Curr Gastroenterol Rep (2014) 16:383 DOI 10.1007/s11894-014-0383-3

SMALL INTESTINE (J SELLIN, SECTION EDITOR)

Radiation Enteritis Ali H. Harb & Carla Abou Fadel & Ala I. Sharara

# Springer Science+Business Media New York 2014

Abstract Radiation enteritis continues to be a major health concern in recipients of radiation therapy. The incidence of radiation enteritis is expected to continue to rise during the coming years paralleling the unprecedented use of radiotherapy in pelvic cancers. Radiation enteritis can present as either an acute or chronic syndrome. The acute form presents within hours to days of radiation exposure and typically resolves within few weeks. The chronic form may present as early as 2 months or as long as 30 years after exposure. Risk factors can be divided into patient and treatment-related factors. Chronic radiation enteritis is characterized by progressive obliterative endarteritis with exaggerated submucosal fibrosis and can manifest by stricturing, formation of fistulae, local abscesses, perforation, and bleeding. In the right clinical context, diagnosis can be confirmed by cross-sectional imaging, flexible or video capsule endoscopy. Present treatment strategies are directed primarily towards symptom relief and management of emerging complications. Recently, however, there has been a shift towards rational drug design based on improved understanding of the molecular basis of disease in an effort to limit the fibrotic process and prevent organ damage. Keywords Radiation . Enteritis . Enteropathy . Radiotherapy

radiation energy exposure. Radiation enteritis is a term commonly used to describe both small as well as large intestinal injury after radiation exposure. This, by definition, excludes injury to the rectum, referred to separately as radiation proctitis. The purpose of this review is to assess the current state of knowledge on radiation enteritis by addressing the burden, presentation, risk factors, pathogenesis, prevention, diagnosis, and management of this emerging problem. This article deals primarily with chronic radiation enteritis and the small intestinal response to radiation exposure. Acute radiation enteritis is briefly discussed while radiation proctitis is not covered. Historical Background The first report of radiation-induced gut injury was described in 1897 [1] when experiments revealed radium-induced death of diseased cells [2], only 1 year after the introduction of radiation as a treatment modality and 2 years after the discovery of the X-ray itself by Roentgen [3]. Walsh described the phenomenon as ‘a direct inflammation of the gastrointestinal mucous membranes’ [1]. A quarter of a century later, Warren and Whipple conducted the first systematic study on dogs to characterize the effects of radiation on intestinal structure and function [4].

Introduction Clinical Burden Definition and Scope Radiation enteritis is by simple definition an inflammatory process occurring at the level of the intestines as a response to This article is part of the Topical Collection on Small Intestine A. H. Harb : C. Abou Fadel : A. I. Sharara Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon A. I. Sharara (*) Division of Gastroenterology, American University of Beirut Medical Center, P.O. Box 11-0236/16-B, Beirut, Lebanon e-mail: [email protected]

Recent reports indicate that as many as 70 % of cancer patients receive radiotherapy during the course of their treatment [5]. Estimates indicate that around 300,000 patients received radiotherapy for pelvic malignancy worldwide in 2007 alone [6]. This widespread use of radiation in cancer therapy [5], along with the high incidence of radiation-induced side effects affecting up to 75 % of radiotherapy receivers [7], has led to a tremendous increase in the incidence of radiation enteritis. The concomitant use of chemotherapy [8] as well as the continued improvement in cancer prognosis are expected to increase this even further [9]. Still, it is believed that the true burden of radiation enteritis may even be larger due to under

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diagnosis and underreporting [10]. Lastly, the significant morbidity and mortality carried by RE in the post-therapy period is not the only thing to be feared [11]. Collateral damage to normal tissue is the main reason for dose limitation, a potential hurdle to treatment [12].

