Radiation colitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Qasim Salau, M.B.B.S., FMCPaed [2]

Synonyms and keywords: Radiation proctocolitis

## Overview

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Radiation therapy is a common treatment modality for abdominal and pelvic malignancy. Radiation colitis may complicate this treatment. Radiation colitis tends to develop insidiously and it is often progressive when chronic.

## Historical Perspective

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* Radiation-induced enteritis was first described by Walsh in an individual working with x rays in 1897.[1]
* In 1917, radiation-induced enteritis was reported following radiation treatment of malignancy.
* The early and late intestinal effect of radiotherapy was first described by Warren and Friedman in 1942.[2]

## Classification

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Radiation colitis may be classified based on duration of symptoms into acute and chronic radiation colitis:[3][4][5][6]

* Acute radiation colitis occurs from after the initiation of therapy to 3 months (90 days) after the onset of therapy.
* Chronic radiation colitis occurs from after 3 months of radiation therapy to years after therapy, with a median duration of 8 to 12 months after completion of radiation therapy.

## Pathophysiology

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### Pathogenesis

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* Radiation colitis occurs following radiation therapy for abdominal and pelvic malignancies.[4][5][7][8][9][10]
* It is more common with radiation doses higher than 45Gy.[4]
* The main site of damage is DNA. The pathogenesis involves direct ionizing damage to the DNA resulting in inhibition of mitosis. Radiation may also affect RNA, proteins, and cell membranes. Oxidative injury to the DNA may also contribute to the development of radiation colitis.
* Injury may occur a few hours to days, up to three months after irradiation in acute radiation colitis. It affects rapidly dividing cells of the epithelium and mucosa crypts. This leads to cell death, recruitment and activation of polymorphonuclear (PMN) inflammatory cells, mucosal edema and damage to small blood vessels. The effect of this damage to the mucosa is fluid, electrolyte and nutrient loss. Radiation also reduces bowel motility. Acute radiation colitis is usually transient and self limiting, with regeneration of the epithelium.
* In chronic radiation colitis, mesenchymal tissue is involved. The damage is progressive with atrophy of the mucosa, fibrosis of the intestinal wall, obliteration of small arteries, chronic ischemia, ulcers, strictures, and fistula formation. This changes usually occur three months to years after radiation. Secondary colonic malignancy may occur.

### Genetics

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There is no specific genetic cause for radiation colitis.

### Gross Pathology

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* Endoscopy should be gentle and performed with care, especially in acute radiation colitis.
* In acute radiation colitis, the mucosa may appear erythematous or pale, edematous, friable with or without small erosions.
* In chronic radiation colitis, mucosa atrophy, fibrosis, obliterative arteritis, stenosis, strictures, fistula, and ulcers are observed.

### Microscopic Histopathology

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Histopathological findings of radiation colitis may be categorized into the following:

* Acute: Reduced mitosis, increased apoptotic bodies, mucin depletion, eosinophilia, presence of crypt abscesses, and evidence of regeneration
* Chronic: Dilated capillaries and lymphatics, hyaline fibrosis, atypical fibroblast and endothelial cells, and distortion of the crypts.

## Differentiating Radiation Colitis from Other Diseases

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Symptoms of acute radiation acute radiation proctitis may overlap with other causes of acute colitis, but prior history of radiation will help in distinguishing the cause. Differential diagnosis of acute radiation colitis include:

* Allergic colitis
* Chemical colitis
* NSAID-induced colitis
* Ischemic colitis

Differential diagnosis of chronic radiation colitis include:

* Ischemic colitis
* Inflammatory bowel disease

* The symptoms of colitis, such as diarrhea (especially bloody diarrhea), and abdominal pain are observed in all forms of colitis. The table below lists the differential diagnosis of common causes of colitis:[11][12]

