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5. Upper Gastrointestinal Tract 5. UPPER GASTROINTESTINAL TRACT JOHANNA C. BENDELL, MD CHRISTOPHER WILLETT, MD Duke University Medical Center, Durham, NC The upper gastrointestinal tract lies within the radiation field for most thoracic and abdominal cancers. Toxicity to the upper gastrointestinal tract often limits the radiation doses that can be given. Radiation therapy causes both acute and late effects. The acute effects of radiation include mucosal denudation, while late effects consist of fibrotic changes leading to decreased mobility and ischemia. Multifield and conformal radiation therapy, as well as patient positioning techniques, reduce the volume of normal tissue exposed to radiation and can decrease the potential toxicity. However, the treatment of radiation toxicity is mainly supportive. The increasing use of concurrent chemotherapy and radiation therapy has required enhanced awareness of potential effects and better methods to decrease toxicity, as this combination of treatments is associated with a higher rate of gastrointestinal toxicity. The first part of this chapter will review the pathologic changes of acute and chronic radiation effects, and the second part will discuss clinical effects, including radiation dosing and management of toxicities. A. BIOLOGY OF RADIATION EFFECTS A1. Esophagus Pathologic studies of animal models have been used to describe and characterize the effects of radiation to the esophagus. Pathologic changes include an acute thinning of the squamous epithelial layer with vacuolization and absence of mitoses, followed by areas of complete denudation and areas of increased basal cell proliferation. Chronic changes include focal coagulation necrosis of the muscularis mucosa and deep muscle as 112 Radiation Toxicity: A Practical Guide well as inflammatory changes around the ganglion cells of the mesenteric plexus in the deep wall.1,2 Physiologically, failure of the peristaltic wave and decreased relaxation of the lower esophageal sphincter are seen. Studies of radiation therapy on the human esophagus have demonstrated similar acute and chronic effects. Studies of radiation therapy effects on the esophagus after radiation to the mediastinum and lung showed clinical and endoscopic evidence of esophagitis.3,4 The acute pathologic findings from doses of 3000 to 4000 cGy and 6000 to 7500 cGy were similar to those seen in the mouse model of acute esophageal toxicity.4 Studies by Lepke and Libshitz5 and Goldstein et al.6 found chronic changes of abnormal motility, aperistalsis, and failure to complete the primary peristaltic wave at 4–12 weeks after completion of radiation therapy at doses of 4500–6000 cGy. Areas of distal aperistalsis and resultant exposure of the lower esophagus to gastric acid were thought to be a cause of esophagitis in these patients. Human studies of chronic histologic changes after esophageal radiation show submucosal fibrosis and chronic inflammation of the lamina propria. Fibrosis was also prominent in the muscularis, especially around the muscle nerve plexus, and possibly the source of physiologic motility abnormalities and stricture. Rare chronic ulceration was also seen.7,8 A2. Stomach Understanding of the pathologic response to radiation of the stomach is based mostly on animal models. Post-radiation changes included ulcerative and erosive gastritis at 2–3 weeks, stomach dilatation and gastroparesis at 4 weeks to 7 months, and gastric obstruction at 7 months in rats given doses between 1400 and 2300 cGy.9 The rats were also found to have late changes of atrophic mucosa and intestinal metaplasia. Histologic changes include coagulation necrosis of the parietal and chief cells of the gastric mucosa.10 In addition, there are mucosal sloughing and thinning and chronic inflammatory changes. A rabbit model also showed gastric ulceration between 23 and 58 days after first external radiation dose of 4000 cGy.11 A3. Small Intestine Histologic damage to the small intestine is seen within hours after the radiation. The most sensitive cells to radiation therapy in the small intestine are the crypts of Langerhans.12 The epithelial lining of the small intestine constantly undergoes shedding and replenish- ment, and damage to the actively proliferating cells results in an inability to replace cells that are naturally shed, causing a generalized mucosal sloughing.13 With the sloughing, the villi shorten, and the area of absorption is decreased.14 This damage is seen at doses as low as 2000 to 3000 cGy. In 2–4 weeks, there is an infiltration of leukocytes with crypt abscess formation. Ulceration may also occur. These effects peak within 3–4 weeks after radiation therapy and then subside.13 Because of these