Presentation Radiation enteritis can present as either an acute or chronic syndrome. The acute form presents within hours to days of radiation exposure and typically resolves within few weeks. The classical presentation includes nausea, vomiting, abdominal pain, diarrhea, and tenesmus. The chronic form may present as early as 2 months or as long as 30 years after exposure [13, 14]. Clinical manifestations differ but may include abdominal pain, malabsorption, diarrhea, cachexia, intestinal bleeding, obstruction, and even perforation [15]. Risk Factors Risk factors for RE can be divided into patient- and treatmentrelated factors. Patient factors include previous abdominal or pelvic surgical operations, low body mass index, concomitant cardiovascular disease, atherosclerosis, diabetes, older age, female sex, and tobacco abuse [16, 17]. Risk factors related to treatment include the dose of radiation used and its fractionation schedule, as well as the volume of small bowel in the radiation field [18] and the concomitant use of chemotherapy [19].

Pathophysiology Acute Radiation Enteritis Acute radiation enteritis is thought to be a consequence of the direct exposure of the rapidly dividing intestinal epithelium, especially crypt stem cells, to the cytotoxic effects of radiation [20]. Apoptosis [21] mediated by the overexpression of p53 [22] and the down-regulation of Bcl-2 [23] plays a central role in the process. The resultant mucositis interferes with the intestinal barrier function and may lead to translocation of luminal bacteria [24, 25]. Recently, however, an increasing body of evidence indicates that injury to the endothelium of the microvasculature supplying the intestines might also be contributory [26–28]. A complex interplay between radiation-induced reduction of thrombomodulin in endothelial cells [29], excess activation of thrombin, and alteration of platelet adhesion properties [30] leads to a more thrombophilic endothelium [31], which is thought to be behind not only acute radiation enteritis but also chronic radiation enteritis if perpetuated [32, 33]. The

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diarrhea experienced by most patients is thought to result from a combined suppression of the Na+/K+ pump, lactose intolerance, and intestinal dysmotility leading to bacterial overgrowth [34–36]. Lebrun et al showed a 40 % decrease in Na-K pump activity in rats 4 days following irradiation. A similar decrease in pump activity was described by Sandle in animal models of colitis. This resultant impairment in sodium and chloride absorption caused watery diarrhea [37]. Chronic Radiation Enteritis Chronic radiation enteritis (CRE), on the other hand, is characterized by progressive obliterative endarteritis [38]. This occlusive vasculitis causes tissue ischemia that in turn leads to an exaggerated submucosal fibrosis [39]. Fibrosis is mostly mediated by TGF-β1 [40–42] and its downstream mediator, connective tissue growth factor (CTGF) [9]. Fibrosis worsens the existing ischemia and sustains the problem. Telangiectatic vessels form in response [43], which, along with lymphatic dilation, complete the microscopic picture [18]. Macroscopically, CRE is manifested by stricturing, formation of fistulae, local abscesses, perforation, and bleeding [44]. Altered motility [45] and malabsorption [46] are additional features. Lately, accumulating evidence suggests that luminal microbiota might have a game-changing influence on human response to radiation [47]. This influence is thought to be mediated by toll-like receptors [48]. Experiments carried out on germ-free mice support an enhanced resistance to radiation-induced colitis [49, 50], while other studies point to microbial dysbiosis as a risk factor for RE [51]. A small study comparing patients who developed diarrhea post-radiotherapy to those who did not found that patients with diarrhea had a different microbial profile at baseline in comparison to the other group. Patients with diarrhea, in addition, developed an alteration in their fecal microbial profile post radiation. These findings suggest a role of gut microbiota in determining diarrhea in the host post radiation exposure [52].

Diagnosis The diagnosis of RE might be challenging especially that its symptoms are nonspecific and sometimes multifactorial [15]. A history of radiation exposure and an appropriate combination of symptoms should not prevent the clinician from first excluding recurrent neoplasia [15]. Cross-sectional imaging with either computed tomography enterography (CTE) (Fig. 1) or magnetic resonance imaging (MRI) might be prudent especially when the patient suffers weight loss [18]. Magnetic resonance enterography (MRE) has the additional

