gastrointestinal tract and abdomen ACUTE AND CHRONIC RADIATION INJURY TO THE LOWER

Rachel E. Beard, MD, and Deborah Nagle, MD

Radiation is an integral part of therapy for many pelvic can- synthase, thrombomodulin, and plasminogen. This can ulti- cers, including rectal, prostate, cervical, and uterine , mately lead to increased infl ammation or even suppression and has been shown to decrease local recurrence and of the infl ammatory response depending on the dose and increase patient survival. Radiation injury is a sequela of schedule of radiation. Important end results are the activa- treatment that manifests different symptoms depending on tion of the coagulation system by way of increased thrombin the organ affected. The most common lower gastrointestinal and the formation of new blood vessels, specifi cally telangi- symptoms are rectal bleeding, , fecal urgency, and ectasias, by way of radiation-induced angiogenesis. Both fecal incontinence, which can range in severity from mild infl ammation and angiogenesis in the treatment fi eld can and self-limiting to chronic, severe, or life threatening.1 clinically manifest as rectal bleeding.1,3 Radiation side effects can occur acutely during therapy or much later and can even develop after several decades. Risk Factors Acute-onset radiation toxicity is defi ned as occurring within 3 months of therapy, whereas late-onset or chronic disease Factors that are either specifi c to the administered radia- typically presents at least 6 months after treatment. The tion therapy or specifi c to the patient have been shown to technique of the administered correlates increase the risk of developing radiation injury [see Table 1]. with the timing of onset of symptoms. Newer intensity- It has been well demonstrated that higher doses of radiation, modulated radiation techniques (IMRTs) allow for the deliv- especially to the anterior rectal wall, increase the incidence 4,5 ery of higher doses of radiation directly to the tumor. With and severity of late-onset rectal bleeding. Serious gastroin- these techniques, surrounding normal tissues receive lower testinal toxicity is rare when the total radiation dose admin- 6 doses of radiation compared with conventional therapies istered does not exceed 50 Gy. A correlation has also been such as three-dimensional conformal technique (3D-CRT). observed between the volume of small bowel irradiated and 7 Patients whose therapy is administered using 3D-CRT are the incidence of small bowel complications. For instance, more prone to the development of late-onset disease when 50% of patients who receive 60 Gy of radiation to a third compared with patients undergoing IMRT.1 of their small bowel volume would be expected to develop radiation in 5 years, whereas the expected dose that would elicit the same response if the whole volume of small Disease Pathology bowel were irradiated is 55 Gy. For the colon, the dose to The therapeutic effect of radiation occurs due to the elicit toxicity in 50% of the population is 65 Gy for a third 8 disruption of DNA synthesis in cells undergoing mitosis.2 of the volume and 60 Gy for the whole volume. Certain Cellular changes occurring throughout a course of radiation radiation techniques, such as opposed and extended fi eld therapy are ultimately what lead to radiation injury and its radiation, are associated with high rates of radiation injury, complications.3 The gut mucosa has a relatively high mitotic rate, and the high cell turnover makes it susceptible to radiation damage.2 Fractionated radiation causes repetitive injury to tissues, and the infl ammatory response to each radiation fractionation may not resolve within 24 hours or prior to the next radiation dose, resulting in an accumulat- ing response. At the end of a course of radiation therapy, the nondiseased tissue that is included in the fi eld is dramati- cally different from what it was at the beginning. Acutely, the mucosal barrier of irradiated tissues becomes disrupted, infl amed, and increasingly permeable because of cell death in the crypt [see Figure 1]. This leads to increased bacterial exposure and stimulation of cytokines, including interleukins and tumor necrosis factor–a (TNF-a). Chronic changes include mucosal atrophy, intestinal wall fi brosis, and sclerosis of the vascular structures [see Figure 2]. Endo- thelial dysfunction leads to increased neutrophil recruitment on the endothelial cell surface, which increases infl amma- tion and ultimately leads to the creation of a procoagulant Figure 1 Microscopic section shows diffuse ulceration and granula- surface by downregulating the activity of nitric oxide tion tissue formation.

