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Overview of gastrointestinal toxicity of radiation therapy

Overview of gastrointestinal toxicity of radiation therapy
Literature review current through: Jan 2024.
This topic last updated: Dec 04, 2023.

INTRODUCTION — Gastrointestinal toxicity can occur following irradiation of thoracic, abdominal, or pelvic malignancies if gastrointestinal structures are located within the radiation therapy (RT) field. These toxicities can limit the maximum tolerated dose of RT and chemotherapy and thus may limit the efficacy of treatment. The incidence and severity of radiation-induced gastrointestinal morbidity depends on both total dose and fraction size, treatment volumes and techniques, the presence or absence of other treatment modalities such as systemic therapy and surgery, and underlying patient comorbidities. The functional arrangement of organs in the gastrointestinal tract can also influence the clinical presentation. The functional arrangement of organs in the GI tract can be categorized as either serial or parallel. Organs arranged in series consist of segments that are reliant on the functionality of the preceding segment such that the loss of any individual segment will make the organ dysfunctional or even nonfunctional downstream, and possibly upstream, from the insult. Much of the luminal gastrointestinal tract has this type of organization. Organs with parallel architecture, on the other hand, have some functional redundancy built in such that the loss of segments up to a point may not manifest clinically. The liver has this type of arrangement. Organs in series are subject to maximum radiation dose constraints given an ablative dose to a small area can manifest as dysfunction of the entire organ. Organs with a parallel functional architecture are subject to constraints that allow for the protection of an adequate relative volume of functional tissue.

This topic will review the adverse effects of RT on the gastrointestinal tract. A more detailed discussion of the indications for RT for specific cancer sites and stages can be found in topic reviews for each cancer site. (See "Radiation therapy techniques in cancer treatment".)

TIMING OF TOXICITY — RT can be associated with side effects that can occur at any time during treatment or even years later. For purposes of this topic review, we will adopt the following definitions of these toxicities:

Acute toxicities refer to those with onset during or shortly after the course of treatment.

Late toxicities are those occurring after three months after completion of RT. These often reflect the spectrum of radiation tissue changes that can be lasting and irreversible.

ESOPHAGITIS

Pathogenesis and risk factors — Normal esophageal mucosa undergoes continuous cell turnover and renewal. Acute radiation esophagitis is primarily due to effects on the basal epithelial layer. This causes a thinning of the mucosa, which can progress to denudation. The late effects of radiation therapy (RT) are believed to be due to inflammation and scar formation within the esophageal musculature.

The radiation dose to the esophagus, technique used for RT administration, the use of concurrent chemotherapy, and the presence of underlying esophageal disease (eg, erosion, gastroesophageal reflux disease [GERD]) influence the likelihood of esophageal complications [1-4].

These results are illustrated by the following examples (see "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus"):

In a retrospective study of 91 patients who were treated with high-dose conformal RT, the percentage of esophageal volume and surface area treated to >50 Gy predicted late esophageal toxicity [5]. Patients who had preexisting GERD or esophageal erosion secondary to tumor were at increased risk. Hyperfractionation was associated with increased incidence of acute toxicity. Similarly, the addition of concurrent chemotherapy to RT appears to increase the incidence of both acute and chronic esophageal toxicity.

The Radiation Therapy Oncology Group (RTOG) 0617 trial compared total doses of 60 Gy versus 74 Gy in the treatment of locally advanced non-small cell lung cancer. A threefold increase in >Grade 3 esophagitis was also noted in the higher dose arm [6]. In the RTOG 85-01, a randomized trial comparing definitive radiotherapy to 64 Gy and conformal radiation therapy to 50 Gy, nearly 20 percent of patients in each arm experienced severe late esophageal toxicity [7]. However, analyses of patients treated with modern planning techniques have found significant reduction in the long-term esophageal sequelae [8].

