Radiation Enteritis

470 | AUGUST 2014 | VOLUME 11 www.nature.com/nrgastro

Surgical Service, Central Arkansas Veterans Healthcare System and Division ofRadiation Health, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA (M.H.J.). Department of Radiation Oncology, University of Newcastle, Newcastle, NSW 2308, Australia (J.W.D.). Department of Medicine, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK (H.J.N.A.).

Correspondence to: M.H.J. mhjensen@ life.uams.edu

Radiation enteropathypathogenesis, treatment and preventionMartin Hauer-Jensen, James W. Denham and H. Jervoise N. Andreyev

Abstract | Changes in cancer incidence and mortality have been modest during the past several decades, but the number of cancer survivors has almost tripled during the same period. With an increasing cohort of cancer survivors, efforts to prevent, diagnose and manage adverse effects of cancer therapy, in general, and those of radiation therapy specifically, have intensified. Many cancer survivors have undergone radiation therapy of tumours in the pelvis or abdomen, thus rendering the bowel at risk of injury. In fact, the current prevalence ofpatients who have longterm radiationinduced intestinal adverse effects exceeds that of IBD. Considerable progress towards reducing toxicity of radiation therapy has been made by the introduction of socalled dosesculpting treatment techniques, which enable precise delivery of the radiation beam. Moreover, new insights into the underlying pathophysiology have resulted in an improved understanding of mechanisms of radiationinduced bowel toxicity and in development of new diagnostic strategies and management opportunities. ThisReview discusses the pathogenesis of early and delayed radiationinduced bowel toxicity, presents current management options and outlines priorities for future research. By adding insight into molecular and cellular mechanisms of related bowel disorders, gastroenterologists can substantially strengthen these efforts.

HauerJensen, M. et al. Nat. Rev. Gastroenterol. Hepatol. 11, 470479 (2014); published online 1 April 2014; corrected online 26 August 2014; doi:10.1038/nrgastro.2014.46

IntroductionRadiation therapy is used in at least 50% of patients with cancer and has a crucial role in 25% of cancer cures.1 Despite advances in treatment delivery techniques, radia-tion toxicity to healthy tissue remains the overwhelmingly most important barrier to cancer cure in patients with localized disease. During radiation therapy of tumours in the abdomen or pelvis, the intestine is at risk of damage. Early radiation enteropathy (intestinal radiation toxicity) occurs within 3months of radiation therapy and affects the quality of life at the time of treatment. As treatment interruption or changes in the original treatment plan might be required, the likelihood of tumour control is compromized. Delayed radiation enteropathy is a major issue for long-term cancer survivors; this progressive con-dition has few therapeutic options available and can lead to substantial long-term morbidity and mortality.

This Review discusses radiation enteropathy as a clinical problem, as well as the pathological features of the con-dition and its underlying cellular and molecular mecha-nisms. Contemporary approaches for prevention and management of radiation enteropathy are also presented. The aim of this Review is to provide an introduction to the subject, tailored to the needs of thegastroenterologist.

Magnitude of the clinical problemDevelopments in treatment techniques have made it pos-sible to deliver radiation to tumours with much greater

precision than before. Nevertheless, healthy tissue tox-icity remains the single most important radiation-dose-limiting factor and obstacle to cancer cure. Moreover, some authors have expressed concern about new treat-ment techniques and what they mean for the spectrum of toxicities.2 During radiation therapy of tumours in the abdominal cavity or pelvis, parts of the small bowel, colon or rectum are inevitably included in the treatment field and represent important healthy tissues at risk.

The incidence and severity of radiation enteropathy are dependent on a number of factors. Therapy-related factors include radiation dose, volume (length) of bowel that is irradiated, time-dose-fractionation parameters and the use of concomitant chemotherapy or biotherapy. Patient-related factors include body mass index (obesity protects, whereas reduced body mass indexpre disposes to radiation toxicity3,4); previous abdominal surgery, which increases the risk of radiation-induced bowel injury (peritoneal adhesions lead to fixation of small bowel loops in the radiation field); and certain comor-bidities including IBD,5 diabetes,6 vascular disorders7 and collagen vascular disease.8,9 Tobacco smoking is a strong independent predictor of intestinal complications after radiation therapy of tumours in the pelvis or abdomen. Genetic pre disposition also has an important role and might explain why certain patients go through therapy without adverse effects, and others, who get exactly the same treatment, experience severetoxicities.10

Radiation enteropathy is generally classified as early (acute) when it occurs within 3months of radiation

Competing interestsThe authors declare no competing interests.

