Radiation damage to the gastrointestinal tract: Mechanisms, diagnosis, and management

Abstract

To summarize current knowledge about gastrointestinal radiation toxicity, with emphasis on mechanisms and clinical diagnosis and management.
While there has been only modest change in cancer incidence and cancer mortality rates during the past 30 years, the number of cancer survivors has more than doubled. Moreover, the recognition of uncomplicated cancer cure as the ultimate goal in oncology has intensified efforts to prevent, diagnose, and manage side effects of radiation therapy. These efforts have been facilitated by recent insight into the underlying pathophysiology.
The risk of injury to the intestine is dose limiting during abdominal and pelvic radiation therapy. Delayed bowel toxicity is difficult to manage and adversely impacts the quality of life of cancer survivors. More than 200,000 patients per year receive abdominal or pelvic radiation therapy, and the estimated number of cancer survivors with postradiation intestinal dysfunction is 1.5-2 million. Worthwhile progress towards reducing toxicity of radiation therapy has been made by dose-sculpting treatment techniques. Approaches derived from an improved understanding of the pathophysiology of bowel injury, however, will result in further advances. This article discusses the mechanisms of radiation-induced bowel toxicity and reviews current principles in diagnosis and management.

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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Radiation damage to the gastrointestinal tract: mechanisms,
diagnosis, and management
Martin Hauer-Jensen
a
, Junru Wang
b
, Marjan Boerma
c
, Qiang Fu
d
and
James W. Denham
e
Purpose of review
To summarize current knowledge about gastrointestinal
radiation toxicity, with emphasis on mechanisms and clinical
diagnosis and management.
Recent findings
While there has been only modest change in cancer
incidence and cancer mortality rates during the past
30 years, the number of cancer survivors has more than
doubled. Moreover, the recognition of uncomplicated
cancer cure as the ultimate goal in oncology has intensified
efforts to prevent, diagnose, and manage side effects of
radiation therapy. These efforts have been facilitated by
recent insight into the underlying pathophysiology.
Summary
The risk of injury to the intestine is dose limiting during
abdominal and pelvic radiation therapy. Delayed bowel
toxicity is difficult to manage and adversely impacts the
quality of life of cancer survivors. More than 200 000
patients per year receive abdominal or pelvic radiation
therapy, and the estimated number of cancer survivors with
postradiation intestinal dysfunction is 1.5–2 million.
Worthwhile progress towards reducing toxicity of radiation
therapy has been made by dose-sculpting treatment
techniques. Approaches derived from an improved
understanding of the pathophysiology of bowel injury,
however, will result in further advances. This article
discusses the mechanisms of radiation-induced bowel
toxicity and reviews current principles in diagnosis and
management.
Keywords
intestines, radiation injuries, radiation therapy
Curr Opin Support Palliat Care 1:23– 29. ß2007 Lippincott Williams & Wilkins.
a
Departments of Surgery and Pathology, University of Arkansas for Medical
Sciences and Surgery Service, Central Arkansas Veterans Healthcare System,
Little Rock, Arkansas, USA,
b
Department of Surgery, University of Arkansas for
Medical Sciences, Little Rock, Arkansas, USA,
c
Department of Pharmaceutical
Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA,
d
Department of Microbiology and Immunology, University of Arkansas for Medical
Sciences, Little Rock, Arkansas, USA and
e
Department of Radiation Oncology,
University of Newcastle, Newcastle, New South Wales, Australia
Correspondence to Martin Hauer-Jensen MD, PhD, Arkansas Cancer Research
Center, 4301 West Markham, Slot 725, Little Rock, AR 72205, USA
Tel: +1 501 686 7912; fax: +1 501 421 0022; e-mail: mhjensen@life.uams.edu
Current Opinion in Supportive and Palliative Care 2007, 1:23 –29
ß2007 Lippincott Williams & Wilkins
1751-4258
Introduction
Radiation therapy is used in about 70% of cancer patients
and plays a critical role in 25% of cancer cures [1]. Even
though technical advances have made it possible to
deliver radiation to virtually any part of the body, normal
tissue radiation toxicity remains the most important
obstacle to cancer cure in patients with localized disease.
During radiation therapy of tumors in the abdomen or
pelvis, the intestine is an important normal tissue at risk.
As in other organs, intestinal radiation toxicity is classified
as acute (early) when it occurs during or within 3 months
of radiation therapy, or delayed (chronic) when it occurs
more than 3 months after radiation therapy.
Early intestinal radiation toxicity affects quality of life at
the time of treatment. The symptoms are usually tran-
sient and cease after completion of radiation therapy.
Severe acute toxicity, however, may require treatment
interruption or alteration of the original treatment plan,
thereby compromising the likelihood of tumor control.
Delayed intestinal radiation toxicity is a highly important
issue in long-term cancer survivors. It is a progressive
condition with few therapeutic options and substantial
long-term morbidity and mortality. Hence, delayed
bowel toxicity significantly affects outcome in long-term
cancer survivors.
This review article discusses mechanisms of radiation-
induced bowel toxicity and reviews contemporary
approaches for diagnosis and management.
Pathology and pathophysiology
The pathology and cellular and molecular mechanisms of
intestinal radiation injury are only discussed briefly. For a
more comprehensive description of the pathological fea-
tures, the reader is referred to reviews by Fajardo et al.
[2,3] and Carr [4], while a discussion of mechanistic
aspects can be found in [5].
Radiation injuries to normal tissues arise from a combi-
nation of three different processes: cytocidal effects
(clonogenic and apoptotic cell death); functional (non-
cytocidal) effects; and secondary effects (reactive and
downstream cellular or tissue phenomena) [6,7]. In the
intestine, acute toxicity is to a large extent a result of
23