A study of 207 patients who received conformal daily RT with or without concurrent chemotherapy found that a maximal esophageal "point" dose of 69 Gy with RT alone and 58 Gy with concurrent chemotherapy predicted significant esophageal toxicity. Severe toxicity was more common in those receiving concurrent chemotherapy (26 versus 1 percent with RT alone) [9].

Multiple trials conducted by the Radiation Therapy Oncology Group found that the incidence of severe esophageal toxicity was significantly increased when chemotherapy was given concurrently with hyperfractionated RT, compared with sequential use of chemotherapy followed by RT or with sequential and concurrent chemotherapy with once-daily RT (34 versus 1 and 6 percent, respectively) [10].

Clinical manifestations

Acute — Symptoms of acute radiation esophagitis include dysphagia, odynophagia, and substernal discomfort. Symptoms usually occur within two to three weeks of initiation of RT. Patients may describe a sudden, sharp, severe chest pain radiating to the back. Acute toxicity rarely causes esophageal perforation or bleeding [11]. Complete epithelial recovery from radiation effects may take 3 to 24 months [12].

Late — Late effects may be seen within three months of completion of RT, with a median time to onset of six months [13,14]. Patients often present with dysphagia secondary to stricture or altered motility caused by fibrosis/muscular damage or nerve injury or odynophagia due to chronic ulceration. Rarely patients may develop a tracheoesophageal fistula and present with dyspnea secondary to aspiration pneumonia.

Diagnosis — The diagnosis of radiation esophagitis is suspected in patients with dysphagia or odynophagia and a history of RT. Upper endoscopy and biopsy serve to establish the diagnosis and rule out other etiologies. (See 'Differential diagnosis' below.)

Upper endoscopy – Patients with acute radiation esophagitis may have mucositis and ulceration [11]. After completion of treatment, basal proliferation and regeneration occur, usually within three weeks [15]. In patients with late radiation esophagitis, esophageal strictures or ulcerations may be seen. Histologic findings include epithelial thickening, chronic inflammation, and submucosal or muscularis fibrosis.

Imaging – We consider performing a barium swallow in patients with a suspected esophageal stricture. Barium swallow can establish the location, length, and number of strictures, determine the diameter of the esophageal lumen, and look for associated pathology such as esophageal diverticula or a hiatal hernia. This information is used to select the dilating technique, to determine the number of sessions that will be required to relieve symptoms, and to counsel the patient about the expected risks of dilation. Barium swallow may demonstrate disrupted peristalsis, with repetitive, nonperistaltic waves above and below the irradiated segment of the esophagus. Evidence of abnormal peristalsis may be observed as early as one to three months after completion of treatment.

Differential diagnosis — The differential diagnosis of radiation esophagitis includes infectious esophagitis in patients with acute radiation esophagitis and malignancy in patients with late onset of dysphagia. Other causes of dysphagia are listed in the table (table 1). (See "Esophageal candidiasis in adults", section on 'Epidemiology'.)

Management

Acute esophagitis – Acute esophagitis is managed symptomatically. Although interruption of RT is occasionally necessary because of severe symptoms, this approach may compromise treatment efficacy and should be avoided whenever possible.

Management measures in patients with dysphagia or odynophagia due to esophagitis or esophageal ulceration include:

Topical anesthetics (viscous lidocaine-based formulations), analgesics (antiinflammatory agents, acetaminophen, narcotics), coating agents (sucralfate), antisecretory therapy (proton pump inhibitors, H2 receptor blockers), and treatment of superimposed infection (candidiasis).

Dietary modification (bland, pureed, or soft foods, soups) to help a patient maintain adequate caloric and liquid intake [16]. Eating more frequent, smaller meals and avoiding foods that are very hot or very cold may also be useful. Avoidance of smoking, alcohol, coffee, spicy or acidic foods or liquids, chips, crackers, and fatty and indigestible foods can be helpful. 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 [16]. In addition, 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.