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Fig. 1 a, b Videocapsule endoscopy showing segmental mucosal edema, erythema, superficial erosions, and functional narrowing in a patient with chronic radiation enteritis presenting with recurrent unexplained abdominal pain and negative abdominal CT. c CT enterography of a 72-year-old woman who received pelvic radiotherapy for cervical carcinoma. Enteric phase images show ileal luminal narrowing and a thickened enhanced bowel wall (arrow) consistent with radiation enteritis [138]. Source of (c): Graça BM, Freire PA, Brito JB, et al. Radiographics 2010; 30: 235–252. With permission of the Radiological Society of North America (RSNA®)

ability to show luminal irregularities [53] without further radiation exposure. Findings are largely non-specific and indicate segmental inflammation. These include bowel thickening, mucosal hyperenhancement, mesenteric stranding, and luminal stricturing [54]. Non-invasive biological markers are unreliable. C-reactive protein is not useful in uncomplicated CRE [55], and data on fecal lactoferrin [56] and calprotectin remain inconclusive [57]. Serum citrulline, a metabolic by-product of intestinal cells, holds the promise of being used to assess the extent of damage as it was found to correlate with the viable enterocyte mass [58–60]. A symptom-directed approach is thus used to guide minimally invasive techniques to investigate symptoms. CTE and MRE are the preferred initial tests when chronic radiation enteritis is suspected. Esophagogastroduodenoscopy may be helpful to exclude other possibilities, and small intestinal contrast studies may disclose subtle strictures, while ileocolonoscopy or balloon-assisted enteroscopy offer the added value of direct visualization and diagnosis of radiation enteritis [18]. When all studies are negative, video capsule endoscopy (VCE) (Fig. 1) remains one of the best methods to reach the diagnosis [61–63]. Because of the high incidence of capsule impaction, a patency capsule should be considered prior to VCE in order to exclude subtle, yet important, luminal narrowing(s) [64, 65]. Bile salt malabsorption [66], bacterial overgrowth [67], and carbohydrate malabsorption [68] often accompany radiation enteritis and are diagnosed with selenium75 homocholic acid conjugated with taurine (SeHCAT) scanning [69], xylose breath test [70], and hydrogen breath test [71], respectively.

Prevention Several studies have validated the use of small bowel studies to determine the amount of small intestines in the pelvis and use the information to modify radiation fields [72–74]. Technical strategies have succeeded by directing the radiation away from normal tissues through improved planning and delivery systems, physical maneuvers [5] like the use of “belly boards” [75], and the use of physical shields. The use of surgery to displace the small bowels from the radiation field has also been reported [13]. Different techniques have been developed including reperitonealization, the use of omental transposition flaps [76], abdominopelvic omentopexy [77], introducing absorbable mesh slings [78–80], and occluding the pelvis with prosthetics [81, 82] or the bladder, or retroverting the uterus [83]. Radioprotective compounds have been used with some success. Cysteine, in mice [84], and amifostine, in a human trial, have been shown to reduce mucosal toxicity [85] of radiation including radiation enteritis [86]. When administered prior to irradiation, L-carnitine resulted in reduction of ileal mucosal damage severity [87].

Management Present treatment strategies are directed mostly towards symptomatic relief. Recently, however, there has been a shift towards rational drug design that utilizes our improved understanding of the molecular basis of disease to curtail the fibrotic process and prevent organ damage.