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
epithelial injury, resulting in breakdown of the mucosal
barrier and mucosal inflammation (intestinal mucositis).
The pathogenesis of chronic radiation enteropathy
is complex and involves changes in most compartments
of the intestinal wall. Prominent structural features
include mucosal atrophy, intestinal wall fibrosis, and
vascular sclerosis. Changes in intestinal function are
dominated by malabsorption, dysmotility, and transit
abnormalities [8,9]. Intestinal fibrosis, stricture formation,
or fistula formation are potentially life-threatening compli-
cations.
In contrast to the earlier notion that acute and delayed
tissue injury are unrelated, clinical studies [10–13], pre-
clinical time–dose–fractionation studies [14 –16], and
animal studies using modifiers of acute injury [17,18]
have shown unequivocally that acute injury may contrib-
ute to development of chronic changes through direct
functional cellular effects and secondary effects [6,7,19

].
Incidence and prevalence
It is estimated that more than 200 000 patients in the US
undergo radiation therapy of abdominal, pelvic, or retro-
peritoneal tumors each year and are at risk for developing
early and delayed intestinal radiation injury. Symptoms
of acute bowel toxicity occur in 60–80% of patients who
receive curative radiation therapy of intraabdominal or
pelvic tumors, and 5–15% will require treatment inter-
ruption or alteration.
Radiation therapy carries a continued, lifetime risk of
delayed complications [20]. Clinical studies published up
to the mid-1990s often reported a 30–40% incidence of
chronic diarrhea and other symptoms after postoperative
therapy of rectal cancer and small-bowel obstruction in
5–15% [21,22]. For example, a comprehensive study of
women treated for cervical cancer reported a 10 –15%
incidence of severe bowel toxicity at 20 years [23]. Mod-
ern dose-sculpting radiation therapy, as well as increased
awareness of the risk and consequences of delayed bowel
toxicity, may eventually lower the incidence of severe
late complications.
Incidence and severity of intestinal radiation toxicity
depend on many therapy-related and patient-related
factors [24]. Therapy-related factors include radiation
dose, volume of bowel irradiated, time–dose–fraction-
ation parameters, and use of concomitant chemotherapy
or biotherapy. Previous abdominal surgery or intra-
abdominal infections increase the risk of radiation
enteropathy [25,26,27

]. Specific comorbidities, for
example, inflammatory bowel disease [28], diabetes
[29], vascular disease [30], scleroderma [31], and
tobacco smoking [32] predispose patients to complica-
tions after radiation therapy.
It is important to recognize that only a fraction of patients
suffering from postradiation intestinal dysfunction seek
medical attention. Moreover, although some manifes-
tations of toxicity may be subtle, they are nevertheless
clinically important and may have a major impact on
patients’functional and psychosocial quality of life.
Hence, studies in which patients have been carefully
and systematically examined show that intestinal dys-
function is present in 60–90% of patients after radio-
therapy of abdominal tumors [33–35]. Similarly, after
pelvic radiation therapy, more than 50% of patients have
persistent anorectal dysfunction with intermittent incon-
tinence, bleeding, or fecal urgency [35–37]. Even more
subtle manifestations of bowel dysfunction, such as accel-
erated osteoporosis or anemia, may lead to significant
morbidity, even though their relationship to radiation
treatment may not be obvious.
If the overall prevalence of delayed postradiation toxicity
in the population could be estimated accurately, bowel
toxicity would almost certainly head the list by a
considerable margin: There are currently more than
10 million cancer survivors in the US, about 50% of whom
are survivors of abdominal or pelvic cancers [38