Esophageal strictures – Esophageal strictures are generally managed with endoscopic dilation. This approach usually results in symptomatic improvement, although multiple dilations may be required. Extended use of proton pump inhibitors following dilation may decrease the risk of stricture recurrence. Tube feedings are only rarely required for patients with significant weight loss or those able to ingest only liquids. (See "Endoscopic interventions for nonmalignant esophageal strictures in adults".)

Dilation of a stricture can cause esophageal rupture, and this approach should be performed carefully. Surgical intervention may be required for patients who develop a perforation or fistula. (See "Complications of endoscopic esophageal stricture dilation".)

GASTRITIS

Pathogenesis and risk factors — Irradiation of the stomach as a consequence of treatment of a range of tumors can cause early and/or delayed toxicity. Low doses of radiation therapy (RT) can cause a decrease in gastric acid production, coagulation necrosis of chief and parietal cells, mucosal thinning, edema, and chronic inflammatory infiltration [14,17]. Acute ulceration results from desquamation and erosion of the damaged mucosa.

Risk factors for gastritis include the radiation dose and use of concurrent chemotherapy.

Radiation dose – The TD5/5 (the dose at which 5 percent of patients develop complications at five years) when the entire stomach is irradiated is estimated to be 50 Gy. The risk of late effects appears to be increased when larger dose fractions are used or when the patient has had prior abdominal surgery [18-21].

Concurrent chemotherapy – Concurrent chemotherapy decreases the tolerance of the gastric mucosa to radiation. Acute gastric side effects are increased when RT is given with taxanes, gemcitabine, and epidermal growth factor or tyrosine kinase inhibitors. Although fluorouracil is a radiation sensitizer, it has been given with RT at doses of 45 to 50 Gy without substantial increases in toxicity.

Clinical manifestations

Acute — Nausea and vomiting may occur within 24 hours after the start of treatment. Approximately one-half of patients receiving upper abdominal irradiation will experience emesis within two to three weeks of the start of treatment [22]. Other early effects of gastric irradiation include nausea, vomiting, dyspepsia, anorexia, abdominal pain, and malaise. Symptoms generally resolve within one to two weeks following completion of RT. These symptoms may be accompanied by development of acute ulceration, occurring shortly after completion of RT [23].

Late — Patients may present with abdominal pain. These symptoms may be due to nonulcer dyspepsia, late gastric ulceration (which usually occurs approximately five months after irradiation), or antral stenosis (which can occur approximately 1 to 12 months after irradiation).  

Diagnosis — A presumptive diagnosis of radiation gastritis is often made in patients with mild symptoms of nausea, vomiting, and abdominal pain during or shortly after RT. However, in patients with severe or late (>3 months after RT) symptoms, we recommend upper endoscopy to establish the diagnosis and rule out other etiologies. Endoscopic findings of radiation gastritis include mucosal erosions, ulceration, mucosal atrophy, and antral stenosis. The diagnosis and evaluation of nausea, vomiting, and abdominal pain are discussed in detail, separately. (See "Approach to the adult with nausea and vomiting" and "Evaluation of the adult with abdominal pain".)

Differential diagnosis — The differential diagnosis in patients with acute onset of nausea and vomiting includes acute gastroenteritis. The differential diagnosis of abdominal pain includes other causes of dyspepsia and includes celiac disease, gastric malignancy, chronic pancreatitis, biliary disease, and drug-induced dyspepsia. The differential diagnosis and diagnostic evaluation of nausea, vomiting, and abdominal pain are discussed in detail, separately. (See "Approach to the adult with nausea and vomiting" and "Evaluation of the adult with abdominal pain".)

Management — Nausea and vomiting are generally managed with antiemetics. The prevention and management of radiation-induced nausea and vomiting are discussed separately. (See "Radiotherapy-induced nausea and vomiting: Prophylaxis and treatment".)