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Treatment Dietary modification might be tried to alleviate symptoms: for example, a high-residue and fatty diet may be eliminated with some symptomatic improvement [88, 89]. Patients who develop lactose intolerance must follow a lactose-free diet [71]. Antidiarrheal agents, such as loperamide, increase transit time and may offer relief [68]. Cholestyramine remains the treatment of choice for patients with bile acid malabsorption [15, 90, 91], while antibiotics may be prescribed to treat confirmed bacterial overgrowth [36]. Antidepressants warrant trial in select patients bearing in mind the strong association of CRE with depression [92, 93]. Parenteral nutrition is also an acceptable adjunct when daily energy requirements cannot be met with oral nutrition alone [94]. However, care must be taken due to the higher incidence of cirrhosis and portal hypertension in patients with short bowel syndrome with a history of radiation exposure [95]. Strictures [96], fistulae, perforations, and obstruction, are best treated surgically [97]. However, surgery in this patient population carries a high complication rate, particularly anastomotic leaks [98], making bypass a favored option over resection-anastomosis [99]. Other studies have found that high-risk patients are better managed either medically or endoscopically, and so should avoid surgery due to the high associated morbidity and mortality [100]. Despite improvements in the medical prevention and treatment of radiation enteritis, the need for surgical treatment has not decreased [101]. Probiotics The idea of using probiotics in RE stems from their antioxidant role given that free-radical production initiates injury [102]. Studied species include Lactobacillus plantarum and lactis [103], Lactobacillus gasseri [104], Lactobacillus fermentum E-3 and E-18 [105], and Streptococcus thermophilus [106], all of which were found to have antiinflammatory effects. Probiotics are thought to act as delivery vehicles for superoxide dismutase [102], an enzyme shown to reduce oxidative stress and downregulate adhesion molecule in mice that had undergone abdominal irradiation [107]. Probiotics can also promote the intestinal release of glutathione [102], an important molecule that helps maintain the mucosal integrity and improve oxidative damage in colitis [108]. In addition, probiotics produce exopolysaccharides which act to reduce the intestinal oxidative stress [109]. With few exceptions like pouchitis and infectious diarrhea, the use of probiotics to manage different conditions has generally been disappointing. Nevertheless, trials evaluating the use in RE have been somewhat supportive. A study of almost 500 patients demonstrated that patients receiving the VSL#3 probiotic mixture prophylactically had a decrease in both severity and frequency of post-radiation diarrhea compared

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to placebo [110]. Similarly, patients receiving Lactobacillus rhamnosus required less anti-diarrheals at a later stage compared to placebo and had more consistent stools [111]. The use of probiotics in the prevention of radiation-induced diarrhea was classified as Recommendation Grade C in 2008, meaning there are some positive studies, but more studies are needed to confirm this beneficial role in radiation enteritis [112]. Experimental Therapies Table 1 lists the experimental therapies used in the treatment or prevention of radiation enteritis. The strongest evidence to date has been for the pentoxyfilline–tocopherol combination shown in two cohort studies to cause relief of symptoms [113, 114] and to attenuate fibrosis [115, 116]. Other studies suggest that anti-inflammatory drugs such as sulfasalazine [117] and methylprednisolone [118] might be beneficial. Additionally, there have been case reports of the successful use of hyperbaric oxygen [119] to enhance recovery. Intraperitoneallyadministered octreotide was shown to protect against oxidative injury and preserve mucosal structure in animal models [120]. Similarly, heparin-binding epidermal growth factor (HB-EGF) was successful in decreasing pro-inflammatory cytokines [121], oxygen-free radical production [122], and intestinal histologic injury, preserving gut barrier function when tested on rats [123]. Statins, shown to decrease radiation pneumonitis [124] have been studied in vitro with results indicating the inhibition of CTGF and collagen production [125, 126]. Cyclooxygenase 2 inhibitors have also been shown to decrease radiation injury in rats [127]. As the role of the endothelium in the pathogenesis of RE unfolds, more endothelial-based therapies are being tested in rats. Direct thrombin inhibitors like hirudin successfully improved radiation enteropathy. In comparison, clopidogrel, an ADP receptor antagonist, had an even higher efficacy in ameliorating enteropathy [128, 129]. Unexpectedly, a trial testing the value of heparin in reducing RE showed a paradoxical worsening in radiation injury [130]. One explanation is offered by another study demonstrating that heparin can decrease the affinity between thrombin and thrombomodulin, causing a further decrease in APC levels in this altered endothelial medium [131]. Rational Drug Design Some drugs remain untested in the context of radiation enteritis despite some apparent theoretical significance. Recombinant thrombomodulin, with proven efficacy in disseminated intravascular coagulation, warrants testing in RE due to its potential in restoring the lost thromboresistance in the endothelial milieu [132, 133]. Recombinant activated protein C, with proven efficacy in severe sepsis, may also be able to achieve that goal [134]. The inhibition of proteinase-activated receptor 1, the

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Table 1 Experimental therapies in the treatment and/or prevention of radiation enteritis Experimental therapy

Study group

End point

Mechanism of action

Cysteine [134]

Animals (rats)