]. If one
assumes that radiation therapy has or will be used in 70%,
and that at least 50% of these patients develop some
degree of intestinal dysfunction, a conservative estimate
of the number of patients with postradiation intestinal
dysfunction living in the US is 1.5–2 million.
Clinical presentation
In this section we discuss the main symptoms of radiation
damage to the small bowel and the anus/rectum.
Small bowel radiation injury
The main symptoms of early small bowel toxicity are
nausea, abdominal pain, and diarrhea. Fatigue is a non-
specific symptom, but may also be quite prominent.
Nausea occurs early during radiation therapy, while diar-
rhea and abdominal pain generally become a problem
2–3 weeks into the course of radiation therapy. In most
patients, the acute symptoms resolve within 2–4 weeks of
completing treatment.
Symptoms of delayed bowel toxicity usually present after
a latency period of between 6 months and 3 years.
Delayed radiation enteropathy, however, may develop
in direct continuity with the acute symptoms, and latency
periods of more than 30 years are not uncommon.
Delayed small bowel radiation injury is characterized
clinically by malabsorption and bowel dysmotility.
Patients often present with intermittent constipation
and diarrhea and are frequently metabolically deranged
and malnourished. Progressive intestinal wall fibrosis may
cause strictures, and localized areas of ischemic necrosis
may give rise to fistulas. A surprising number of patients
24 Gastrointestinal symptoms

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
with small bowel injury present initially as surgical
emergencies, with acute intestinal obstruction, fistulas,
or bowel perforation. Significant bleeding is an infre-
quent manifestation of small bowel radiation injury
[39]. Polyvisceral necrosis is an exceedingly rare compli-
cation [40,41] that results from ischemic gangrene due to
central vascular injury, rather than direct radiation injury
to the intestine.
The prognosis of patients with severe delayed small
bowel radiation injury is poor. Corrective surgery is
associated with high postoperative morbidity and
mortality, and some patients require prolonged parenteral
nutrition [42

]. Most patients experience persistent or
recurrent symptoms, and about 10% die as a direct result
of radiation enteropathy [43–48].
Symptoms and signs of delayed radiation injury of the
colon differ somewhat from those of small bowel injury,
reflecting the role of the colon in water absorption and as
fecal conduit, rather than in the uptake of nutrients.
Patients with colonic injury typically suffer from inter-
mittent diarrhea and constipation caused by fibrotic
strictures or pseudo-obstruction (functional obstruction
without anatomical stricture), but are not commonly
metabolically deranged.
Compared with patients with small bowel injury, the
long-term prognosis of patients with colonic injury is
more favorable, mainly because of less pronounced meta-
bolic and nutritional derangement and the ‘expendabil-
ity’of the colon.
Anorectal radiation injury
The hallmark clinical features of early radiation injury of
the anus/rectum (radiation proctopathy) are diarrhea,
tenesmus (fecal urgency with crampy pain), and hema-
tochezia (bloody stools). Even when virtually no small
bowel is included in the radiation field during pelvic
irradiation, many patients experience symptoms from the
upper abdomen, suggesting a role for neurogenic mech-
anisms, cytokines, or other circulating factors.
Clinical manifestations of delayed radiation proctopathy
include frequent or clustered bowel movements, anal
discharge, rectal pain, urgency, tenesmus, incontinence,
and hematochezia. The clinical picture depends on what
type of injury predominates. Bleeding may be the main
symptom in patients with severe mucosal injury, rectal
pain may predominate in patients with chronic ulcers,
and urgency may be the chief complaint in patients in
which fibrosis causes loss of anorectal compliance. In
many instances the patient is more socially disabled by
the need to find a lavatory quickly, that is, by urgency and
tenesmus, than by the passage of blood in the bowel
movements [49].
Delayed proctopathy often pursues a remittent course,
possibly due to exacerbation of symptoms associated with
periodic breakdown of the mucosa. In many patients,
hematochezia is at its worst 18 –24 months after therapy,
but then improves spontaneously [50].
Diagnostic evaluation
In this section we discuss the diagnosis of small bowel
radiation injury and radiation proctopathy.
Small bowel radiation injury
Due to the rather well defined clinical picture and
temporal relationship to radiation therapy, acute intesti-
nal radiation toxicity seldom poses diagnostic dilemmas,
and diagnostic tests are usually not indicated. In contrast,
the diagnosis and therapy of delayed radiation entero-
pathy is less straightforward because of the multifaceted
nature of the disorder, variations among patients in terms
of the dominant pathophysiological process(es), and
tumor recurrence as a differential diagnosis. A pathophy-
siology-based approach is clearly preferable to an empiric
(trial-and-error) approach.
The manifestations of small bowel radiation injury usually
result from mucosal dysfunction (due to atrophy, reduced
activity of brush border membrane enzymes, reduced
mucosal blood flow, or impaired lymph drainage); or intes-
tinal dysmotility with bacterial overgrowth and digestive
dysfunction (due to stricture formation and neuromuscular
dysfunction). The relative significance of these processes
varies from patient to patient, and, thus, it is important to
individualize the diagnostic and therapeutic approach.
Diagnostic tests to considerin the work-up of patients with
chronic-recurrent abdominal symptoms after radiation
therapy includeimaging (e.g. computed tomography,ultra-
sonography, enteroclysis, fistulogram); measurement of
intestinal transit; endoscopy; various tests for malabsorp-
tion (e.g. fecal fat excretion, lactose absorption test,
Schilling test, bile acid breath tests); tests for maldigestion
(e.g. xylose breathtest); assessment of intestinal microflora;
motility studies; permeability assessment; and histopatho-
logic examination of mucosal biopsies. The goal of the
workup should be to make a diagnosis that is as precise
as possible in terms of determining the pathophysiologi-
cally importantfactors and the anatomiclocation and extent
of the pathology in the individual patient. The objective of
diagnostic work-up inpatients with colonic radiation injury
is mainly to clarify anatomical details, rule out malignancy
by colonoscopy, and delineate strictures and fistulas
by appropriate radiological imaging studies.
Radiation proctopathy
As for acute radiation enteropathy, the diagnosis of acute
radiation proctopathy is usually straightforward with no
need for diagnostic studies.
Radiation damage to the gastrointestinal tract Hauer-Jensen et al. 25