Patients with abdominal pain and dyspepsia should be treated with antisecretory medications, including a proton pump inhibitor and/or H2 blockers, as well as sucralfate. These may be helpful on a long-term basis to avoid late ulceration. Patients with severe pain may require narcotic and non-narcotic analgesics as needed. In rare instances, endoscopic therapeutic approaches or even surgery may be required to treat severe bleeding, refractory ulceration, gastric outlet obstruction, fistula formation, or perforation. (See "Overview of complications of peptic ulcer disease".)

ENTERITIS — Radiation therapy (RT) can cause an acute injury to the small and large intestines that develops during or shortly after treatment of a variety of malignancies. The initial toxicity generally resolves within a matter of weeks, but chronic changes can develop months or years after therapy.

Pathogenesis — The gastrointestinal epithelium has a high proliferative rate, making it susceptible to injury from both radiation and chemotherapy. The primary effect of radiation is on mucosal stem cells within the crypts of Lieberkühn. Stem cell damage, either acutely as a direct consequence of radiation or subsequently as a result of microvascular damage, leads to a decrease in cellular reserves for the intestinal villi. This results in mucosal denudation with associated intestinal inflammation, edema, shortened villi, and decreased absorptive area.

The initial histologic evidence of damage is seen within hours of irradiation. This is followed by an infiltration of leukocytes with crypt abscess formation within two to four weeks; ulceration may also occur. Subsequent changes include a progressive occlusive vasculitis 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 [24].

The small bowel becomes thickened [25]. The vessel walls of small arterioles are obliterated, causing ischemia. Lymphatic damage results in constriction of the lymphatic channels, which contributes to mucosal edema and inflammation [26]. The mucosa is atrophied, with atypical hyperplastic glands and intestinal wall fibrosis [12]. Telangiectasias may be present and can cause bleeding. (See "Argon plasma coagulation in the management of gastrointestinal hemorrhage".)

Mucosal ulcerations can lead to perforation, fistulas, or abscess formation. As the ulcers heal, there can be fibrosis with narrowing of the intestinal lumen and stricture formation or even obstruction. Stasis can lead to small intestinal bacterial overgrowth. Even if the intestine appears normal, patients are at risk of spontaneous perforation [27].

These chronic changes can impair absorption of fats, carbohydrates, protein, bile salts, and vitamin B12, leading to loss of water, electrolytes, and protein in the small intestine [28,29]. Lactose degradation may be impaired, which can lead to increased bacterial fermentation and associated flatulence, abdominal distention, and diarrhea, possibly accompanied by bacterial overgrowth [30]. There is also evidence of altered gut motility acutely following RT. Bile salt resorption may be impaired, causing increased amounts of conjugated bile salts to enter the colon. These bile salts are then deconjugated by bacteria, resulting in intraluminal water retention with resultant diarrhea. The large intestine is generally believed to be less radiosensitive than the small intestine. When radiation injury does involve the colon, patients can develop a pancolitis that mimics inflammatory bowel disease (IBD).

Risk factors — A number of factors can affect the risk of developing radiation enteritis, including the dose of radiation to the intestines and the use of concomitant chemotherapy. There is some evidence that patients who develop acute intestinal toxicity are at increased risk for chronic effects [31].

Dose and schedule of RT – The total RT dose, fraction size, treatment duration, and volume of intestine within the RT field all influence the likelihood of enterotoxicity. Mitigating the risk and severity of radiation enteritis and chronic small bowel injury is commonly the radiation dose-limiting factor in the radiotherapeutic management of most abdominal and pelvic malignancies, emphasizing the importance of careful radiation planning. The radiation dose at which 5 percent of patients will develop complications at five years (TD5/5) for limited volumes of small bowel is estimated to be 50 Gy. Significant intestinal toxicity is rare when treatment is limited to 45 to 50 Gy in 1.8 to 2.0 Gy daily fractions [32].