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Evaluation and Treatment of Radiation-Induced Gastrointestinal Injury

Consider pharmacolgic prevention, especially in high-risk patients Acute symptoms Radiation therapy Beclomethasone dipropionate (< 3 months) enemas, amiofostine enemas or injections, oral probiotics

Chronic symptoms (> 6 months) Persistent or severe symptoms Mild symptoms, no → often self-limiting, observation, reassurance Initial workup Mild, do not interfere with quality of life, no Changes not consistent anemia → observation, with barium with radiation → reassurance additional workup Transrectal or endoanal ultrasonography Evaluate for secondary Anorectal physiology malignancy: computed Resolution of symptoms tomography, magnetic → observation resonance imaging, positron emission tomography Evaluate remainder small Findings consistent with radiation injury bowel: upper endoscopy, small bowel contrast Pharmacologic therapy: oral , Persistent symptoms, study, capsule study enemas, oral vitamin A, short-chain acute or severe Workup for : fatty acid (butyrate) enemas breath tests, selenium-75 Endoscopic therapy: homocholic acid conjugated • First line: thermal with taurine scanning ablation with , formalin application Persistent symptoms, • Alternative: thermal chronic in nature coagulation with laser or bipolar • Newer techniques still Hyperbaric oxygen therapy being investigated: cryoablation, radiofrequency Persistent, severe, or life-threatening ablation symptoms

Surgical therapy: • Diversion without resection • Resection without anastomosis • Resection with anastomosis, with or without diversion

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Figure 2 The rectal wall is thickened by dense white tissue grossly suggestive of radiation effect.

as are short-course radiotherapy regimens, which employ Certain patient-related risk factors also increase the likeli- larger fraction sizes over a shorter time period.9 Preopera- hood of developing radiation injury, namely conditions tive, as opposed to postoperative, chemoradiotherapy in the with a common end point of increased infl ammation and multimodal treatment of rectal leads to statistically endothelial dysfunction.1 Patients with infl ammatory bowel lower toxicities, as does the concurrent administration of disease, such as Crohn disease or ulcerative , are at a 10,11 adjuvant chemotherapy and radiotherapy. greater than 20% risk of developing severe acute gastrointes- tinal toxicity following radiation.12 Collagen vascular dis- eases such as systemic lupus erythematosus, scleroderma, polymyositis, and dermatomyositis have been associated Table 1 Risk Factors Predisposing Patients to with severe late radiation effects, although, interestingly, the Development of Radiation Injury rheumatoid arthritis does not demonstrate a similar associa- tion.13 Diabetes has been shown to be an independent risk Treatment-related risk factors factor for late-stage gastrointestinal and genitourinary toxic- Higher radiation doses Higher volume of irradiated small bowel ity following radiation therapy, and when diabetic patients Extended- or opposed-field radiation techniques also have hypertension, the risk of late toxicities is even Short-course radiotherapy higher.14,15 Patients who are heavy smokers (defi ned as at Postoperative chemoradiotherapy Concurrent administration of chemotherapy least one pack per day) and who have abnormally low body Patient-related risk factors mass indexes (BMIs; defi ned as less than 18.5) are at Diabetes increased risk. An association with abnormally high BMIs is Hypertension less clear.16,17 Genetic predispositions have also been demon- Inflammatory bowel disease (Crohn disease, UC) Connective tissue disorders (SLE, scleroderma, polymyositis, strated. For instance, heterozygotes carrying the ataxia- dermatomyositis, excluding RA) gene have been shown to experience increased Heavy smoking (at least one pack per day) severe late effects of toxicity.18 Lastly, previous abdominal Abnormally low BMI (< 18.5) Previous abdominal or pelvic surgery and pelvic surgery has been associated with an increased Genetic predisposition (AT heterozygotes) risk of radiation , perhaps owing to adhesions that fi xate the small bowel in a nonanatomic position in the AT = ataxia-telangiectasia; BMI = body mass index; RA = rheumatoid arthritis; SLE 19 = systemic lupus erythematosus; UC = . pelvic radiation fi eld.