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2014 Macmillan Publishers Limited. All rights reserved

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NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY VOLUME 11 | AUGUST 2014 | 471

therapy, or delayed (chronic) when it occurs >3months after radiation therapy. Annually, it is estimated that >200,000 patients in the USA receive pelvic or abdominal radiation therapy with a 6080% incidence of symptoms of acute bowel toxicity. Currently, there are >13million cancer survivors in the USA, and this number will prob-ably increase to 18 million by 2022.11 More than half of these patients are survivors of abdominal or pelvic cancers (Figure1).12 The incidence of severe (grade 34) delayed radiation enteropathy has diminished over time, largely thanks to developments in radiation treatment planning and radiation delivery techniques. However, series with careful follow-up show that at least half of the patients will have some form of chronic gastrointestinal dysfunction. Most clinical studies greatly underestimate the true prevalence of delayed bowel toxicity.13 However, some authors claim that some degree of gastrointestinal dysfunction is an almost inevitable consequence of pelvic or abdominal radiation therapy.14,15 Our conservative estimate of the number of patients with post-radiation

Key points

Radiation therapy planning and delivery methods have improved substantially, but the risk of intestinal radiation injury remains the single most important doselimiting factor in radiation therapy for abdominal and pelvic tumours

Early (acute) radiation enteropathy generally occurs during the course of radiation therapy, whereas delayed (chronic) radiation enteropathy develops after a latency period of variable length

Delayed radiation enteropathy is among the most common radiationtherapyrelated adverse effects; the prevalence of radiation enteropathy exceeds that of IBD

The risk of radiation enteropathy limits the uncomplicated cancer cure rate andadversely affects the quality of life of cancer survivors

As the number of cancer survivors steadily increases, radiation enteropathy represents a significant challenge for future research

Finding safe and effective pharmacological methods to reduce the incidence and severity of radiation enteropathy is an unmet need

intestinal dysfunction living in the USA most certainly exceeds 1.6 million, which is in contrast to a prevalence of 396 per 100,000 persons for IBD16 or ~1.4 million people with IBD in the USA.17

Clinical and pathological characteristicsEarly intestinal injury manifests within days of beginning a course of radiation therapy and is primarily a result of cell death in the rapidly proliferating crypt epithelium and a protracted acute inflammatory reaction in the lamina propria. Crypt cell death results in insufficient replace-ment of the villus epithelium, breakdown of the mucosal barrier and mucosal inflammation. Figure2 shows an example of experimental radiation mucositis using a clinically relevant model for localized irradiation of rat small bowel18 and Figure3 displays an example of clinical radiation mucositis in the rectum from a patient under-going radiation therapy for prostate cancer. Symptoms of early bowel toxicity (nausea, abdominal pain, diar-rhoea and fatigue) develop in 6080% of patients during radiation therapy of tumours in the abdomen or pelvis. Nausea typically occurs relatively early, whereas diar-rhoea and abdominal pain usually become problematic 23weeks into the course of radiation therapy. In most patients, acute symptoms of bowel toxicity resolve within 13months of c ompletingtreatment.

Symptoms of delayed bowel toxicity can develop before symptoms attributable to early toxicity subside, but typi-cally present after a latency period of 6months to 3years. However, latency periods of 2030years after radiation therapy are not uncommon. The pathogenesis of delayed radiation enteropathy is complex and involves changes in most compartments of the intestinal wall. Atrophy of the mucosa, fibrosis of the intestinal wall and microvascular sclerosis are prominent, and are currently irreversible features (Figure4). The main clinical features of delayed radiation enteropathy are altered intestinal transit, nutri-ent malabsorption and gut dysmotility.19 Delayed radia-tion enteropathy is a chronic, often progressive disorder and associated with substantial long-term morbidity. Severe (grade 34) late effects, as mentioned above, have become less common than they were in the past. Nevertheless, for example, the incidence of severe toxicity after chemoradiation therapy of cervical cancer remains at ~10%.20 Severe delayed radiation enteropathy might progress to intestinal obstruction, fistulae formation or frank intestinal perforation. Corrective surgery is associ-ated with high postoperative morbidity and mortality. In the long term, the majority of patients have persistent or recurrent symptoms, and ~10% of patients die as a direct result of radiation enteropathy.21,22 Patients with isolated colonic injury have fewer problems with nutrition, fluid and electrolyte balance and their long-term prognosis is better. A comprehensive description of clinical and pathological features of radiation e nteropathy has been provided elsewhere.2325

Understanding the toxicityThe classic understanding of radiation enteropathy was based entirely on the target cell theory, which was

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Figure 1 | Cancer survivors and cancer prevalence rates in the USA. a | Cancer incidence and death rates have been fairly flat during the past four decades, whereas the cohort of cancer survivors has increased by 23% per year, exceeding 13 million people in 2013, and is expected to reach 18 million in 2022.11 Approximately half of all cancer survivors have had abdominal or pelvic tumours,12 many of whom have had or will have radiation therapy. Radiation enteropathy, therefore, seems to be a major obstacle to uncomplicated cancer cures. b|Prevalence rates.