Chemotherapy – Combining chemotherapy with RT increases the risk of radiation enteritis. Several studies in patients treated with fluorouracil (FU)-based chemoradiotherapy for rectal cancer have found a strong correlation between acute toxicity and the amount of small bowel irradiated at each dose level analyzed [33-35]. Limiting the volume of small bowel receiving >15 Gy in patients receiving concomitant chemotherapy may decrease the occurrence of severe diarrhea and improve treatment tolerance [35]. Data from phase I and II studies suggest that integration of agents such as oxaliplatin, irinotecan, and vascular endothelial growth factor (VEGF) receptor and epidermal growth factor receptor (EGFR) inhibitors with RT may significantly increase the frequency of severe gastrointestinal toxicity as compared with 5-FU-based regimens [36-38].

Other risk factors

Limited bowel mobility – Factors that limit bowel mobility within the abdomen increase the amount of radiation delivered to a specific segment of the intestines. This increased focal irradiation can cause increased toxicity. Bowel mobility may be decreased in the following groups of patients:

-Females, older patients, and thin patients may have larger volumes of small bowel in the pelvic cul-de-sac [39]

-Prior abdominal or pelvic surgery, which can cause adhesions that limit intestinal mobility [40-42]

-Previous pelvic inflammatory disease or endometriosis that may result in scarring and decreased bowel mobility [43,44]

Vascular disease – Patients with preexisting vascular disease due to smoking, diabetes, hypertension, or atherosclerosis appear to be at increased risk for radiation enteritis [45]. The pretreatment abnormalities are exacerbated by the pathologic changes of chronic radiation injury, which include vasculitis obliterans and ischemia.

Collagen vascular disease – Patients with collagen vascular disease (eg, rheumatoid arthritis, systemic lupus erythematosus, polymyositis) may have a lower gastrointestinal tolerance to radiation and an increased risk of acute and chronic radiation-induced injury [46-49]. The late effects induced by RT can be additive to these preexisting changes that include transmural fibrosis, collagen deposition, and inflammatory infiltration of the mucosa. Patients whose comorbid disease is quiescent or well controlled appear to fare better than patients with active disease. (See 'Pathogenesis' above.)

Inflammatory bowel disease – Patients with IBD may be at an increased risk of acute and late bowel complications, particularly if active and/or poorly controlled, although the data appear to be conflicting, especially when trying to tease out the effects related to RT from those that might be related to the natural history of IBD [47,48,50].

Clinical manifestations

Acute — Symptoms of acute radiation enteritis include diarrhea, abdominal cramping and pain, nausea and vomiting, anorexia, and malaise. Radiation-induced diarrhea often appears during the third week of treatment, with reports of frequency ranging from 20 to 70 percent [51]. Diarrhea may occur after doses of 18 to 22 Gy delivered using conventional fractionation and will occur in most patients who receive doses of 40 Gy. The symptoms subside as the acute pathologic effects resolve, and typically disappear two to six weeks after the completion of RT [52]. Patients who develop acute small intestinal toxicity may be at higher risk for late effects.

Late — Late radiation effects typically manifest 8 to 12 months after RT, although toxicity may not appear until years later in some cases [14,53]. In some cases, the clinical manifestations of chronic radiation enteritis worsen over time.

Late effects include dysmotility, stricture formation, malabsorption, and diarrhea. Patients may have bloating, excessive gas, and borborygmi due to small intestinal bacterial overgrowth. Other symptoms include bleeding or abdominal pain due to ulceration, and fever secondary to abscess formation. Patients with severe disease may develop intermittent, partial, or complete small bowel obstruction due to strictures [54]. (See "Etiologies, clinical manifestations, and diagnosis of mechanical small bowel obstruction in adults".)

Laboratory findings include vitamin B12 deficiency due to small intestinal bacterial overgrowth, and hypoalbuminemia and anemia due to malnutrition or bleeding. (See "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis", section on 'Laboratory findings'.)