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Disease Prevention diarrhea.29,30 Probiotics have been shown to be effective in A number of strate- the prevention and treatment of diarrhea induced from a gies have been proposed variety of etiologies, including infectious and antibiotic 31–33 to prevent or minimize associated, in both adults and children. Studies to date the damage to normal have suggested a possible benefi cial effect of probiotics for tissues and subsequent the prevention of radiation-induced diarrhea, but further radiation-induced injury studies are needed to clearly demonstrate a statistically 34–36 [see Table 2]. These signifi cant effect. should be especially considered in high-risk Clinical Presentation patients. The topical administration of a acute injury glucocorticoid such as Acute injury occurs beclomethasone dipropionate has been shown to reduce the within the fi rst few risk of rectal bleeding following pelvic radiation in random- months following radia- ized trials.5 Sucralfate enemas have also been studied but tion therapy. It is pri- have not been shown to reduce the likelihood of radiation marily an infl ammatory toxicity and rectal bleeding in the acute period or later.20–22 response and tends to The oral administration of sucralfate has also been studied be self-limited. Symp- but was not shown to reduce proctitis symptoms and was toms such as bleeding, actually associated with increased rectal bleeding.22 Mesala- diarrhea, urgency, and incontinence are reported in up to zine (5-aminosalicylic acid [5-ASA]) enemas were also pre- three quarters of patients. The majority of acute injuries heal viously studied as a possible preventive measure, but trials spontaneously, although it may take up to 6 months after failed to demonstrate an improvement in symptoms, and the cessation of radiation therapy.1,37 On histologic examina- some studies actually demonstrated worsened rectal toxicity tion, acute injury is usually confi ned to the mucosa with and bleeding.23 Amifostine is an organic triphosphate and fi ndings of decreased mitotic rate, thickened lamina propria, was the fi rst cytoprotective drug to be used in clinical prac- and patchy proliferation of fi broblasts, whereas the submu- tice.24 It was initially shown to reduce radiation toxicities cosa and blood vessels remain normal.38 such as mucositis and dysphasia in patients receiving Local skin toxicity in the radiated fi eld can be signifi cant. therapy for head and neck and lung cancers.25,26 When Dermatitis, from mild to severe, with desquamation and applied to the treatment of radiation-induced proctitis, both ulceration can occur [see Figure 3]. The relationship between intrarectal enemas and subcutaneous injections of the drug toxicity symptoms in the acute phase following radiation were shown to reduce mucositis, and the subcutaneous form therapy and the development of a more chronic condition was also effective in preventing urinary toxicities such as remains controversial. Although the development of chronic nocturia and dysuria.27,28 Octreotide acetate has been widely injury has not been directly related to initial acute symp- used for the prevention of chemotherapy-induced diarrhea, toms, there is some suggestion of an association that may be but randomized trials in which it was administered intra- related to the dose of radiation administered as both the muscularly prior to and during radiation therapy failed to acute and chronic syndromes occur more frequently with demonstrate any reduction in the incidence or severity of higher doses.39–41

Table 2 Investigated Prophylactic Therapies to Prevent Radiation Injury Medication Strategy Administration Effect Beclomethasone dipropionate Reduce inflammation Enema Reduction in rectal bleeding Mesalazine (5-ASA) Reduce inflammation Enema No benefit or worsened rectal bleeding Sucralfate Mechanical shielding Enema No significant reduction in toxicity Oral No reduction in toxicity, increased rectal bleeding Amifostine Prevention of DNA damage Enema Reduced morbidity Subcutaneous Reduced morbidity, decreased urinary toxicity Octreotide Reduction of gastrointestinal Intramuscular and Failed to reduce the incidence or severity secretion and motility subcutaneous of diarrhea Probiotics Promote intestinal bacterial Oral Suggested benefit in reducing diarrhea, flora but further studies are needed

5-ASA = 5-aminosalicylic acid.