Diseases  | History and Symptoms  | Physical Examination  | Laboratory findings

|
|
|

Diarrhea | Rectal bleeding | Abdominal pain | Atopy | Dehydration | Fever | Hypotension | Malnutrition | Blood in stool (frank or occult)  | Microorganism in stool  | Pseudomembranes on endoscopy  | Lab Test 4
Allergic Colitis  | \+  | ++  | \+  | ++  |  |  |  |  | ++  |  |  |
Chemical colitis  | \+  | ++  | ++  |  | \+  | \+  |  |  | ++  |  | \+  |
Infectious colitis  | ++  | ++  | ++  |  | +++  | +++  | ++  | \+  | ++  | ++  | \+  |
Radiation colitis  | \+  | ++  | \+  |  | \+  |  |  | \+  | ++  |  |  |
Ischemic colitis  | \+  | \+  | ++  |  | \+  | \+  | \+  | \+  | ++  |  |  |
Drug-induced colitis  | \+  | \+  | ++  |  |  | \+  |  |  | ++  |  | \+  |

## Epidemiology and Demographics

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The exact prevalence and incidence of radiation colitis is not certain due to different methods of definition. The incidence of acute radiation injury to the bowel is said to be about 75% to 80% of patients receiving pelvic radiotherapy, while 15% to 20% of patients receiving pelvic radiotherapy will develop chronic radiation injury to the bowel. [4][6][10][13]

### Age

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The prevalence of radiation colitis is more among older age group (over 60 years) patients. This may be a reflection of the increase frequency of predisposing malignancy requiring radiotherapy in this age group.[6][13][14]

### Gender

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Men and women are affected equally by radiation colitis.

### Race

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There is no racial predilection to radiation colitis.

## Risk Factors

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Common risk factors for developing radiation colitis include:[5][6][15]

* Radiation dose greater than 54 Gy
* Advanced age (above 60 years)
* Past radical abdominal or pelvic surgery such as radical hysterectomy and radical colectomy
* Asthenic individuals
* Smoking
* Chronic co-morbid medical diseases such as diabetes mellitus, hypertension, and atherosclerosis
* Prior pelvic inflammatory disease
* Collagen vascular disease
* HIV infection, which is hypothesized to increase risk for radiation toxicity in the colon

## Screening

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There are no established screening guidelines for radiation colitis[16]

## Natural History, Complications and Prognosis

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### Natural History

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The symptoms and extent of radiation colitis are variable and usually develop insidiously. The symptoms depend on the dose and duration of the radiation and how sensitive the bowel is to radiation. In acute radiation colitis, symptoms usually start shortly after commencement of radiation therapy and progress reaching a peak 1 to 2 weeks later. The symptoms of acute radiation colitis may not start for up to 3 months after commencement of radiation. In most cases, the symptoms of acute radiation colitis are self-limiting and resolve following termination of radiation therapy. The symptoms of chronic radiation colitis often become noticeable months to years after the completion of radiotherapy. The symptoms may occasionally follow acute radiation colitis. However, previous acute radiation colitis does not increase the risk of a patient developing chronic radiation colitis. Also, absence of acute radiation colitis, does not prevent chronic radiation colitis from occurring. Treatment is required for chronic radiation colitis because resolution of the symptoms is uncommon without intervention.[4][17]

### Complications

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Possible complications of radiation colitis include:[4][17]

* Anemia
* Intestinal obstruction
* Intestinal perforation
* Fistula
* Fecal incontinence
* Strictures
* Malabsorption
* Failure to thrive
* Sepsis, due to loss of the mucosal protective barrier
* Secondary malignancy (uncommon)[18][19]

### Prognosis

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The prognosis of radiation colitis varies with the subtype, severity, duration and responsiveness to treatment.[4][15][17]

* Acute radiation colitis is usually self-limiting, with resolution of symptoms few weeks after stopping radiotherapy.
* Chronic radiation colitis is progressive and difficult to manage. The patients may develop secondary radiation-associated malignancy which has a poor prognosis due to late diagnosis.