Diagnosis — The diagnosis of acute radiation enteritis is suspected in patients with diarrhea and abdominal pain during the course of radiation treatment. While the diagnosis can be made based on clinical history, in patients with diarrhea we sometimes perform stool cultures to rule out other causes of infectious diarrhea. CT imaging may reveal thickened loops of bowel correlating with the radiation portal. The diagnosis of chronic radiation enteritis is discussed in detail, separately. (See "Diagnosis and management of chronic radiation enteritis", section on 'Diagnosis'.)

Differential diagnosis — The differential diagnosis of acute radiation enteritis includes infectious gastroenteritis. The differential diagnosis of chronic radiation enteritis is discussed separately. (See "Approach to the adult with acute diarrhea in resource-abundant settings", section on 'Etiology' and "Diagnosis and management of chronic radiation enteritis", section on 'Differential diagnosis'.)

Management — The management of chronic radiation enteritis is discussed in detail, separately. (See "Diagnosis and management of chronic radiation enteritis", section on 'Management'.)

PROCTITIS — Radiation proctitis is usually encountered following treatment of cancers of the anus, rectum, cervix, uterus, prostate, urinary bladder, and testes. Radiation proctitis is discussed in more detail, separately. (See "Radiation proctitis: Clinical manifestations, diagnosis, and management".)

ANAL TOXICITY

Pathogenesis and risk factors — The anal canal is typically spared from significant radiation exposure except when radiation therapy (RT) is used to treat anal, low rectal, or gynecologic cancers. In these settings, the acute toxicity includes diarrhea caused by exposure of the rectum to irradiation. Damage to the anus itself can cause mucosal edema and friability, which can progress to desquamation or ulceration. These changes may be exacerbated by diarrhea [55].

Acute anal toxicity is relatively common, and its incidence is increased with concurrent chemotherapy or large RT fraction size [56-59]. Conformal RT techniques may significantly decrease the incidence of skin toxicity [60,61]. Doses of 45 to 60 Gy in fractions of 1.8 to 2.0 Gy are generally considered safe, resulting in severe toxicity in 0 to 22 percent of cases. Doses above 65 Gy or fraction size above 2 Gy result in a higher incidence of toxicity [56]. There does not appear to be an increase in chronic anal toxicity when chemotherapy is combined with RT [57,62-72]. Patients with HIV who are treated with combined chemotherapy and RT may have an increased risk of acute and late anal toxicity [73].

Clinical manifestations

Acute — Acute anal toxicity presents as a perianal skin reaction that ranges from minimal skin changes to moist desquamation and erythema. Pain typically accompanies worsening desquamation in the perianal skin region, and inflammation of the anal canal and distal rectum can also cause pain, bleeding, and tenesmus.

Late — Late toxicity can appear months to years after completion of therapy. The most common late complication is anorectal ulceration. Anal strictures (stenosis) or anorectal fistulas may also occur [56,57,62,68]. Patients usually present with anal pain and anal incontinence.

Diagnosis — The diagnosis of acute anal toxicity is suspected in patients with perianal erythema and desquamation that occurs in the setting of radiation treatment. In patients with anal ulceration or stenosis/stricture, biopsy is required to establish the diagnosis and rule out other etiologies. The evaluation of a patient with genital tract ulceration is discussed separately. (See "Approach to the patient with genital ulcers".)

Differential diagnosis — The differential diagnosis of anal ulcers includes Crohn disease and anal cancer. Other causes of perianal ulceration include infectious causes, including herpes simplex virus (genital herpes), Treponema pallidum (syphilis), Haemophilus ducreyi (chancroid), Chlamydia trachomatis (lymphogranuloma venereum), and Klebsiella granulomatis, formerly known as Calymmatobacterium granulomatis (donovanosis or granuloma inguinale).

Management — Management of acute toxicity is supportive and includes proper skin care, dietary modification in patients with fecal incontinence, pain medications, and corticosteroid-based suppositories. The acute RT side effects are generally self-limited and usually resolve within weeks after the end of therapy. However, treatment interruptions may be required if toxicity is severe [55,60,63].