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formulated in the 1920s and 1930s and provided us with a formal framework in the 1940s.26 According to this concept, the intestine was considered a more or less inert tube, covered on the inside by a rapidly proliferating epi-thelium, with the rest of the bowel tissues more or less irrelevant. The severity of epithelial injury was the only determinant of early pathology, whereas a different, more slowly proliferating, target cell (fibroblast, endothelial cell) was used to explain delayed effects. The sequence of structural and functional manifestations of radiation enteropathy has not changed, but our understanding of the underlying pathobiology has improved over the years. Hence, the contemporary view is that many tissues and cell types in the gut participate and contribute to injury. For example, the intestinal immune system is the largest in the human body and profoundly influences the development of secondary changes after radiation. The enteric nervous system is the second largest nervous system, with a greater number of neurons than the spinal cord, and strongly regulates radiation enteropathy develop ment.27 The intestinal microvasculature is also recognized as an important contributor to radiation tox-icity of the bowel. Furthermore, 100 trillion bacteria in the gut lumen, 10-fold the number of cells in the human body, profoundly influence radiation enteropathy devel-opment.28 In other words, we have progressed beyond the single target cell concept and now recognize that, in addition to epithelial injury, the intestinal microvascula-ture, immune mechanisms, neuro immune interactions, the gut microbiome, the composition of the intra luminal contents and a host of other factors have important roles (Figure5).

Consequential late effectsThe recognition that delayed radiation injury might develop in the wake of severe acute injury was recognized clinically by Bourne and colleagues29 and Peters et al.30 subsequently coined the term consequential late effects.Consequential late effects serve an important purpose by helping to eradicate the old dogma of independence between early and delayed radiation effects; improving our understanding of the pathophysiology and patho-genesis of delayed normal tissue injury; and for interpret-ing and modelling radiation responses invivo. However, it has become increasingly clear that the terminology fails to recognize the complexity of radiation effects in multicellular tissues and organs; the co-existence of consequential and primary injury (although the response might be skewed in one direction or the other); and evi-dence that early effects unrelated to cell death might give rise to subsequent chronic injury. Many pharmacological and genetic models have also shown that the relation-ship cannot be explained simply by consequential late effects. For example, rats deficient in mast cells, sensory nerve-ablated rats and TGF- heterozygous rats all show dissociations between early and delayed injury,3134 that is, they all have exacerbated epithelial injury, but reduced levels of intestinal fibrosis.

As these observations fundamentally conflicted with the traditional notion of consequential late tissue injury,

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Figure 2 | Radiation mucositis in the rat intestine. Unirradiated (control) rat withintestine transposed to the left scrotum (parts ac). a | Bioluminescence image (luminol). No increase in bioluminescence indicating little or no myeloperoxidase activity. b | Small intestine stained with antitransferrin antibody. Few granulocytes are seen in the mucosa or submucosa. c | Small intestine stained with antiED2(CD163) antibody. There are few macrophages in the mucosa/submucosa. Rat with intestine transposed to the left scrotum and exposed to localized, fractionatedirradiation (parts df). d | Bioluminescence image (luminol) 5days after localized irradiation. Significant increase in bioluminescence indicating substantial myeloperoxidase activity. Intestine procured 2weeks after irradiation showing e|accumulation of granulocytes inmucosa/submucosa and f | accumulation of macrophages in mucosa or submucosa. Original magnification of all rat intestine images 40.

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Figure 3 | Human endoscopic biopsy samples of rectal mucosa obtained from a patient before and during ongoing radiation therapy of prostate cancer. a|PAS staining of healthy rectal mucosa before the start of radiation therapy. Note intact surface epithelium, straight glands and the many PASpositive goblet cells. b|Glandular atrophy, mucosal inflammation, and loss of PASpositive goblet cells 2weeks into the course of radiation therapy. Original magnification of both images 20. Abbreviation: PAS, periodic acidSchiff.

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a new terminology for classifying healthy tissue radiation responses was proposed in 2001.35 According to this clas-sification, there are three types of effect. First, cytocidal effects, in which radiation causes cell death including clonogenic cell death, mitotic catastrophe and apopto-sis. Second, functional effects, in which radiation leads to changes including transcription factor activation and protein modification in the intracellular environment, plasma membrane and extracellular space. Third, sec-ondary effects that occur in response to the initial radia-tion insult, such as cellular inflammation and release of cytokines and other mediators. It is important to remem-ber that all three types of effect interact and contribute to organ dysfunction.

Fractionated radiation therapyMost radiation therapy regimens are delivered as frac-tions of 1.82.0 Gy on weekdays for a number of weeks. The radiotherapy response differs from other types of tissue damage in that a burst of free radicals is produced, which not only causes immediate DNA damage, but also alters proteins, lipids, carbohydrates and other complex molecules. When considering healthy tissue radiation responses, it is important to also consider that they occur as a result of multiple repetitive injuries (fractions) rather than as a response to a single insult,36 with each fraction contributing to inflammatory cell recruitment as well as to the accumulation of direct tissue injury. Furthermore, each fraction affects tissue that already exhibits a dynamic spectrum of cellular injury, ongoing repair, inflamma-tion and other pathophysiological responses. Therefore, with repetitive radiation exposure, many cellular and molecular responses will be substantially exacerbated, suppressed or substantially altered when compared with the situation after a single exposure to radiation or trau-matic injury. Nowhere is this effect more evident than in the intestine. The number of patients with symptoms of toxicity increases steadily during a 6-week course of frac-tionated radiation, as does the toxicity score.37 However, mucosal pathology and functional bowel injury (intesti-nal permeability assessed with differential urinary excre-tion of disaccharides and monosaccharides) is actually substantially worse after just 2weeks irradiation than towards the end of the treatment course.37,38 The fact that the patient has received a threefold higher radiation dose at the end of the radiation therapy course than at 2weeks points to the remarkable regenerative capacity of the intestine and raises i nteresting questions about the real cause of the symptoms.