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the most common symptom of chronic radiation proctitis, occurring in up to 50% of patients but requiring transfusion in only one third of cases and further intervention in less than 6%.2,43 Bleeding occurs secondary to the formation of friable that develop as the mucosal capillaries attempt to compensate for the relative ischemia resulting from vascular changes. This ischemia can also make the bowel wall prone to perforation, ulceration, or abscess or fi stula formation [see Figure 4]. Whereas bleeding is often self-limited and resolves without intervention, symptoms such as strictures, abscesses, and fi stulae are unlikely to resolve without intervention and often require surgery [see Figure 5].2 Fecal urgency and incontinence can manifest in 3 to 53% of patients as a result of connective tissue fi brosis that leads to decreased rectal compliance.42,44 Given the signifi cant variation in both the type and severity of symp- toms, a scoring system, such as the one developed by Talley and colleagues [see Table 4],45 can be useful to objectively measure proctitis. It is important to note that chronic radiation injury is not limited to bleeding and changes in bowel habits. Chronic skin changes may occur in the radiated fi eld with “woody” induration of the perianal and gluteal areas. Some studies have also shown an increased rate of small bowel obstruc- Figure 3 Severe perianal dermatitis following pelvic radiation. tions in irradiated rectal cancer patients compared with those who underwent surgery only.46,47 Urinary dysfunction is also reported, albeit less commonly than gastrointestinal symptoms.48 Lastly, increased rates of deep vein thrombo- embolisms and fractures of the pelvis and femoral neck have chronic injury also been reported in patients undergoing preoperative ra- Chronic proctitis aris- diation therapy in addition to surgery for rectal cancer as es in up to one fi fth opposed to those undergoing surgery alone.47 of patients and usually develops at least 6 months following radia- tion therapy.2,37 Symp- toms include rectal bleeding, diarrhea, fecal urgency, and fecal incontinence, and the reported incidence of these symptoms varies widely [see Table 3]. Unlike the pathogenesis of acute injury, vascular changes include subintimal fi brosis, platelet throm- bi, and endothelial degeneration and ultimately lead to relative ischemia.42 These vascular changes, in combination with severe lamina propria fi brosis and crypt distortion, distinguish chronic from acute injury.2,38 Rectal bleeding is

Table 3 Reported Frequencies of Symptoms of Chronic Radiation Proctitis Symptom Reported Frequency (%) Rectal bleeding Up to 50 Diarrhea Up to 50 Fecal incontinence 3–53 Small 9–13

Urinary dysfunction 3–4 Figure 4 Radiation proctitis with ulceration.

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Assessment and Diagnosis initial workup of postradiated patients Diagnostic workup for radiation injury should be focused on those patients who have clinically signifi cant signs, such as a docu- mented decreased he- matocrit or a transfusion requirement, or symp- toms that are persistent and have a deleterious effect on quality of life.1 A thorough history should address all symp- tomatology relevant to the gastrointestinal tract, as well as urinary, sexual, and neurologic symptoms that may also be 53 Figure 5 Severe radiation proctitis with fi stula (arrow). manifestations of radiation injury. Questionnaires such as the LENT-SOMA (late effects in normal tissues – subjective, objective, management, analytical) and the Radiation secondary cancers Therapy Oncology Group questionnaires have been devel- In addition to symptomatology that can have a detrimen- oped to assess the severity of symptoms experienced by postradiation patients, although their clinical utility is tal effect on quality of life, pelvic radiation also carries an 54 increased risk of the development of a second cancer. DNA debatable. Initial laboratory tests should include hemato- logic and biochemical profi les, as well as tumor markers, changes, including diploid and aneuploid DNA, have been and can help direct further testing.55 Patients’ overall nutri- demonstrated in rectal tissue in both acute and chronic proc- tional status should be taken into account in addition to titis following radiation. Studies have reported a threefold the status of their cancer and overall prognosis. Perineal higher risk of rectal cancer after radiation for pelvic malig- 44,49,50 examination should be performed to evaluate for internal nancies, including cervical and prostate cancers. The or external skin and tissue changes such as dermatitis, relationship to radiation dosage is not clear, and it has been ulceration, fi stulae, or masses. shown that rectal cancer can arise without clinical proctitis Endoscopic evaluation, by either sigmoidoscopy or colo- 51 at the time of radiation therapy. Radiation for rectal cancer noscopy, with biopsies to allow for tissue diagnosis, is often has also shown an increased risk of secondary cancers in the most useful initial investigation. The classic appearance adjacent organs, mostly commonly the prostate, colon, and of radiation proctitis is erythema, friability, and ulceration of urinary bladder, although overall the combined risk of the mucosa of the bowel wall as well as prominent telangi- either a rectal cancer recurrence or a secondary malignancy ectasias. The spectrum of fi ndings on endoscopy ranges remains lower in radiated compared with nonradiated from mild to severe and may include necrosis of tissues [see patients.52 Figure 6, Figure 7, and Figure 8].56 Colonoscopy may be more

Table 4 Scoring System for Symptoms and Endoscopic and Histologic Results45 Score Variable 01 2 Symptom Urgency None Mild (5–20 min) Moderate or severe (< 5 min) Bleeding per rectum (per week) 0 < 4 ≥ 4 Quantity of blood per rectum (per week) None Streaks Obvious Diarrhea (days per week) 0 1 > 1 Number of stools ≤ 1 2–3 > 3 Rectal pain None Pain present — Endoscopy (rectum) Erythema None Mild Moderate Granularity or edema None Mild Moderate Telangiectasia None Few or some Sparse or florid Ulcer None Few or numerous — Histology (rectum) Overall grade Normal Abnormal —