Prevention of acute RE

Repletion of glutathione

Amifostine [82]

Humans

L-carnitine [84]

Animals (rats)

Pentoxyfilline-tocopherol [110]

Humans

Sulfasalazine [114]

Humans

Hyperbaric oxygen [116]

Humans

Octreotide [117]

Animals (rats)

Heparin-binding epidermal growth factor (HB-EGF) [120]

Animals (mice)

Statins [122]

Human explants (in vitro) Animals (rats)

Cyclooxygenase-2 Animals (rats) inhibitors (COX-2) [124] Hirudin [125]

Animals (rats)

Clopidogrel [126]

Animals (rats)

Comments

Oxothiazolidine carboxylate (OTZ), a cysteine prodrug, was given orally to rats with sarcoma before and following abdominal radiation → at day 4 there was a significant increase in glutathione in jejunum. Prevention of acute and Antioxidant Patients with pelvic malignancies randomized chronic radiation injury to radiotherapy ± IV amifostine 15 min before radiotherapy → reduction in acute lower GI toxicity at weeks 3–7. Lesser protection observed at 12 month follow-up Prevention of acute RE Antioxidant Whole-body radiation followed by intraperitoneal L-carnitine × 4 days → significant ↓ in serum MCP-1, IFN- γ and reduced severity of mucosal damage. Apoptotic cells of ileal crypt ↑ early after irradiation and ↓ by 4th day Symptomatic relief Antioxidant 21 patients with radiation proctitis/enteritis Inhibit TGF-β1/Smad treated with pentoxifylline and tocopherol targets → 15/21 patients (71 %) experienced relief of symptoms Diarrhea and acute RE Anti-inflammatory Significant ↓ diarrhea with oral sulphasalazine symptoms vs. placebo GI complications of Promotes angiogenesis Improved complete and partial response chronic RE rates (43 and 25 %, respectively) Prevention of acute RE Antioxidant Irradiation ↑ intestinal myeloperoxidase activities, intestinal malondialdehyde levels and NFκ-B expression. Octreotide preserved mucosal structure, ↓ NFκ-B expression, end organ damage and inflammation Acute radiation injury Antioxidant Intraperitoneal HB-EGF led to increase in proliferative crypts and decrease in severe histologic injury and intestinal permeability Attenuate endothelial cell TNF-α antagonist Inhibits Rho activity, type I collagen, and injury and fibrosis fibronectin in vitro. Pravastatin improves radiation enteropathy in rats with decreased deposition of CCN2 and extracellular matrix deposition Decrease in COX-2 Anti-inflammatory Treatment with rofecoxib significantly ↓ overexpression radiation-induced overexpression of COX-2 Acute radiation injury Direct thrombin inhibitor Attenuates radiation-induced mucosal damage, reactive intestinal wall thickening, TGF-β immunoreactivity levels, and collagen III deposition Acute radiation injury Platelet ADP receptor Attenuates the severity of post-radiation antagonist vascular sclerosis and loss of mucosal surface area

downstream mediator of thrombin’s rheological effect through a specific antagonist that is currently being developed [135] is also very appealing [32]. At the other end of the spectrum, IFN-γ, an antagonist of TGF-β, might prevent the fibrotic cascade that leads to damage of irradiated organs [136].

Conclusion Radiation enteritis is an old yet emerging problem spurred by the rise of cancer radiotherapy. Radiation enteritis usually affects patients with some predisposing characteristics, but is

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largely influenced by treatment-related factors. The modification of these factors has, so far, been key to prevention. A complex interplay between intestinal epithelium, capillary endothelium, and luminal bacteria is thought to underlie its pathogenesis. Cross-sectional imaging and endoscopy are the mainstay of diagnosis. Treatment is usually palliative, but some experimental therapies and rational drug design hold promise at curtailing the inflammatory process and preventing organ damage. Effective treatment and prevention are critical in minimizing the burden of this daunting disease and at preserving radiation as an effective therapy in combating abdominal cancers. Compliance with Ethics Guidelines Conflict of Interest Ala Sharara, Ali Harb, and C. Abou Fadel disclose no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors [137].

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