risk for radiation complications and in the development of new therapeutic approaches. Careful radiation planning is critical in preventing acute and chronic radiation enteritis.

INCIDENCE AND CLINICAL FEATURES

Acute and chronic injury of the large intestine is similar to injury of the small intestine just discussed. Acutely, there is a decrease in the stem cell mitotic rate, resulting in a depletion of precursor cells required to replenish the epithelium as it normally sheds. Acute injury can be accompanied by superficial mucosal erosions and lamina proprial hemorrhage. There is also a thickening of the mucosa with proliferation of fibroblasts (Fig. 39-6).¹²⁹ Late changes include vascular fibrosis with associated ischemia and formation of telangiectasias which can be a source of bleeding (Fig. 39-7). Late radiation bowel changes can lead to fluid and electrolyte malabsorption, obstruction, chronic proctitis, and fistula formation. Ischemic changes also include ulceration (Fig. 39-8), perforation, and fistulae.⁵⁶ Bowel wall fibrosis may also occur, causing decreased motility, stricture and compliance.¹³⁰ A decrease in rectal compliance may reduce the ability of the rectum to act as a reservoir, leading to fecal frequency, urgency, and incontinence.

Figure 39-6. Acute radiation injury to the rectum. Rectal mucosa with superficial mucosal erosion and focal lamina propria hemorrhage are seen. (Hematoxylin and eosin, ×100.)

(Courtesy Dr. Robin Amirkahn, Dallas, Tex.)

Figure 39-7. Typical findings of radiation colitis in a patient treated for prostate cancer. Top panels: Endoscopic view of the rectum reveals the characteristic fine tortuosity and curling of the new vessels. Lower panels: These demonstrate superficial burns from argon plasma coagulation, which was used to stop this patient’s bleeding. It is not necessary to ablate the lesions completely, but merely to cause mucosal and submucosal fibrosis, thereby entrapping the vessels in the scarring process.

(Courtesy of Lawrence J. Brandt, MD, Bronx, New York.)

Figure 39-8. Rectal mucosa after radiotherapy. Residual but malformed rectal crypts and flat, regenerating surface mucosa in the region of a radiation-induced rectal ulcer are seen. Note fibrosis and inflammation of the lamina propria. (Hematoxylin and eosin, ×100.)

(Courtesy Dr. Robin Amirkahn, Dallas, Tex.)

Acute colitis from radiation therapy manifests clinically as diarrhea, cramping, tenesmus, urgency, incontinence, and less commonly as mucoid or bloody rectal discharge. These symptoms can result from rectal inflammation, edema, and spasm. Symptoms often begin two to three weeks into treatment, and usually resolve within several weeks to three months following radiation completion. A relationship between the incidence of acute and chronic radiation injury is uncertain.^131,132 Chronic changes appear within six months to two years and beyond following completion of radiation therapy, with symptoms similar to acute injury. Patients may present with tenesmus, bleeding, low-volume diarrhea, rectal pain, and occasionally low-grade obstruction or fistulae.¹³³ Patients can develop a pancolitis that mimics inflammatory bowel disease. It should be remembered that pelvic irradiation is a risk factor for development of rectal cancer.¹³⁴

The large intestine is less radiosensitive than the small intestine. This may be partially explained by the fact that higher doses of radiation are often delivered to smaller volumes of the rectum compared with small intestine (i.e., focal “collateral” rectal irradiation in prostate cancer therapy, focal collateral rectal irradiation in high-dose gynecologic malignancy implants, and so on). The rectum is also a readily accessible organ by endoscopy, allowing early diagnosis as well as intervention, possibly preventing symptomatic progression. Series have reported the risk of serious late rectal complications is 5% or less when less than 80 Gy is delivered.¹⁷ Radiation injury of the large intestine occurs most frequently in the rectum due to its location adjacent to the prostate, bladder, cervix, uterus, and ovaries, exposing it to collateral radiation dose with treatment of these organs.¹⁵ Acute rectal injury is often self-limited, but the incidence of chronic radiation proctitis is increasing with increased use of pelvic radiation therapy and radiation dose escalation.^135,136