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challenging in postradiation patients owing to the relative immobility of the secondary to fi brosis, lumi- nal narrowing, and possible stricture formation.37 However, it is important to exclude more proximal sources of rectal bleeding such as colonic adenocarcinomas, diverticulae, or arteriovenous fi stulae.2 Computed tomographic (CT) colo- nography, barium enemas, and cross-sectional imaging can be useful adjuncts to endoscopic imaging. Barium enema and CT colonography may reveal masses in the more proxi- mal colon; there are also characteristic radiologic features suggestive of late radiation injury, including ulceration, stenosis, fi stulae, decreased bowel distensibility, and intesti- nal fi xation. These studies can be useful in demonstrating the extent of disease.57 Transrectal and endoanal ultrasonog- raphy has been used in the workup of rectal complications following pelvic radiation. Characteristic fi ndings of radia- tion injury include thickening of the perirectal connective Figure 6 Mild radiation proctitis as seen on endoscopy. tissue, obscuring of the submucosal layer of the rectal wall, and scarring of the musculature.37,58 Anorectal physiology may be undertaken when symptoms are primary functional, such as fecal urgency and incontinence, and most often demonstrates decreased compliance associated with decreased fi rst sensation volumes, lower resting pressures, and lower maximal tolerated rectal volumes.2,37

secondary testing If fi rst-line workup is either unrevealing or not consistent with radiation proctitis, the range of possible etiologies to explain a patient’s symptoms must be expanded. It is important to rule out cancer recurrence or the development of a sec- ondary malignancy as Figure 7 Prominent telangiectasia. the etiology of a patient’s symptoms, particularly if the symptoms are more constitutional and include signifi cant weight loss. Cross-sectional imaging, such as CT or mag- netic resonance imaging (MRI), is frequently used.54 CT may demonstrate acute radiation injury fi ndings such as bowel wall edema and enhancement of the mucosa with contrast [see Figure 9]. Chronic changes of radiation injury to the pelvis structures include thickening and increased density of the perirectal fat, fascia, and rectal wall and fi brosis between the sacrum and rectum. Edema and enhancement of the mucosa are no longer present in the chronic phase of injury [see Figure 10].59 MRI may demonstrate increased signal uptake indicative of infl ammatory changes as well as a characteristic pattern of varying edema [see Figure 11].60,61 However, both CT and MRI can fail to differentiate between postradiation changes and recurrent malignancy.37 Positron emission tomography (PET) is not considered to be fi rst-line testing for , but it has been shown to be more accurate in differentiating postradiation change from recurrent malignancy than other cross-sectional imaging Figure 8 Anal necrosis due to radiation. modalities.62

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Figure 9 Helical computed tomography (CT) in the transverse (a) and sagittal (b) planes after intravenous administration of iodinated contrast shows an infl amed rectum (arrows), which has increased mucosal enhancement (star) as well as heterogeneous enhancement in the wall with fl uid attenuation in the wall consistent with edema, indistinctness of the outer rectal wall, and edema in the perirectal fat (arrowheads), all consistent with acute proctitis.

If symptomatology is more suggestive of an upper Medical Therapy gastrointestinal etiology, investigation of the remainder of the gastrointestinal tract may be carried out with upper pharmacologic endoscopies, small bowel contrast studies, or capsule endos- therapies copies.9 If a satisfactory diagnosis to explain a patient’s Medical therapy is the symptoms still cannot be established, it may be worthwhile fi rst line of treatment to pursue workup of small bowel bacterial overgrowth and for radiation injury. The malabsorption syndromes with investigations such as glu- pathology of radiation- cose, xylose, lactulose, and hydrogen breath tests to evaluate induced injury is not an for carbohydrate malabsorption and selenium-75 homocho- infl ammatory one; how- lic acid conjugated with taurine (SeHCAT) scanning to work ever, historically, treat- up possible .9 ments were aimed at a b

Figure 10 Helical computed tomography in the transverse (a) and sagittal (b) planes after administration of intravenous iodinated contrast and rectal barium shows the rectal wall to have thin mucosa with normal enhancement, mural fat, and a thickened but sharply defi ned enhancing outer wall of fi brotic tissue (arrows), consistent with chronic proctitis. There is no edema in the perirectal fat outlined by the levator ani (solid arrowhead) but persistent stranding in the presacral space (open arrowhead), which is commonly seen chronically after radiation.

