REVIEWS

Radiation enteropathypathogenesis,
treatment and prevention
Martin 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 long-term radiation-induced intestinal adverse effects exceeds that of IBD. Considerable
progress towards reducing toxicity of radiation therapy has been made by the introduction of so-called 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 radiation-induced 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.
Hauer-Jensen, 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

Introduction

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 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, radiation 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 condition 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 condition and its underlying cellular and molecular mechanisms. 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 problem

Developments in treatment techniques have made it possible to deliver radiation to tumours with much greater
Competing interests
The authors declare no competing interests.

470 | AUGUST 2014 | VOLUME 11

precision than before. Nevertheless, healthy tissue toxicity remains the single most important radiation-doselimiting factor and obstacle to cancer cure. Moreover,
some authors have expressed concern about new treatment 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 indexpredisposes
to radiation toxicity 3,4); 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 comorbidities 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 predisposition 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

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Key points
Radiation therapy planning and delivery methods have improved substantially,
but the risk of intestinal radiation injury remains the single most important
dose-limiting 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 radiation-therapyrelated 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

20
18

Patients (millions)

16
14

b
Survivors (13 million)
Projected in 2022 (18 million)
New cases (1.66 million)
Deaths (580,000)

12
10
8
6
4

Prostate cancer (19%)

Other abdominal/
pelvic tumours (32%)
Breast cancer (22%)

19

75
19
80
19
85
19
90
19
95
20
00
20
05
20
10
20
15
20
20
20
25

0
Year

Lung cancer (4%)

Other tumours (23%)

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.

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 probably 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

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 IBD 16 or ~1.4 million
people with IBD in the USA.17

Clinical and pathological characteristics

Early 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 replacement 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 undergoing radiation therapy for prostate cancer. Symptoms
of early bowel toxicity (nausea, abdominal pain, diarrhoea and fatigue) develop in 6080% of patients during
radiation therapy of tumours in the abdomen or pelvis.
Nausea typically occurs relatively early, whereas diarrhoea 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 completingtreatment.
Symptoms of delayed bowel toxicity can develop before
symptoms attributable to early toxicity subside, but typically 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, nutrient malabsorption and gut dysmotility.19 Delayed radiation 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 associated 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 enteropathy has been
provided elsewhere.2325

Understanding the toxicity

The classic understanding of radiation enteropathy

was based entirely on the target cell theory, which was

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a

Counts
220
200
180
160
140
120
100
Image
Min=50
Max=431

Colour bar
Min= 85
Max =225

p/s/
cm2/sr
8,000

6,000
4,000
2,000
Colour bar
Image
Min=1.25 103 Min= 1.73 103
4
Max=1.07 10 Max =9.03 103

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 anti-transferrin antibody.
Few granulocytes are seen in the mucosa or submucosa. c | Small intestine
stained with anti-ED2(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.

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 PAS-positive goblet cells.
b|Glandular atrophy, mucosal inflammation, and loss of PAS-positive goblet cells
2weeks into the course of radiation therapy. Original magnification of both images
20. Abbreviation: PAS, periodic acidSchiff.

472 | AUGUST 2014 | VOLUME 11

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 epithelium, 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
development.27 The intestinal microvasculature is also
recognized as an important contributor to radiation toxicity 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 development.28 In other words, we have progressed beyond
the single target cell concept and now recognize that, in
addition to epithelial injury, the intestinal microvasculature, immune mechanisms, neuroimmune interactions,
the gut microbiome, the composition of the intraluminal
contents and a host of other factors have important
roles (Figure5).

Consequential late effects

The 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 pathogenesis of delayed normal tissue injury; and for interpreting 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 evidence that early effects unrelated to cell death might give
rise to subsequent chronic injury. Many pharmacological
and genetic models have also shown that the relationship 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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a

Fractionated radiation therapy

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.