## Diagnosis

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### Diagnostic Criteria

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There is no definitive diagnostic criteria for radiation colitis. Diagnosis of radiation colitis is primarily clinical; it is based on history, physical examination and endoscopic findings.[4][17]

### History and Symptoms

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Obtaining a complete history including dietary history is an important aspect in making a diagnosis of radiation colitis. It provides insight into the cause, and any associated underlying conditions. Radiation colitis should be suspected in any individual who presents with intestinal symptoms and has a previous history of abdominal and/ or pelvic radiotherapy. Symptoms of radiation colitis may be categorized according to duration as follows:

#### Acute radiation colitis

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* Diarrhea
* Abdominal pain which is colicky (cramping and intermittent)
* Nausea
* Urgency
* Fecal frequency
* Tenesmus
* Mucus discharge
* Rectal bleeding

#### Chronic radiation colitis

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* Symptoms of acute radiation colitis
* Rectal bleeding, which may be severe
* Symptoms of sepsis
* Constipation
* Abdominal pain
* Abdominal distension
* Vomiting
* Fecal vomiting, especially when stricture develops

### Physical Examination

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Physical examination findings may reveal:

* Signs of dehydration such as lethargy, tachycardia, and hypotension
* Abdominal tenderness which may be more prominent in lower abdominal quadrants due to involvement of the distal sigmoid colon and/ or rectum
* Fever due to dehydration or in individuals who have developed sepsis
* Pallor
* Toxic appearance in those with bowel perforation and sepsis

### Laboratory Findings

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Initial investigations should include hematological, biochemistry profiles and stool examination.

#### Hematology

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* Anemia
* Leukocytosis with left shift may be seen with sepsis common, but leukopenia may be observed

#### Electolytes

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* Hyponatremia

#### Stool Examination

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Stool analysis may show:

* Fecal blood
* Fecal leukocytes
* Negative stool culture

### Endoscopy

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Endoscopy is important to confirm the diagnosis of radiation colitis. However, endoscopy should be performed with care due to the fragile nature of the bowel following radiation therapy. Biopsy is generally not recommended during endoscopy especially in acute radiation colitis.[4][17]

* Features observed in acute radiation colitis on endoscopy include friable, hyperemic, edematous mucosa with/ or without ulcers that are often shallow. The features in acute radiation colitis are limited to the superficial parts of the colonic mucosa.
* Chronic radiation colitis involves the whole of the colonic mucosa. Features include mucosal pallor, fibrosis, strictures, ulcers, and telangiectasias, which bleeds easily. The colonic wall is often rigid.

### Other Diagnostic Studies

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Other diagnostic studies in radiation colitis include:[10]

#### Barium enema

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May show decreased peristalsis and distention of the colon, stenosis, presence of ulcers, and fistulas. It is less sensitive to endoscopy

#### CT

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CT findings include increased density and fibrosis of the pericolonic fat, fascia and colonic wall. It also helps to rule out perforation. It is difficult to distinguish between radiation colitis and cancer.

#### X Ray

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There are no specific x ray features of radiation colitis. However, it may be helpful to rule out perforation.

## Treatment

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### Medical Therapy

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The mainstay of treatment for radiation colitis is conservative medical therapy. Medical therapy depends on whether radiation colitis is acute or chronic.[4][5][9][10][15][20]

#### Acute radiation colitis

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Acute radiation colitis is a self-limiting illness which usually resolves on stopping radiotherapy. Supportive therapy is the only treatment required in the majority of cases. These include:

* Correction of dehydration and electrolyte derangements by giving intravenous fluids or oral rehydration therapy whenever feasible
* Use of anti-diarrheal medications, such as loperamide
* Dietary modification by decreasing fat and lactose intake
* Use of synthetic somatostatin analog octreotide in patients with refractory diarrhea
* Steroid and 5-aminosalicylic acid suppositories have also been used to treat bowel inflammation associated with radiation therapy
* Definitive treatment is by stopping radiation therapy

#### Chronic radiation colitis

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Chronic radiation colitis is a progressive disease that is often difficult to treat. The colon is fragile with fibrosis and neovascularization, making it prone to bleeding with minimal trauma. The most frequent symptom of chronic radiation colitis is diarrhea. Treatment of chronic radiation colitis includes:

* Supportive fluid and electrolyte replacement due to chronic diarrhea and use of anti-diarrhea medications
* Giving high fiber (low residue) diet, with low lactose and fats
* Anti-inflammatory therapy using non-steroidal anti-inflammatory drugs (NSAIDs) such as 5-aminosalicylic acid or sulfasalazine with/without the addition of steroids is often the first-line treatment used in most cases of chronic radiation colitis
* Sucralfate (a sulphated polyanionic disaccharide) is used when anti-inflammatory therapy fails to improve symptoms. It is thought work through promotion of healing of the intestinal epithelium and formation of a protective barrier in the bowel.
* Hyperbaric oxygen therapy (HBO) is also used in the treatment of chronic radiation colitis. It is thought to work through its angiogenic and antibacterial effects, reducing tissue hypoxia and therefore promoting colonic mucosa healing and regeneration.
* Short chain fatty acid (SCFA) enemas have also been used in the treatment of radiation colitis. They stimulate colonic mucosa proliferation and have vasodilatory effect on the arteriole walls.
* Anti-oxidants such as vitamins A, C and E have been used as adjuncts in the treatment of chronic radiation colitis, with favorable response.
* Transfusion may be required to treat anemia from hemorrhagic telengiectasia.

### Ablative therapy

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Ablative treatment using formalin, endoscopic coagulation, or argon plasma coagulation is done when symptom fail to improve with medical therapy. Ablative treatment should be done with care in patients with chronic radiation colitis because of the fragile bowel which increases the risk of complications such as bleeding, stenosis, perforation and fistula formation.

### Surgical Therapy

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Surgical intervention in chronic radiation colitis is commonly reserved for management of complications or rarely for diagnosis. About 10 to 30 percent of individuals with radiation colitis will require surgery.[4][15] Indications for surgery in radiation colitis include:

* Intestinal obstruction
* Intestinal perforation
* Fistulae formation
* Severe bleeding
* Rarely, for treatment of uncontrollable pain

Surgical interventions for chronic radiation colitis include intestinal bypass procedures, colonic resection, and bowel reconstruction.

## Prevention

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### Primary prevention

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There is presently no established method of prevention for radiation colitis. However, individuals with chronic radiation colitis should be followed up closely because of the risk of development of secondary radiation-induced malignancy.

### Secondary prevention

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There are no secondary prevention methods for radiation colitis.