For severe or refractory anal ulcerations, there are limited data to guide management. Case reports suggest that hyperbaric oxygen and oral vitamin A may be useful in treating anorectal ulcerations [55,74,75]. Sphincter dilation is the standard treatment for anal strictures or stenosis. Rare patients may require a colostomy if symptoms are severe.

RADIATION-INDUCED LIVER DISEASE

Pathogenesis — The pathogenesis of radiation-induced liver disease (RILD) is not fully understood. At the tissue level, a veno-occlusive process results in retrograde congestion, leading to hemorrhage and secondary alterations in surrounding hepatocytes [76]. Acute RILD can be fatal, and hepatic toxicity can progress to fibrosis, cirrhosis, and liver failure.

Fibrin deposition in the central veins is thought to be the cause of the venoocclusive injury. The etiology of the fibrin deposition is unknown. Tumor growth factor-beta is increased during exposure to radiation, which may stimulate fibroblast migration to the site of injury, causing fibrin and collagen deposition. Foci of necrosis are found in the affected portion of the lobules [77]. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents" and "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults" and "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Introduction'.)

Risk factors — The likelihood of developing RILD is directly related to the extent of liver irradiation and radiation dose delivered (the dose-volume relationship of the radiation treatment plan) [77]. Radiation hepatitis occurs in approximately 5 percent of patients when the dose of radiation to the whole liver reaches 30 to 35 Gy in 2 Gy fractions [78,79]. Significantly higher doses can be given safely if sufficient normal liver is not irradiated. Specific dose-volume relationships for the development of clinically significant liver injury following partial liver irradiation are emerging [80,81]. When considering the appropriateness of liver-directed therapy in a patient, consideration of baseline liver function is important. Patients are presently stratified based upon their Child-Pugh score. Other grading systems exist (eg, Model for End-Stage Liver Disease [MELD] score, albumin-bilirubin [ALBI] score), but they have not been extensively evaluated in patients receiving RT. Most trials investigating the use of RT in the treatment of hepatocellular carcinoma have excluded patients with severe liver disease.

Combining chemotherapy and radiation can increase liver damage, particularly when chlorambucil, busulfan, or platinum agents are used. This is a particular problem when radiation therapy is part of the conditioning regimen for bone marrow transplantation. In contrast, fluoropyrimidines do not seem to increase radiation-related hepatotoxicity [79,82]. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults".)

Clinical manifestations — Classic RILD is a clinical syndrome consisting of anicteric hepatomegaly, ascites, and elevated liver enzymes. RILD occurs typically between two weeks and four months after completion of RT. Patients note fatigue, weight gain, increased abdominal girth, and occasionally right upper quadrant pain. Serum alkaline phosphatase levels are elevated out of proportion to other liver enzymes, and initially the total serum bilirubin level is normal. A nonclassic form of RILD can be seen in patients undergoing partial liver irradiation and consists of worsening liver function reflected in abnormal laboratory markers [80].

Diagnosis — The diagnosis of classic RILD should be suspected in patients with ascites, hepatomegaly, and elevated liver tests in the setting of recent radiation treatment. Evaluation includes exclusion of other causes of elevated liver tests. While the presence of well-demarcated areas of hypo- or hyperattenuation in a nonanatomic distribution on computed tomography scan or magnetic resonance imaging is suggestive of RILD, the diagnosis can be established on liver biopsy. (See "Approach to the patient with abnormal liver biochemical and function tests".)

Management — The management of patients with classic RILD is supportive and involves symptomatic management (eg, treatment of ascites). The majority of patients recover completely in three to five months, while a minority develop worsening liver fibrosis and failure, rarely developing fulminant hepatic failure.