Radiation enteropathy as a model of IBDRadiation enteropathy could be considered an ideal model of gastrointestinal inflammation for several reasons. First, radiation enteropathy is highly clini-cally relevant; as pointed out above, the prevalence of r adiation-induced gastrointestinal dysfunction is higher than that of IBD. Second, animal models and patients have identical pathology and pathophysiology, so thetranslational value of the observations made in the animal model is clear (Figure6). Third, animal models of radiation enteropathy have made it possible to easily and precisely adjust the dose of the toxic agent (radiation), and so doseresponse relationships can be investigated in greater detail than is true for other animal models of IBD. For example, a particularly useful, clinically rele-vant rat model has been published and used extensively for studies of time-dose-fractionation relationships.39 This model, which can be created by a simple surgical pro cedure prior to irradiation, enables delivery of frac-tionated irradiation to a defined loop of small intes-tine and can be further modified to study intraluminal delivery of radiation response modifiers directly into the irradiated bowel loop.40 Finally, by using the iden-tical causative agent (radiation), radiation enteropathy studies can be directly translated to the human disease

Figure 4 | Resection specimens of small intestine. a | A healthy intestine and b | intestine from a woman with severe delayed radiation enteropathy; note atrophic mucosa and severe fibrosis in the submucosa and subserosa. Original magnification of both images 0.5.

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Figure 5 | Involvement of the intestinal immune system and microvascular endothelium in the regulation of acute radiation mucositis and subsequent adverse tissue remodelling (intestinal fibrosis). When the mucosal barrier becomes disrupted (such as after radiation exposure), bacterial products and otheractivating agents gain access to the intestinal tissues and stimulate a variety of immune cells to produce cytokines and other proinflammatory and antiinflammatory mediators. Moreover, radiationinduced endothelial dysfunction leads to loss of thromboresistance, resulting in thrombin formation, neutrophil recruitment and activation, and stimulation of mesenchymal cells. In addition tothe mechanisms depicted here, a host of other mechanisms, for example, thoserelated to mast cells, the enteric nervous system and the gut microbiome, haveimportant roles in the pathogenesis of radiation enteropathy. Abbreviations: FASL,Fas ligand; IFN, interferon; IL, interleukin; LT, Lymphotoxin alpha; LTB4, LeukotrieneB4 omegahydroxylase 2; PAR, proteaseactivated receptor; ROS,reactive oxygen species; TNF, tumour necrosis factor.

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situation. Methodological and mechanistic insight from other types of gastrointestinal injury or disease pro-cesses (such as IBD, intestinal ischaemia or enteropathy induced by NSAIDs) applied to radiation enteropathy will probably help advance this important area of research. Nevertheless, as with all animal models, those of radia-tion enteropathy have limitations, for example, in terms of the applicability of radiosensitivity, repair capacity and differential responses to certain treatments.

Outstanding issuesMuch discussion has evolved around whether the pre-dominant mode of radiation-induced cell death in the epithelium is by mitotic cell death, apoptosis or by some other mechanism. The role of enterocyte apoptosis has been particularly hotly debated. Crypt cell apoptosis has been well described and, to some extent, taken as a measure of intestinal radiation toxicity.41 However, although p53-deficient mice exhibit greatly diminished crypt cell apoptosis, they are actually sensitized to intes-tinal radiation injury.42 Moreover, using conditional Bax-deficient mice on a Bak1-deficient background, Kirsch and co-workers showed that deletion of these pro-apoptoti c genes from the intestinal epithelium did not protect the mice from intestinal radiation syndrome.43 Itis possible that the explanation is to be found in the effect of p53/p21 on apoptotic versus non-apoptotic cell death.44

Radiation predominantly kills rapidly proliferat-ing cells, such as the progenitor cells in the intestinal crypts, which leads to insufficient replacement of the villus epithelium. Much attention has therefore been devoted to understanding the intestinal stem cell popu-lation.45,46 Currently, at least two types of intestinal stem cell are believed to exist, namely LGR5 (leucine-rich

repeat-containing G-protein coupled receptor5) stem cells and polycomb complex protein BMI-1 stem cells.47 In mice, Lgr5-positive cells are normally mito tically active and are considered radioresistant, whereas Bmi1-positive cells are quiescent and considered more radio-sensitive.48 Although both types of stem cell seem to contribute to regeneration of intestinal crypts after irradi - ation,49 data from a study published in 2014 indicate that only Lgr5-postive cells are required.50 The intense activity in the field of regenerative medicine, as well as the recognition of the unmet need for medical counter-measures for use in radiological and/or nuclear emerg-encies, highlights the area of intestinal stem cells as particularlypromising.