## References

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1. ↑ Walsh D (1897). "Deep Tissue Traumatism from Roentgen Ray Exposure". Br Med J. 2 (1909): 272–3. PMC 2407341. PMID 20757183.
2. ↑ Warren S, Friedman NB (1942). "Pathology and Pathologic Diagnosis of Radiation Lesions in the Gastro-Intestinal Tract". Am J Pathol. 18 (3): 499–513. PMC 2032955. PMID 19970638.
3. ↑ Denton AS, Andreyev HJ, Forbes A, Maher EJ (2002). "Systematic review for non-surgical interventions for the management of late radiation proctitis". Br J Cancer. 87 (2): 134–43. doi:10.1038/sj.bjc.6600360. PMC 2376119. PMID 12107832.CS1 maint: Multiple names: authors list (link)
4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 Do NL, Nagle D, Poylin VY (2011). "Radiation proctitis: current strategies in management". Gastroenterol Res Pract. 2011: 917941. doi:10.1155/2011/917941. PMC 3226317. PMID 22144997.CS1 maint: Multiple names: authors list (link)
5. ↑ 5.0 5.1 5.2 5.3 Kennedy GD, Heise CP (2007). "Radiation colitis and proctitis". Clin Colon Rectal Surg. 20 (1): 64–72. doi:10.1055/s-2007-970202. PMC 2780150. PMID 20011363.
6. ↑ 6.0 6.1 6.2 6.3 Shadad AK, Sullivan FJ, Martin JD, Egan LJ (2013). "Gastrointestinal radiation injury: symptoms, risk factors and mechanisms". World J Gastroenterol. 19 (2): 185–98. doi:10.3748/wjg.v19.i2.185. PMC 3547560. PMID 23345941.CS1 maint: Multiple names: authors list (link)
7. ↑ Keith NM, Whelan M (1926). "A STUDY OF THE ACTION OF AMMONIUM CHLORID AND ORGANIC MERCURY COMPOUNDS". J Clin Invest. 3 (1): 149–202. doi:10.1172/JCI100072. PMC 434619. PMID 16693707.
8. ↑ Bansal N, Soni A, Kaur P, Chauhan AK, Kaushal V (2016). "Exploring the Management of Radiation Proctitis in Current Clinical Practice". J Clin Diagn Res. 10 (6): XE01–XE06. doi:10.7860/JCDR/2016/17524.7906. PMC 4963751. PMID 27504391.CS1 maint: Multiple names: authors list (link)
9. ↑ 9.0 9.1 Nelamangala Ramakrishnaiah VP, Krishnamachari S (2016). "Chronic haemorrhagic radiation proctitis: A review". World J Gastrointest Surg. 8 (7): 483–91. doi:10.4240/wjgs.v8.i7.483. PMC 4942748. PMID 27462390.
10. ↑ 10.0 10.1 10.2 10.3 Hayne D, Vaizey CJ, Boulos PB (2001). "Anorectal injury following pelvic radiotherapy". Br J Surg. 88 (8): 1037–48. doi:10.1046/j.0007-1323.2001.01809.x. PMID 11488787.CS1 maint: Multiple names: authors list (link)
11. ↑ Thielman NM, Guerrant RL (2004). "Clinical practice. Acute infectious diarrhea". N Engl J Med. 350 (1): 38–47. doi:10.1056/NEJMcp031534. PMID 14702426.
12. ↑ Khan AM, Faruque AS, Hossain MS, Sattar S, Fuchs GJ, Salam MA (2004). "Plesiomonas shigelloides-associated diarrhoea in Bangladeshi children: a hospital-based surveillance study". J Trop Pediatr. 50 (6): 354–6. doi:10.1093/tropej/50.6.354. PMID 15537721.CS1 maint: Multiple names: authors list (link)
13. ↑ 13.0 13.1 Tortora A, Purchiaroni F, Scarpellini E, Ojetti V, Gabrielli M, Vitale G; et al. (2012). "Colitides". Eur Rev Med Pharmacol Sci. 16 (13): 1795–805. PMID 23208963.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
14. ↑ Eifel PJ, Levenback C, Wharton JT, Oswald MJ (1995). "Time course and incidence of late complications in patients treated with radiation therapy for FIGO stage IB carcinoma of the uterine cervix". Int J Radiat Oncol Biol Phys. 32 (5): 1289–300. doi:10.1016/0360-3016(95)00118-I. PMID 7635768.CS1 maint: Multiple names: authors list (link)
15. ↑ 15.0 15.1 15.2 15.3 Kountouras J, Zavos C (2008). "Recent advances in the management of radiation colitis". World J Gastroenterol. 14 (48): 7289–301. PMC 2778112. PMID 19109862.
16. ↑ US preventive service task force.radiation colitis. http://www.uspreventiveservicestaskforce.org/accessed on November 13, 2016
17. ↑ 17.0 17.1 17.2 17.3 17.4 Gilinsky NH, Burns DG, Barbezat GO, Levin W, Myers HS, Marks IN (1983). "The natural history of radiation-induced proctosigmoiditis: an analysis of 88 patients". Q J Med. 52 (205): 40–53. PMID 6603628.CS1 maint: Multiple names: authors list (link)
18. ↑ Asano N, Iijima K, Terai S, Uno K, Endo H, Koike T; et al. (2011). "Signet Ring Cell Gastric Cancer Occurring after Radiation Therapy for Helicobacter pylori-Uninfected Mucosa-Associated Lymphoid Tissue Lymphoma". Case Rep Gastroenterol. 5 (2): 325–9. doi:10.1159/000329559. PMC 3124325. PMID 21712948.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
19. ↑ Narui K, Ike H, Fujii S, Nojiri K, Tatsumi K, Yamagishi S; et al. (2006). "[A case of radiation-induced rectal cancer]". Nihon Shokakibyo Gakkai Zasshi. 103 (5): 551–7. PMID 16734262.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
20. ↑ Andreyev HJ, Davidson SE, Gillespie C, Allum WH, Swarbrick E, British Society of Gastroenterology; et al. (2012). "Practice guidance on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer". Gut. 61 (2): 179–92. doi:10.1136/gutjnl-2011-300563. PMC 3245898. PMID 22057051.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)

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