effects, malabsorption of fat, carbohydrates, protein, bile salts, and vitamin B12 occurs.15 There is also evidence of altered gut motility acutely after radiation.16 Late radiation effects occur at a median of 8–12 months following the radiation therapy, though they can appear as late as years later.17 Progressive occlusive vasculitis with foam cell invasion of the intima and hyaline thickening of the arteriolar walls, as 5. Upper Gastrointestinal Tract 113 well as collagen deposition and fibrosis occurs. The small bowel becomes thickened with telengiectasia, while the vessel wall of small arterioles is obliterated,18 causing ischemia of the small bowel. Lymphatic damage results in constriction of the lymphatic channels, which contributes to mucosal edema and inflammation.19 The mucosa is atrophied, with atypical hyperplastic glands and intestinal wall fibrosis.7 Mucosal ulceration is common, and can lead to perforation, fistulae, and abscesses. As the ulcers heal, there can be fibrosis with narrowing of the intestinal lumen with subsequent stricture formation. The bowel generally appears thickened and edematous. It should be noted that even if the gut appears normal, patients can still be at risk of spontaneous perforation.20 A4. Liver Radiation-induced liver disease (RILD) is seen in 5–10% of patients when the whole liver radiation dose reaches 3000–3500 cGy.21,22 The pathologic lesion in RILD is cen- tral vein thrombosis at the lobular level, or venoocclusive disease, which results in marked retrograde congestion leading to hemorrhage and secondary alterations in the surround- ing hepatocytes.23 Fibrin deposition in the central veins is thought to be the cause of the venoocclusive injury. It is unknown what stimulates the fibrin deposition, but there are hypotheses that suggest that TGFB 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.24 Severe acute hepatic toxicity changes often progress to fibrosis, cirrhosis, and liver failure. A5. Kidney The major focus of injury after radiation therapy is on the arterial glomerular region rather than the tubular epithelium.22 The cortical rather than the medullary tubules are involved, and this involvement usually follows, rather than proceeds, vascular alterations. Glomerular damage can be seen months before tubular changes. Microangiography dramatically shows glomerulosclerosis as a function of increasing dose, so that complete obliteration of glomeruli occurs at single doses of 500–2000 cGy. Animal experiments show that histological changes of toxicity with low doses of radiation (15 cGy) can occur 3 months after radiation.25 B. CLINICAL ISSUES B1. Esophagus Clinical radiation esophagitis presents as dysphagia or a substernal burning sensation, with acute esophagitis occurring approximately 2 weeks after the initiation of radiation therapy.17 Patients may describe a sudden, sharp, severe chest pain radiating to the back. The symptoms may be confused with candidal esophagitis, which can occur in conjunction with radiation esophagitis. These symptoms typically resolve after 2 days without radiation treatment, but can last as long as 7–10 days. Perforation and bleeding are rare in the acute phase.26 The occurrence of acute toxicity is not predictive of chronic toxicity. Chronic toxicity presents most commonly within 4–8 months after completion of radiation therapy, but can occur as long as years later.27 The symptoms of 114 Radiation Toxicity: A Practical Guide chronic toxicity include dysphagia from stenosis of the esophagus, strictures, or motility abnormalities. Though rare, ulcerations can lead to hemorrhage and fistulas. Patients can also present with pseudodiverticula.4 Patients with symptoms of chronic radiation effects should be evaluated with a barium swallow or upper endoscopy, as these patients are at risk for cancer recurrence or new primary cancer, which can present as esophageal stricture, ulceration, pseudodiverticula, and fistulas. Much work has been done to investigate dose tolerance of the esophagus and addi- tional factors that increase toxicity. Seaman and Ackerman treated patients at doses of 6000–7500 cGy.3 Doses of 6500–7500 cGy did cause a severe esophagitis with stricture in some patients. Three patients with moderate esophagitis received over 6000 cGy. Their conclusion was that the upper limit of dose tolerance for patients was 6000 cGy given at 1000 cGy per week. Other studies treated patients with 6000 cGy and noted a late complication rate of 1.2–18%.28 Using standard radiation therapy, doses of 4500– 6000 cGy are associated with acceptable toxicity. With the increased use of conformal radiation therapy and concurrent use of chemotherapy, further studies have been done to evaluate
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