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
In delayed radiation proctopathy, hematochezia is a
result of friable rectal mucosa with telangiectatic
vessels. In all patients with hematochezia, it is import-
ant to rule out lesions proximal to the rectum by
colonoscopy, even when a firm diagnosis of chronic
radiation proctopathy has been established. Radiologi-
cal contrast studies may be used to demonstrate points
of bowel fixation, decreased compliance, and strictures.
Anorectal function tests, which are usually normal or
near normal during the early postradiation period, show
frequent abnormalities in the chronic phase [51]. These
tests, however, are seldom helpful in clinical decision-
making.
Therapy
In this section we discuss the management of early and
delayed radiation enteropathy, and acute and delayed
radiation proctopathy.
Early radiation enteropathy
Management of early radiation toxicity of the small bowel
and colon is symptomatic and follows general guidelines
for treating similar symptoms in other situations. Hence,
conventional antidiarrheal, antiemetic, spasmolytic, and
defoaming agents are mainstays in the management of
acute bowel toxicity.
The synthetic somatostatin analogue, octreotide, potently
ameliorates acute intestinal radiation toxicity in pre-
clinical studies [18,52], and a recent clinical study con-
firmed that the efficacy of octreotide is superior to that
of conventional antidiarrheal drugs [53]. Therefore,
patients with severe diarrhea that do not respond to
first-line antidiarrheal medication should be considered
candidates for treatment with octreotide.
When the effect of conventional antiemetics is
unsatisfactory, 5-hydroxytryptamine (HT3, serotonin)
receptor antagonists may relieve symptoms [54]. Pro-
phylactic therapy may be considered in patients at high
to moderate risk of radiation-induced emesis [55].
Additional administration of steroids may be beneficial
[56].
Delayed radiation enteropathy
Delayed radiation enteropathy, uncomplicated by intes-
tinal obstruction, perforation, or fistula formation, is
usually managed nonoperatively. In general, the medical
management of patients with chronic radiation entero-
pathy should be directed at the specific underlying
abnormalities (nutritional deficits, intestinal dysmotility,
bile acid malabsorption, and bacterial overgrowth),
depending on the outcome of diagnostic studies. For
example, a patient with a stricture in the distal ileum
may be helped by elective surgical resection if functional
testing before and after a course of antimicrobial therapy
rules out widespread mucosal dysfunction. A detailed
discussion of therapeutic strategies is beyond the scope of
this article, and the reader is referred elsewhere for more
comprehensive reviews [8,33,57,58].
Indications for surgery in delayed radiation enteropathy
include intestinal obstruction, perforation, fistula for-
mation, and occasionally, severe bleeding and malabsorp-
tion. Due to frequent widespread radiation-induced
alterations in the intestine and mesentery and poor
nutritional status of the patient, wound healing is
delayed, and surgery carries a high risk of anastomotic
dehiscence and iatrogenic fistulas. As for the medical
management of patients with delayed radiation entero-
pathy, the surgical management should be highly indi-
vidualized. Surgical options include resection of involved
intestinal segments, intestinal bypass procedures, enter-
ostomy, or –in select patients –stricturoplasty [59].
Surgery in patients with radiation-induced fistulas is
often particularly challenging, since the surrounding
tissue often exhibits prominent inflammation and radi-
ation fibrosis. Details regarding surgical management
of radiation-induced fistulas can be found in [60].
Acute radiation proctopathy
As for radiation injury of the small bowel and colon,
management of acute radiation proctopathy is sympto-
matic and follows the general principles of treating
similar symptoms in other situations. Topical lignocaine
preparations often have a soothing effect on anorectal
irritation and loperamide will reduce tenesmus. Steroid-
containing suppositories may be helpful when inflamma-
tory symptoms are severe.
Delayed radiation proctopathy
Hematochezia is frequently the main symptom of
delayed radiation proctopathy, but urgency and fre-
quency can be difficult to control and be even more
disabling than bleeding.
First-line therapy for radiation proctopathy with bleeding
is sucralfate enemas, which often have rapid and dramatic
effects [61]. The benefit of sucralfate in the chronic
setting is in stark contrast to the lack of effect of this
drug in the acute setting in most studies [62 –65].
In patients with hemorrhagic proctitis refractory to sucral-
fate enemas, bleeding can usually be controlled by local
(endoscopic) interventions, such as, topical formalin
application [66–68] or coagulation using electrocautery
[69], laser [70–73], or argon plasma beam [74–77]. When
sucralfate enemas, formalin applications, and coagulation
therapy fail, or in patients with intractable pain because
of rectal ulcers, hyperbaric oxygen (HBO) therapy may
be considered [78,79]. Several uncontrolled studies
suggest a benefit of HBO in patients with severe radiation
26 Gastrointestinal symptoms