PREVENTION — Multiple techniques are used to decrease the volumes of nontarget gastrointestinal tissues treated, including the use of multiple treatment fields to avoid "hot spots," treating in the prone position, use of a "belly board" or false table-top, as well as treating with a full bladder to displace bowel out of the radiation therapy (RT) field [83].

Improved imaging and computer capabilities have made three-dimensional (3D) treatment planning widely available, in contrast to the two-dimensional approaches used in the past. Intensity-modulated RT, an advanced form of 3D planning, is widely used and utilization and may permit further dose escalation while decreasing toxicity [84,85] (see "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'). Similarly, the use of proton therapy, a form of particle therapy, may further enhance normal tissue sparing through its' inherent dose-distribution properties.

Several chemopreventive agents have been evaluated for preventing radiation-induced toxicity in the gastrointestinal tract. However, none have an established role, other than amifostine, for prevention of xerostomia in patients receiving RT only for head and neck cancer. (See "Management and prevention of complications during initial treatment of head and neck cancer", section on 'Amifostine'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Radiation-induced gastrointestinal toxicity".)

SUMMARY

Gastrointestinal toxicity can occur following irradiation of thoracic, abdominal, or pelvic malignancies if gastrointestinal structures are located within the radiation therapy (RT) field. These toxicities can limit the maximum tolerated dose of RT and chemotherapy and thus may limit the efficacy of treatment. (See 'Introduction' above and 'Timing of toxicity' above.)

The incidence and severity of RT side effects depend upon the site, volume of tissue exposed, and treatment schedule, including total dose, dose per fraction, and type of radiation. Other risk factors for radiation induced GI toxicity include the use of concomitant chemotherapy.

Symptoms of acute radiation esophagitis include dysphagia, odynophagia, and substernal discomfort. Patients with late toxicity often present with dysphagia secondary to stricture or altered motility caused by fibrosis/muscular damage or nerve injury or odynophagia due to chronic ulceration. (See 'Esophagitis' above.)

Acute radiation gastritis can cause nausea and vomiting within 24 hours after the start of treatment. Symptoms generally resolve within one to two weeks following completion of RT. Manifestations of late radiation gastritis include abdominal pain due to nonulcer dyspepsia, gastric ulcers, and antral stenosis. (See 'Gastritis' above.)

Symptoms of acute radiation enteritis include diarrhea, abdominal pain, nausea and vomiting, anorexia, and malaise. Radiation-induced diarrhea often appears during the third week of treatment and typically disappears two to six weeks after the completion of RT. Late effects include malabsorption and diarrhea. Patients may have bloating, excessive gas, and borborygmi due to small intestinal bacterial overgrowth. Other symptoms include bleeding or abdominal pain due to ulceration, and fever secondary to abscess formation. Patients with severe disease may develop intermittent, partial, or complete small bowel obstruction due to strictures. (See 'Enteritis' above.)

Acute anal toxicity presents as a perianal skin reaction that ranges from minimal skin changes to moist desquamation and erythema. Late complications of RT include anorectal ulceration, anal strictures or stenosis, and anorectal fistulas. Patients with late anal radiation toxicity usually present with anal pain and anal incontinence. (See 'Anal toxicity' above.)

Patients with radiation-induced liver disease present with fatigue, weight gain, increased abdominal girth, and occasionally right upper quadrant pain. On physical examination, patients have hepatomegaly and ascites. Laboratory findings include elevated alkaline phosphatase, but transaminases and bilirubin remain may normal. However, patients with underlying liver disease present with jaundice and markedly elevated serum transaminase (more than five times the upper limit of normal). (See 'Radiation-induced liver disease' above.)

Multiple techniques are used to decrease the volumes of nontarget gastrointestinal tissues treated, including the use of multiple treatment fields to avoid "hot spots," treating in the prone position, use of a "belly board" or false table-top, as well as treating with a full bladder to displace bowel out of the RT field and use of intensity-modulated radiation therapy. (See 'Prevention' above.)

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Topic 7054 Version 21.0

References

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