As is true with the other sites, the incidence of large bowel toxicity is associated with radiation dose, volumes treated, and the use of concurrent chemotherapy. In an early study of radiation therapy for testicular cancer, radiation injury to the colon occurred in 18% of patients after 45 Gy and in 37% of patients after 60 to 64 Gy.¹³⁷ The treatment of rectal cancer commonly uses doses of 45 to 54 Gy, whereas treatment of prostate and cervical cancer uses higher doses, ranging from 60 to 80 Gy. The incidence of severe rectosigmoid toxicity in cervical cancer patients was 4% or less for patients receiving doses below 80 Gy, and 13% for doses greater than 95 Gy.¹³⁸ The treatment of prostate cancer with doses of 60 to 70 Gy has been associated with an incidence of severe proctitis below 8%.¹³⁹ Radiation doses of 60 to 70 Gy for anal cancer yield an incidence of severe rectal toxicity of 5% or less.^140–142 Treatment using conformal radiation, three-field, and four-field techniques further decreases the risk of rectal toxicity.^138,143 A trial of conformal versus conventional radiation for prostate cancer reported less radiation proctitis (5% versus 15%, respectively).¹⁴⁴ The use of IMRT (discussed later) may further improve this rate, as demonstrated by a recent series treating of prostate cancer patients to doses greater than 80 Gy. Of 772 patients, 4.5% developed acute grade 2 rectal symptoms and no patient developed acute grade 3 or above rectal symptoms. Eleven patients (1.5%) developed late grade 2 rectal bleeding and four patients (0.1%) experienced late grade 3 rectal toxicity requiring either transfusion or laser cauterization. No late grade 4 rectal complications were observed.¹⁴⁵

Combining chemotherapy with radiation therapy increases toxicity rates. A study of 5-FU plus cisplatin and radiation therapy for cervical cancer showed a combined incidence of severe small and large bowel toxicity of 18%.¹⁴⁶ In contrast, a combination of 5-FU and mitomycin C with radiation doses of 40 to 55 Gy in the treatment of anal cancer was associated with a less than 5% risk of severe rectal complications.¹⁴⁷ Multiple trials have combined 5-FU–based chemotherapy and radiation therapy as neoadjuvant and adjuvant treatment for rectal cancer.^{88,91,148,149} The toxic effect of combined chemotherapy and radiation has varied, from no significant increase in toxicity to a 24% incidence of severe diarrhea and a 25% incidence of chronic bowel injury.¹⁵⁰ Because of the increase in toxicity seen with single or opposed-only radiation fields, the use of conformal and multifield techniques is necessary when using combination therapy. The increasing use of neoadjuvant chemoradiotherapy has also raised the concern of increased postoperative complications in these patients. However, a large randomized trial showed a significant reduction in the rates of acute and chronic gastrointestinal toxicity in patients treated neoadjuvantly versus patients treated adjuvantly.¹⁴⁹

In contrast to small bowel injury, previous abdominopelvic surgery does not appear to predispose the rectum to radiation injury, likely due to the fact it is not otherwise mobile. However, because of the similarity of vascular changes seen with small bowel radiation injury, a history of diabetes, hypertension, cardiovascular disease, or peripheral vascular disease may predispose large bowel to radiation toxicity.^76–79 Patients with collagen vascular disease and inflammatory bowel disease also have an increased propensity for large bowel radiation toxicity (as discussed in the section on small bowel toxicity).

TREATMENT AND PREVENTION

Management of large bowel radiation toxicity is based on symptom control. Acute toxicity is treated with antimotility agents, such as loperamide or diphenoxylate with atropine, and a low-residue diet. Opiates and anticholinergics may also be of benefit. Glucocorticoid-containing suppositories may be helpful in the management of patients with anorectal inflammation. Colonoscopy should be avoided if possible because of the potential risk of perforation associated with the friability of the rectal mucosa during radiation.¹⁵¹

For chronic diarrhea due to decreased rectal compliance, stool softeners or fiber supplements can help. As in acute proctitis, steroid suppositories may be beneficial. The benefit of steroid retention enemas is unclear.¹⁵² Sucralfate enemas, also controversial, may be used for ulcerative lesions. Short-chain fatty acids, which nourish the colonic mucosa, have been studied in acute and chronic radiation proctitis. Initial relief of symptoms can be seen, but symptoms recur shortly after stopping treatment.¹⁵³ Hyperbaric oxygen has been used to stabilize bleeding related to telangiectasias, but this treatment is not widely available and requires many treatments before any effect is seen.^154,155 Nonetheless, a randomized trial in patients with refractory chronic radiation proctitis reported that hyperbaric oxygen therapy significantly improved healing.¹⁵⁶

Treatment of colorectal ulcerations associated with bleeding is initially endoscopic, with the use of coagulation techniques, such as argon plasma coagulation. Bleeding due to radiation proctopathy is usually minor and often controlled endoscopically with conservative measures such as cauterization of the telangiectasias with laser treatment (see Fig. 39-7),^157–160 or by application of formalin.^161–164 Sucralfate enemas may alleviate radiation proctopathy by forming a protective complex with the rectal mucosa. It also increases the local levels of fibroblast growth factors and prostaglandins. Sucralfate enemas appear to be helpful in chronic proctopathy but their benefit is unclear during the acute period.^165–167 Short-chain fatty acid enemas may be also helpful for management of chronic hemorrhagic radiation proctopathy by inhibiting the inflammatory response including the NF-κB pathway^168,169 (see Chapter 2).