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
proctopathy [80], although a ‘placebo’-controlled assess-
ment has yet to be performed.
Surgical intervention may be considered in patients
with persistent, transfusion-dependent bleeding that
is refractory to the therapies discussed above and in
cases complicated by nonhealing ulcers, intractable
pain, or complications such as stenosis or fistula
formation.
For further discussion of strategies for treating delayed
radiation proctopathy the reader is referred to other texts,
for example [81].
Prophylaxis
Over the past 20 years, many pharmacological com-
pounds, biological response modifiers, nutritional supple-
ments, and diets have undergone preclinical and, to a
lesser extent, clinical testing as potential intestinal radi-
ation response modifiers.
Interventions aimed at ameliorating intestinal radiation
injury fall into two conceptually different categories. The
first is strategies that interfere with more or less radiation-
specific mechanisms of injury, for example, antioxidants,
free radical scavengers, and other cytoprotective agents.
The second, fundamentally different approach is to
modulate various pathophysiological, cellular, or molecu-
lar characteristics of the tissue to increase its radiation
tolerance or enhance its repair capacity.
For a comprehensive discussion of intestinal radiation
response modifiers, the reader is referred to [5].
Conclusion
Due to the exponentially growing cohort of cancer
survivors and increased awareness of treatment-related
side effects, the importance of normal tissue radiation
responses is being increasingly recognized. In the US
alone, more than 200 000 patients receive abdominal or
pelvic radiation therapy each year and 1.5–2 million
likely suffer from chronic postradiation bowel dysfunc-
tion. The earlier notion that radiation responses are
linked exclusively to radiation-induced cell kill has
been supplanted by the recognition that functional
radiation effects, as well as secondary phenomena,
contribute to postradiation organ dysfunction. This
finding offers new opportunities for development of
pharmacological interventions to prevent or treat intes-
tinal radiation injury and for an individualized approach
to diagnosis and management of patients with post-
radiation bowel dysfunction.
Acknowledgements
Financial support from National Institutes of Health (grants CA71382
and CA83719).
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