The microvasculature is known to have a central role in the regulation of radiation responses in many healthy tissues, including the intestine.51,52 Radiation induces many changes in endothelial cells, such as apoptosis, detachment from the basement membrane, increased endothelial permeability, interstitial fibrin deposition and shifting of the thrombo-haemorrhagic balance towards coagulation. Although microvascular injury clearly has at least some role in explaining the self-perpetuating nature of chronic radiation fibrosis,5355 its role in early radiation enteropathy, particularly in the so-called gastro intestinal acute radiation syndrome, is more controversial. Paris and co-workers, in 2001, published the first in a series of articles showing that endothelial apoptosis was the primary lesion responsible for this syndrome.56 Although subsequent publications are supportive,57 there has been serious challenge to this notion by groups who have been unable to identify a role for endothelial apoptosis.43,58,59 There is clearly a need for additional research in this important area. Moreover, as the radiation threshold forapoptosis in the endothelium is high, endothelial cell apoptosis is unlikely to play a significant part during con-ventionally fractionated radiation therapy. Despite this (still ongoing) controversy, it is known from other fields of biology that preserving the intestinal micro circulation after an insult has a protective effect on the gut epithe-lium and the intestinal mucosa.60 Hence, it is conceiv-able that radiation-induced endothelial cell apoptosis might be the bellwether or tip of the iceberg, indicating a broader state of dysfunction in the intestinal micro-vasculature, and that endothelial dysfunction indirectly affects the radiation tolerance and/or repair capacity of the crypt epithelium.61,62

Under healthy conditions, the enteric nervous system regulates intestinal motility, blood flow and entero-cyte function, and has a central role in maintaining the physiological state of the intestinal mucosa, as well as in co ordinating inflammatory and fibroproliferative pro-cesses. Interactions between afferent nerves, mast cells and other cells of the resident mucosal immune system maintain mucosal homeostasis and ensure an appropri-ate response to injury, including radiation entero pathy develop ment.27 These interactions are mediated by substanceP, calcitonin gene-related peptide and other neuropeptides secreted by the sensory nerves, whereas resident immune cells signal to enteric nerves by the

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Figure 6 | Radiationinduced changes in the proximal jejunum from nonhumanprimates. Proximal jejunum from a | unirradiated Rhesus macaque and bd|Rhesus macaque 4, 7 and 12days after exposure to singledose irradiation. Note conspicuous disappearance of plicae circulares, crypt irregularity and pronounced villus atrophy after irradiation. Partial recovery of postirradiation changes is seen at 12days, with near complete recovery of the epithelium and partial reappearance of plicae circulares. Original magnification of all images 1.4.

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release of cytokines, growth factors and other mediators. Elucidating the role of interactions between the enteric nerves and the local immune system in radiation entero-pathy development will probably identify new targets for intervention and provide additional mechanistic insight.

The parallel between radiation-induced inflamma-tion and primary IBD is noteworthy: colonization with microbiota is necessary for the development of colitis in mouse models, whereas germ-free mice are resistant to both inflammatory colitis and radiation enteropathy development.63 A similar parallel is apparent for NSAID-induced enteropathy, which is exacerbated by dysbiosis and greatly attenuated in germ-free animals.64 Owing to the critical role of gut-associated sepsis in lethal-ity after exposure to total body irradiation, substantial literature exists, dating back >5 decades, on the impor-tance of intestinal bacteria in the radiation response.6567 Most intestinal bacteria are considered detrimental in the context of radiation and antibiotic therapy or gut-decontamination generally improves outcome in experi-mental animals after exposure to total body irradiation. Early studies also suggested that microbiota are critical in humans. By contrast, it is clear that sterilizing the bowel is impossible in the clinical situation, antibiotic use tends to select resistant organisms and that certain bacteria are more harmful than others. As with IBD, the potential of probiotics in mitigating gastrointestinal inflam mation during radiation therapy has generated substantial interest.6871 Based on encouraging results from several randomized controlled trials with Lactobacillus-based probiotics, the Multinational Association for Supportive Care in Cancer in the 2013 update to their evidence-based guidelines recommended probiotics for preven-tion of radiotherapy-induced intestinal adverse effects.72 Techniques for assessment of bacterial flora in the healthy state and after exposure to radiation7376 com-bined with development of powerful gnotobiotic animal models77,78 and an improved understanding of the impor-tance of the gut microbiome in health and disease are some of the reasons why this promising area of research is constantly evolving.

Therapy and preventionMany natural products, peptides and small molecules have been tested preclinically for the purpose of pre-venting, mitigating (strategies that are applied after irradiation, but before symptoms occur), and treating radiation enteropathy. However, substantial differences exist between what has proven to be effective in animal models and what has proven to be effective clinically, especially when proper evidence-based criteria are used, as discussed in more detail below.79

Clinical strategiesThe management of acute radiation enteropathy remains largely symptomatic and follows guidelines for treat-ing similar symptoms in other situations. Patients with severe diarrhoea who do not respond to first-line anti-diarrhoeal medication can be treated with octreotide or other somatostatin analogues. The free-radical scavenger

amifostine is the only drug currently approved by the FDA for reduction of radiation therapy adverse effects. Although amifostine has shown impressive effects in some animal studies, and has also shown some effect in preventing clinical gastrointestinal radiation toxicity, serious adverse effects from the drug (nausea, vomit-ingand hypotension), a narrow therapeutic time window and lingering concerns about the possibility of tumour protection have severely hampered its use.80

Medical management of patients with delayed radia-tion enteropathy should be individualized and directed at the specific underlying abnormalities. A comprehensive discussion of specific diagnosis and management princi-ples and algorithms in delayed radiation enteropathy is beyond the scope of this Review. However, it is evident that many patients can be markedly helped by a system-atic approach.81 An algorithm depicting the approach to patients with radiation-induced bowel problems and common treatment options that is used at the Royal Marsden Hospital, London, UK, is provided in Figure7.