Activating
agents

Intestinal lumen

IFN-
IL-2
LT
FAS-L
LTB4

Mucositis

Adverse remodelling

IL-6
IL-12
IL-18
TNF

ROS

IL-1

PARs

Neutrophil activation,
adhesion, migration

Proliferation
collagen

IL-8
Thrombin

Vessel lumen

Epithelium

Endothelium
Platelets, fibrin

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, radiation-induced 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, Leukotriene-B4 omegahydroxylase 2; PAR, protease-activated receptor; ROS,reactive oxygen species; TNF,
tumour necrosis factor.

a new terminology for classifying healthy tissue radiation

responses was proposed in 2001.35 According to this classification, there are three types of effect. First, cytocidal
effects, in which radiation causes cell death including
clonogenic cell death, mitotic catastrophe and apoptosis. 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, secondary effects that occur in response to the initial radiation insult, such as cellular inflammation and release of
cytokines and other mediators. It is important to remember that all three types of effect interact and contribute
to organ dysfunction.

Most radiation therapy regimens are delivered as fractions of 1.82.0Gy 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, inflammation 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 traumatic injury. Nowhere is this effect more evident than in
the intestine. The number of patients with symptoms of
toxicity increases steadily during a 6week course of fractionated radiation, as does the toxicity score.37 However,
mucosal pathology and functional bowel injury (intestinal permeability assessed with differential urinary excretion 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 interesting questions about the
real cause of the symptoms.

Radiation enteropathy as a model of IBD

Radiation enteropathy could be considered an ideal

model of gastrointestinal inflammation for several
reasons. First, radiation enteropathy is highly clinically relevant; as pointed out above, the prevalence of
radiation-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 relevant 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
procedure prior to irradiation, enables delivery of fractionated irradiation to a defined loop of small intestine and can be further modified to study intraluminal
delivery of radiation response modifiers directly into
the irradiated bowel loop.40 Finally, by using the identical causative agent (radiation), radiation enteropathy
studies can be directly translated to the human disease

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a

2 mm

Figure 6 | Radiation-induced 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 single-dose irradiation.
Note conspicuous disappearance of plicae circulares, crypt irregularity and
pronounced villus atrophy after irradiation. Partial recovery of post-irradiation
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.

situation. Methodological and mechanistic insight from

other types of gastrointestinal injury or disease processes (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 radiation enteropathy have limitations, for example, in terms
of the applicability of radiosensitivity, repair capacity and
differential responses to certain treatments.

Outstanding issues

Much discussion has evolved around whether the predominant 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 intestinal radiation injury. 42 Moreover, using conditional
Bax-deficient mice on a Bak1-deficient background,
Kirsch and co-workers showed that deletion of these proapoptotic 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 proliferating 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 population.45,46 Currently, at least two types of intestinal stem
cell are believed to exist, namely LGR5 (leucine-rich
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repeat-containing Gprotein coupled receptor5) stem

cells and polycomb complex protein BMI1 stem cells.47
In mice, Lgr5-positive cells are normally mitot ically
active and are considered radioresistant, whereas Bmi1positive cells are quiescent and considered more radio
sensitive.48 Although both types of stem cell seem to
contribute to regeneration of intestinal crypts after irradiation,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 countermeasures 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 gastrointestinal
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 conventionally fractionated radiation therapy. Despite this
(still ongoing) controversy, it is known from other fields
of biology that preserving the intestinal microcirculation
after an insult has a protective effect on the gut epithelium and the intestinal mucosa.60 Hence, it is conceivable that radiation-induced endothelial cell apoptosis
might be the bellwether or tip of the iceberg, indicating
a broader state of dysfunction in the intestinal microvasculature, 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 enterocyte function, and has a central role in maintaining the
physiological state of the intestinal mucosa, as well as in
coordinating inflammatory and fibroproliferative processes. Interactions between afferent nerves, mast cells
and other cells of the resident mucosal immune system
maintain mucosal homeostasis and ensure an appropriate response to injury, including radiation enteropathy
developm ent. 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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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 inflammation 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 NSAIDinduced enteropathy, which is exacerbated by dysbiosis
and greatly attenuated in germ-free animals.64 Owing
to the critical role of gut-associated sepsis in lethality after exposure to total body irradiation, substantial
literature exists, dating back >5 decades, on the importance of intestinal bacteria in the radiation response.6567
Most intestinal bacteria are considered detrimental in
the context of radiation and antibiotic therapy or gutdecontamination generally improves outcome in experimental 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 inflammation
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 evidencebased guidelines recommended probiotics for prevention of radiotherapy-induced intestinal adverse effects.72
Techniques for assessment of bacterial flora in the
healthy state and after exposure to radiation7376 combined with development of powerful gnotobiotic animal
models77,78 and an improved understanding of the importance of the gut microbiome in health and disease are
some of the reasons why this promising area of research
is constantly evolving.