Strictures can also be endoscopically dilated. For patients who have refractory bleeding, stricture, perforation, or fistulae, surgical management may (rarely) be necessary. Management of a pelvic fistula (e.g., vaginal or bladder fistula) is complex and requires fecal diversion before the corrective surgery. A thorough radiographic investigation such as barium enema, small bowel follow-through, or enteroclysis to delineate the extent of the fistula should be performed before surgery. Patients with fistulas may present with additional challenges such as electrolyte imbalance, malnutrition, and infections. Many surgical techniques have been described to repair fistulas, but the corrective surgery is best done when the patient is medically stable and enough time has elapsed after the surgical diversion. This allows healing and decreased inflammation of the affected tissues.^170,171

Prevention of large bowel toxicity from radiation has been studied. Prostaglandins have been investigated as a potential radioprotector. Prostaglandin E₂ and prostaglandin analogs display radiation protection in animal studies.^172–175 Misoprostol suppositories also have been shown to reduce symptoms of acute radiation enteritis in patients undergoing radiation therapy for prostate cancer.¹⁷⁶ However, a randomized placebo-controlled trial from Germany in patients with prostate cancer undergoing irradiation found that significantly more patients experienced rectal bleeding in the misoprostol group.¹⁷⁷

Amifostine is a sulfhydryl compound that is converted intracellularly to an active metabolite, which in turn binds to free radicals and protects the cell from radiation injury.¹⁷⁸ Amifostine has been investigated for the prevention of chronic radiation enteritis. Amifostine has demonstrated protection of the small as well as the large intestines in preclinical studies.¹⁷⁹ Amifostine has also been shown to reduce the incidence of early and delayed radiotherapeutic injuries at several anatomic sites. In one randomized study the late effects of radiation were significantly reduced in the group receiving parenterally administered amifostine.¹⁸⁰ However, the median follow-up was quite short (24 months), and longer follow-up is necessary to confirm the benefits of the medication given the incidence of late complications increases with time. Another randomized trial evaluated 205 patients with pelvic malignancies who received radiation therapy, alone or with intravenous amifostine. Patients receiving amifostine experienced a significantly lower incidence of grades 2 and 3 bladder and lower gastrointestinal tract toxicity, with no significant difference between the two groups in tumor response to treatment.¹⁸¹ There is also evidence to suggest that intrarectal application of amifostine may reduce the risk of proctitis in patients undergoing radiotherapy for prostate cancer.¹⁸²

A preclinical study showed a possible role for anti–TGF-β1 interventions to reduce delayed radiation fibrosis and enteropathy.¹⁸³ Many special diets and nutrients such as fiber, elemental diets, short-chain fatty acids, and amino acids such as glutamine may reduce radiation toxicity to the intestine. However, consistent clinical results were not observed.^184–189

Preventive therapy must have high efficacy, low toxicity, low cost, and not protect the tumor from radiation therapy. Unfortunately, no currently available therapy fulfills all of these objectives. As described previously, careful radiation planning and delivery are of paramount importance.

INCIDENCE AND CLINICAL FEATURES

The anal canal is typically spared from significant radiation exposure except in irradiation for anal, low rectal, and gynecologic cancers. The primary acute toxicity from anal cancer irradiation is diarrhea from the exposure of the large bowel to irradiation. However, damage to the anus itself can occur in the form of acute desquamation or ulceration, with later development of ulcers, strictures, anorectal fistulae, and incontinence.¹⁹⁰ The primary data on anal toxicity from radiation therapy come from studies using radiation or chemoradiotherapy for the treatment of anal cancer itself. Anal toxicity manifests as mucosal edema and friability.¹⁹¹ These changes are often exacerbated by diarrhea that occurs from rectal toxicity. Chronically, anal fibrotic changes may evolve.