Rectal radiation injury (radiation proctopathy) is usually considered separately from injury to the small bowel and colon and is a common complication of radia-tion therapy for prostate cancer. First-line therapy for radiation proctopathy with bleeding is sucralfate enemas, which often produce rapid and dramatic effects.82,83 Inpatients with haemorrhagic proctopathy that is refrac-tory to sucralfate enemas, bleeding can be controlled with local (endoscopic) interventions or hyperbaric oxygen therapy.84

Evidence-based reviews of strategies to minimize early and/or delayed radiation enteropathy and radiation proctopathy have been published, for example, by the Multinational Association of Supportive Care in Cancer.79

Preclinical researchDrugs to protect healthy tissues from radiation represent a striking unmet need, both in cancer treatment and in the context of radiological emergencies. Therefore, there is intense interest in finding safe, non-toxic ra dioprotective compounds that do not confer tumour protection.

Interventions aimed at protecting healthy tissue against radiation injury fall into two conceptually different cat-egories. The first involves strategies that interfere directly with radiation-specific mechanisms of injury. Most radia-tion injury is initiated by reactive oxygen species, there-fore, antioxidants, free radical scavengers and various cytoprotectors have been the subjects of active study for more than half a century. For example, amifostine is a potent scavenger of free radicals.85 Superoxide dismutase and various superoxide dismutase mimetics are also being pursued as potential radioprotective strategies.86 The vitaminE analogue -tocotrienol is the most potent non-toxic natural radioprotective compound discovered to date.87 The problems with most of these compounds in the cancer therapy situation, however, is that it is often unclear to what extent they also protect tumour cells. Toxicity and a narrow therapeutic time window are also obstacles related to some of the compounds in thiscategory.

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The second, fundamentally different approach consists of agents that modulate various pathophysiological, cel-lular or molecular responses that occur downstream from radiation. These interventions seek to increase radiation tolerance, ameliorate secondary normal tissue injury or enhance repair capacity. Such approaches include, for example, various immune-modulating drugs,40,88 entero-trophic agents,8996 compounds that modulate intra-luminal contents,97,98 and a variety of other strategies.99104 Interventions that target downstream radiation effects might be generally more appealing in the cancer treat-ment situation because they do not interfere directly with the mechanism of radiation. Therefore, tumour protection is often, albeit by no means always, less of a concern than it is with free radical scavengers and antioxidants. Acom-prehensive, up-to-date discussion of the various strategies that have been and are under investigation is beyond the scope of this Review, but has been covered elsewhere.25

Screening for compoundsMany compounds have demonstrated fairly robust radio-protective effects in animal studies. However, few have advanced to clinical testing and most of those that do fail, either because of clinical toxicities, a lacklustre protective effect or concerns about tumour protection. Moreover, substantial barriers need to be overcome in the drug development process. First, there is a false perception that the prevalence of radiation enteropathy is lower than it

really is (again, the prevalence of radiation enteropathy is actually higher than that of IBD). Second, there is a lack of general public appeal for radiation enteropathy and also a lack of interest from clinicians and institutions (some-times motivated by financial or medico-legal considera-tions). Third, radiation enteropathy is a complex disorder that requires multidisciplinary expertise often not readily available in the cancer treatment environment. Fourth, many clinicians feel that any treatment of delayed radia-tion enteropathy is unlikely to be successful. Finally, the pharmaceutical and biotechnology industry has devoted little attention to radiation enteropathy research from.

The interest in finding so-called medical counter-measures against radiation (drugs for use in the radio-logical and nuclear emergency situation, in which radiation injury to the bone marrow and intestine is the main determinant of survival) has spawned a resurgence in activities to find compounds to protect the intestine against radiation. Such drugs can potentially also benefit the cancer patient who undergoes radiation therapyso called dual benefit drugs. The recommended steps in the development process of such drugs have been reviewed by Movsas and co-workers.105 First, for a candidate drug to be selected, there needs to be evidence of general or organ-specific healthy tissue protection and lack of tumour protection. Drug candidates that fulfil these cri-teria undergo testing to determine the maximal-tolerated dose, pharmacokinetics, pharmacodynamics and toxicity.