Therapy and prevention

Many natural products, peptides and small molecules

have been tested preclinically for the purpose of preventing, 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 strategies
The management of acute radiation enteropathy remains
largely symptomatic and follows guidelines for treating similar symptoms in other situations. Patients with
severe diarrhoea who do not respond to first-line antidiarrhoeal 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, vomitingand 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 radiation enteropathy should be individualized and directed at
the specific underlying abnormalities. A comprehensive
discussion of specific diagnosis and management principles 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 systematic 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 radiation 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 refractory 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 research
Drugs 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 radioprotective
compounds that do not confer tumour protection.
Interventions aimed at protecting healthy tissue against
radiation injury fall into two conceptually different categories. The first involves strategies that interfere directly
with radiation-specific mechanisms of injury. Most radiation injury is initiated by reactive oxygen species, therefore, 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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Refer appropriately e.g.:
Gynaecology
Urology
Psychological support
Pain team
Rheumatology
Lymphoedema services
Physiotherapy

Bleeding from
radiation-induced
telangiectasia

Non-GI unmet needs identified

GI symptoms

Holistic assessment

Recurrence unlikely

Minimal symptoms
Not affecting QOL
No alarm features

Possible recurrence

New GI
Symptoms following
cancer treatment

Longstanding GI
symptoms pre-dating
cancer treatment

Re-stage
Cross-sectional imaging
Tumour markers
Appropriate endoscopy

GI symptoms
affecting QOL

Investigate and
manage as with any
non-cancer GI patient

Positive

Refer to oncologist

Reassure
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 definitive 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-GI
causes for
the symptoms?

Intermittent or constant
steatorrhea or diarrhoea
Exclude: SIBO/BAM/
pancreatic insufficiency/
FFA malabsorption/
lactose intolerance/
endocrine causes

Nocturnal
defecation/
obstructive
episodes
indicate
organic
disease

Urgency/faecal incontinence
If no organic disease:
Assess fibre intake
Pelvic floor and toileting
exercises
Stool bulking agent
Anti-diarrhoeals
Tricyclic antidepressants
Biofeedback

Figure 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 malabsorption; FFA, free fatty acid; GI, gastrointestinal; QOL, quality of life; SIBO, small intestinal bacterial overgrowth.

The second, fundamentally different approach consists

of agents that modulate various pathophysiological, cellular 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 treatment 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. Acomprehensive, 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 compounds

Many compounds have demonstrated fairly robust radioprotective 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
476 | AUGUST 2014 | VOLUME 11

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 (sometimes motivated by financial or medico-legal considerations). 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 radiation 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 radiological 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 criteria undergo testing to determine the maximal-tolerated
dose, pharmacokinetics, pharmacodynamics and toxicity.

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REVIEWS
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 well-defined cohorts
of cancer survivors to define true prevalence of late effects of radiation
Determine the medical, quality-of-life-related, social and financial consequences
of radiation-induced 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

The next stage is to verify evidence of normal tissue protection 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 gastroenterologist

Few gastroenterologists fully appreciate how much can

be achieved for the symptomatic patient after pelvic
irradiation. 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 mechanisms 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 fibrosis can be predicted. Conversely, the radiation biology
community has, until now, been largely deprived of the
insights which gastroenterologists could bring from their
1.

2.

3.

4.

5.

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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.

Conclusions

Despite technological advances in radiation therapy,

radiation enteropathy remains an important obstacle to
uncomplicated cancer cures and is a much more important 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
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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 development of exciting new therapeutic strategies. As a model
of IBD, radiation enteropathy offers substantial advantages in terms of methods and clinical relevance. Aparadigm shift is needed to make it possible to adequately deal
with the ever-increasing cohort of cancer survivors and
their adverse effects (Box1).
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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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Acknowledgements
M.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 contributions
M.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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REVIEWS
CORRECTION
Radiation enteropathypathogenesis, treatment and prevention
Martin Hauer-Jensen, 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 para-aminosalicylic 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.

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY

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