Clinically, anal toxicity presents initially as a perianal skin reaction that ranges from minimal skin changes to moist desquamation and erythema, as well as diarrhea. These changes are self-limited and usually resolve within a few weeks of completion of therapy. Acute toxicity can lead to an interruption of therapy, although this may be less common with modern radiation treatment techniques.^147,191,192 The incidence of acute toxicity is high, and is increased with concurrent chemotherapy delivery or use of a large dose per fraction.^{142,193–195} Phase III studies and series of patients treated with combined chemotherapy and radiation therapy have noted an incidence of skin toxicity of grade 3 or above in 26% to 78% of patients using doses of 45 to 60 Gy in 1.8- to 2.25-Gy fractions.^{147,190,195–199} A study using conformal radiation techniques (50.4 Gy in 1.8-Gy fractions) combined with chemotherapy reported grade 3 (or higher) acute skin toxicity in only 20% of patients.²⁰⁰ In a recent multi-institutional experience of anal cancer patients treated with IMRT-based chemoradiotherapy, grade 3 skin toxicity was seen in 38% of patients with no grade 4 toxicity observed, comparing favorably to the results of previous randomized trials.¹⁹² Further studies of advanced radiation therapy techniques are needed to confirm this improvement.

Late anal toxicity occurs within months to years following completion of therapy. The most common late complication is anorectal ulceration. Patients also may develop anal stricture or stenosis, incontinence, anal pain, or anorectal fistulae.^{190,194,195,201} There does not appear to be an increase in the occurrence of chronic anal toxicity with the addition of chemotherapy to radiation therapy.^147,199,201 Doses of 45 to 60 Gy in fractions of 1.8 to 2 Gy are considered safe, resulting in chronic grade 3 (or higher) toxicity rates of zero to 22%.^{140,141,193,195,202,203} Doses greater than 65 Gy or fraction size greater than 2 Gy results in a high incidence of anal toxicity.¹⁹⁴ Patients with HIV and anal cancer who are treated with combined chemotherapy and radiation therapy have an increased risk of acute and late anal toxicity.²⁰⁴

TREATMENT

Treatment of acute toxicity is primarily supportive, including proper skin care, dietary modifications, pain medications and topical steroid medications, with breaks in radiation treatment if severe. The effects are self-limited, and usually resolve within weeks of conclusion of therapy. Treatment for chronic toxicity with anal stricture and stenosis includes sphincter dilatation. Rare patients can require colostomy for severe symptoms. Small studies of hyperbaric oxygen therapy have shown efficacy in treating chronic anorectal ulcers.²⁰⁵ There is also a report of oral vitamin A therapy as a treatment for anorectal ulceration, but confirmatory studies are lacking.¹⁹¹

INCIDENCE AND CLINICAL FEATURES

Radiation-induced liver disease (RILD) is seen in approximately 5% of patients when the whole liver radiation dose reaches 30 to 35 Gy at 2 Gy per fraction.^206,207 The pathologic lesion in RILD is central vein thrombosis at the lobular level (veno-occlusive disease), which results in marked sinusoidal congestion leading to lobular hemorrhage and secondary injury to surrounding hepatocytes.²⁰⁸ Fibrin deposition in the central veins is thought to be the cause of the veno-occlusive injury. It is unknown what stimulates the fibrin deposition, but there are hypotheses that suggest that TGF-β is increased in the setting of exposure to radiation, and this in turn stimulates fibroblast migration to the site of injury, causing fibrin and collagen deposition. Foci of necrosis are found in the affected portion of the lobules.²⁰⁹ Severe acute hepatic toxicity may progress to fibrosis, cirrhosis, and liver failure.

Radiation-induced liver disease is a clinical syndrome consisting of anicteric hepatomegaly, ascites, and elevated liver enzymes, particularly serum alkaline phosphatase, which may be elevated out of proportion to serum aminotransferase activity or serum bilirubin. RILD occurs typically between two weeks to four months after completion of radiation therapy. Patients note fatigue, weight gain, increased abdominal girth, and occasionally right upper quadrant pain. Abdominal imaging with computed tomography (CT) scan or MRI can be used in diagnosis. RILD can progress to a chronic phase in which patients can develop increasing fibrosis and liver failure.

Recent studies have emphasized the effect of the liver volume irradiated in addition to dose.²⁰⁸ Although radiation hepatopathy can occur after doses of 35 to 40 Gy to the entire liver, significantly higher doses can be given with few clinical complications if sufficient normal liver is spared. Studies by Lawrence and colleagues report that if less than 25% of the normal liver is treated with radiation therapy there may be no upper limit on dose associated with radiation hepatopathy.²⁰⁸ Estimates of the hepatic irradiation doses associated with a 5% risk of RILD for uniform irradiation of one third, two thirds, and the whole liver are 90 Gy, 47 Gy, and 31 Gy, respectively. Combining chemotherapy and radiation can increase liver damage, particularly if the chemotherapeutic agents are hepatotoxic. Chlorambucil, busulfan, and platinum drugs are used with radiation in bone marrow transplantation and are hepatotoxic agents. In contrast, fluoropyrimidines do not seem to increase radiation-related hepatotoxicity.^207,210

TREATMENT

RILD is often fatal once it occurs because there are no effective treatments.