Refer appropriately e.g.: Gynaecology Urology Psychological support Pain team Rheumatology Lymphoedema services Physiotherapy

Non-GI unmet needs identied Holistic assessment GI symptoms

Recurrence unlikely Possible recurrence

New GISymptoms following

cancer treatment

Longstanding GIsymptoms pre-dating

cancer treatment

Re-stage Cross-sectional imaging Tumour markers Appropriate endoscopy

Bleeding from radiation-induced

telangiectasia

GI symptoms affecting QOL

Minimal symptomsNot affecting QOLNo alarm features

Investigate andmanage as with any

non-cancer GI patient

Positive

Refer to oncologistReassure

Flexible endoscopy assessment Optimize bowel function Bleeding not affecting QOL: reassure; no treatment needed Bleeding affecting QOL; stop/reduce anticoagulants if possible; if severe start sucralfate enemas Discuss denitive treatment options: hyperbaric oxygen therapy (may improve other symptoms but time-consuming) argon plasma coagulation (easily available but high risk of serious complications) formalin therapy (simple to perform but long-term outcomes unknown)

Are there lifestyle/ medication/

dietary/ endocrine/ psychological/ other non-GIcauses for

the symptoms?

Intermittent or constant steatorrhea or diarrhoea

Exclude: SIBO/BAM/pancreatic insufciency/

FFA malabsorption/lactose intolerance/ endocrine causes

Nocturnal defecation/obstructive episodes indicateorganicdisease

Urgency/faecal incontinenceIf no organic disease: Assess bre intake Pelvic oor and toileting exercises Stool bulking agent Anti-diarrhoeals Tricyclic antidepressants Biofeedback

Refer appropriately e.g.: Gynaecology Urology Psychological support Pain team Rheumatology Lymphoedema services Physiotherapy

Non-GI unmet needs identied Holistic assessment GI symptoms

Recurrence unlikely Possible recurrence

New GISymptoms following

cancer treatment

Longstanding GIsymptoms pre-dating

cancer treatment

Re-stage Cross-sectional imaging Tumour markers Appropriate endoscopy

Bleeding from radiation-induced

telangiectasia

GI symptoms affecting QOL

Minimal symptomsNot affecting QOLNo alarm features

Investigate andmanage as with any

non-cancer GI patient

Positive

Refer to oncologistReassure

Flexible endoscopy assessment Optimize bowel function Bleeding not affecting QOL: reassure; no treatment needed Bleeding affecting QOL; stop/reduce anticoagulants if possible; if severe start sucralfate enemas Discuss denitive treatment options: hyperbaric oxygen therapy (may improve other symptoms but time-consuming) argon plasma coagulation (easily available but high risk of serious complications) formalin therapy (simple to perform but long-term outcomes unknown)

Are there lifestyle/ medication/

dietary/ endocrine/ psychological/ other non-GIcauses for

the symptoms?

Intermittent or constant steatorrhea or diarrhoea

Exclude: SIBO/BAM/pancreatic insufciency/

FFA malabsorption/lactose intolerance/ endocrine causes

Nocturnal defecation/obstructive episodes indicateorganicdisease

Urgency/faecal incontinenceIf no organic disease: Assess bre intake Pelvic oor and toileting exercises Stool bulking agent Anti-diarrhoeals Tricyclic antidepressants Biofeedback

Figure 7 | Algorithm depicting simplified principles of workup and common approaches for managing patients with delayed gastrointestinal symptoms after radiation therapy used at the Royal Marsden Hospital, London, UK. Abbreviations: BAM, bile acid malabsorption; FFA, free fatty acid; GI, gastrointestinal; QOL, quality of life; SIBO, small intestinal bacterial overgrowth.

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The next stage is to verify evidence of normal tissue pro-tection invitro and invivo, absence of tumour protection invivo in pertinent xenograft models and further testing of biological mechanisms. Finally, before proceeding to clinical screening, comprehensive drug evaluation and formulation studies should be performed.

The role of the gastroenterologistFew gastroenterologists fully appreciate how much can be achieved for the symptomatic patient after pelvic i rradiation. Moreover, they also do not recognize the value of a preclinical model, which has so many parallels with IBD and where the initiating insult (radiation) can be so finely adjusted. Indeed, although fibrosis in the liver has deservedly received substantial attention, the mecha-nisms of intestinal fibrosis have barely been investigated, even though it is a critical pathophysiological process in a large numbers of patients after radiotherapy. Progressive fibrosis not only contributes to substantial morbidity, but it is also important in many other gastrointestinal diseases, such as pouchitis, Crohns disease, ischaemic colitis and scleroderma. Moreover, progressive fibrosis is easy to study in a model in which the onset of fibro-sis can be predicted. Conversely, the radiation biology community has, until now, been largely deprived of the insights which gastroenterologists could bring from their

knowledge of gastrointestinal pathophysiology in other disease processes. Cross-fertilization between the fields of gastroenterology and radiation biology might thus generate substantial methodological and mechanistic insight into gastrointestinal disease processes initiated by radiation, as well as how these processes are influenced by human genetic profiles, immunological responses and microbial make-up.

ConclusionsDespite technological advances in radiation therapy, radiation enteropathy remains an important obstacle to uncomplicated cancer cures and is a much more impor-tant clinical problem than previously recognizedthe prevalence of radiation enteropathy exceeds that of IBD. The pathogenesis of radiation enteropathy is multi-factorial and far more complex than previously assumed and the traditional target cell concept is largely obsolete. Although some correlation exists, histopathological and endoscopic changes do not parallel subjective symptoms. The complexity of this condition requires rethinking of some of the old dogmas, but opens up the field for devel-opment of exciting new therapeutic strategies. As a model of IBD, radiation enteropathy offers substantial advan-tages in terms of methods and clinical relevance. Apara-digm shift is needed to make it possible to adequately deal with the ever-increasing cohort of cancer survivors and their adverse effects (Box1).

Box 1 | Priorities for future research

Obtain an improved understanding of physiological versus pathological responses of the intestine to radiation injury

Perform clinical, epidemiological and outcomes studies in welldefined cohorts of cancer survivors to define true prevalence of late effects of radiation

Determine the medical, qualityofliferelated, social and financial consequences of radiationinduced bowel injury

Develop predictive assays to identify patients who are more prone than others to develop delayed healthy tissue toxicity after radiation therapy

Strengthen molecular epidemiology research aimed at identifying genetic orepigenetic characteristics that correlate with susceptibility to delayed radiation enteropathy

Testing of radiation response modifiers in clinical trials Engage the pharmaceutical and biotechnology industries in developing

strategies to modulate radiation enteropathy

Review criteria

Comprehensive searches in Ovid and/or PubMed were performed by combining the following search statements with AND: Statement #1: exp abnormalities, radiationinduced/ or exp doseresponse relationship, radiation/ or exp radiation/ or exp radiation dosage/ or exp radiation effects/ or exp radiation injuries/ or exp radiation injuries, experimental/ or exp radiation oncology/ or exp radiation pneumonitis/ or exp radiation tolerance/ orexp radiation,ionizing/ or radiation.mp. Statement #2: exp fibrosis/ or exp inflammation/ or exp inflammation mediators/. Statement #3: exp intestines/ or intestine.mp or exp intestinal diseases/ or intestinal diseases.mp.

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AcknowledgementsM.H.J. has received support related to the submitted work from the US NIH (grants R37 CA71382 and U19AI67798), the US Biomedical Advanced Research and Development Authority (BARDA, contract HHSO100201100045C) and from the US Veterans Administration. All authors declare that there is no support from any other organization.

Author contributionsM.H.J. contributed to all aspects in the preparation ofthis article. J.W.D. substantially contributed to thediscussion of content and reviewed/edited the manuscript before submission. H.J.N.A. researched data for the article, substantially contributed to the discussion of content and reviewed/edited the manuscript before submission.

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NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY VOLUME 11 | AUGUST 2014 | i

CORRECTION

Radiation enteropathypathogenesis, treatment and preventionMartin HauerJensen, James W. Denham & H. Jervoise N. Andreyev

Nat. Rev. Gastroenterol. Hepatol. 11, 470479 (2014); doi:10.1038/nrgastro.2014.46

In the version of this article originally published online and in print, the definition for PAS was listed incorrectly as paraaminosalicylic acid instead of periodic acidSchiff in the legend for Figure 3. The error has been corrected for the HTML and PDF versions of the article.

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Radiation enteropathypathogenesis, treatment and preventionMartin Hauer-Jensen, James W. Denham and H. Jervoise N. AndreyevIntroductionMagnitude of the clinical problemClinical and pathological characteristicsUnderstanding the toxicityKey pointsFigure 1 | Cancer survivors and cancer prevalence rates in the USA. a | Cancer incidence and death rates have been fairly flat during the past four decades, whereas the cohort of cancer survivors has increased by 23% per year, exceeding 13 million peopleFigure 2 | Radiation mucositis in the rat intestine. Unirradiated (control) rat withintestine transposed to the left scrotum (ac). a | Bioluminescence image (luminol). No increase in bioluminescence indicating little or no myeloperoxidase activity. b | Figure 3 | Human endoscopic biopsy samples of rectal mucosa obtained from a patient before and during ongoing radiation therapy of prostate cancer. a | PAS staining of healthy rectal mucosa before the start of radiation therapy. Note intact surface epitheConsequential late effectsFractionated radiation therapyRadiation enteropathy as a model of IBDFigure 4 | Resection specimens of small intestine. a | A healthy intestine and b | intestine from a woman with severe delayed radiation enteropathy; note atrophic mucosa and severe fibrosis in the submucosa and subserosa. Original magnification of both iFigure 5 | Involvement of the intestinal immune system and microvascular endothelium in the regulation of acute radiation mucositis and subsequent adverse tissue remodelling (intestinal fibrosis). When the mucosal barrier becomes disrupted (such as after Figure 6 | Radiation-induced changes in the proximal jejunum from non-humanprimates. Proximal jejunum from a | unirradiated Rhesus macaque and bd|Rhesus macaque 4, 7 and 12days after exposure to single-dose irradiation. Note conspicuous disappearanceOutstanding issuesTherapy and preventionFigure 7 | Algorithm depicting simplified principles of work-up and common approaches for managing patients with delayed gastrointestinal symptoms after radiation therapy used at the Royal Marsden Hospital, London, UK. Abbreviations: BAM, bile acid malabsThe role of the gastroenterologistConclusionsBox 1 | Priorities for future researchReview criteriaAcknowledgementsAuthor contributions

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Radiation Enteritis

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