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Figure 11 Magnetic resonance imaging (MRI) of the pelvis with transverse T2-weighted images with fat suppression (STIR) (a) and transverse

T1-weighted, fat–suppressed, contrast-enhanced images after administration of a gadolinium-based contrast agent (b). The infl amed rectum

(arrows) has increased signal intensity on the T2-weighted images (in b) in the mucosa more than the wall consistent with edema as well as increased mucosal enhancement (in b). As on computed tomography, there is indistinctness of the outer rectal wall and edema in the perirectal fat (arrowheads), both consistent with acute proctitis. Extensive anterior subcutaneous and muscular edema are seen, which are changes from radiation toxicity. reducing infl ammation, perhaps because of the misleading signifi cant reduction in rectal bleeding, an improvement in term proctitis. With this concept in mind, therapies such as endoscopic scores, and an increase in hemoglobin values steroids and mesalazine have previously been proposed as when compared with placebo in small, randomized trials.68,69 fi rst-line therapies.63 A systematic review of both random- Other similar studies, however, failed to demonstrate this ized and nonrandomized prospective trials suggest that difference.45 these therapies are of little benefi t to patients.64 Other thera- pies that have been investigated include pentoxifylline, nutritional strategies tocopherol, vitamin E, thalidomide, probiotics, and rebamip- Although nutritional support is certainly important when ide. Studies to date have failed to convincingly demonstrate treating patients with radiation injury, previously studied a clinical benefi t of these therapies, although future studies specifi c diets such as elemental or exclusionary diets have may be warranted.5,9 Antimotility agents such as loperamide failed to demonstrate clinical effi cacy.9 The strategy of or codeine phosphate may be transiently useful for symp- “bowel rest” by using parenteral nutrition has also been tomatic relief of diarrhea but do not treat the underlying explored to treat radiation enteritis and has been shown to pathology and are unlikely to provide a sustained effect.9 improve nitrogen balance and clinical parameters compared If stools are diffi cult to pass or patients have chronic consti- with patients receiving an elemental feeding.70 Bowel pation, however, stool softeners may help minimize trauma rest and parenteral nutrition have also been studied as an to friable gastrointestinal mucosa. alternative to immediate surgery for patients with radiation Pharmacologic therapies that have demonstrated clinical enteritis–associated bowel obstruction. Some studies benefi t in randomized trials include metronidazole, sucral- have demonstrated resolution of intestinal obstruction and fate enemas, vitamin A, and short-chain fatty acid enemas equivocal or improved overall survival with this strategy, [see Table 5]. Metronidazole is an antibiotic that kills primar- although others have shown higher rates of clinical ily anaerobic bacteria. A randomized trial found that 4 weeks recurrence with bowel rest and parenteral nutrition when of therapy with oral metronidazole in combination with oral compared with patients who had surgery.71–73 mesalazine and betamethasone enema decreased rectal bleeding, mucosal ulcers, diarrhea, and edema for up to hyperbaric oxygen 12 months after treatment when compared with treatment therapy with mesalazine and betamethasone alone.65 Sucralfate is a If medical therapies sucrose sulfate-aluminum complex that has shown a better fail to control the symp- clinical response in a small randomized trial when adminis- toms of radiation thera- tered as an enema twice daily over 4 weeks when compared py, hyperbaric oxygen with patients receiving oral sulfasalazine in combination therapy can be consid- with rectal prednisolone, although a difference in endoscop- ered for the treatment ic improvement was not demonstrated.66 Vitamin A has of ongoing, chronic been shown to be benefi cial for wound healing, and in symptoms.1 Hyperbaric one small, randomized trial, oral therapy demonstrated a oxygen therapy acts by statistically signifi cant reduction in symptoms of radiation promoting neoangio- proctopathy compared with placebo.67 Short-chain fatty genesis and revascularization. There is a signifi cant ischemic acid therapies, primarily using butyrate, have shown a component to the disease pathology leading to radiation

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Table 5 Pharmacologic Therapies that Have Demonstrated Clinical Benefi t in Randomized Trials Admin- Duration of Follow- Study Statistically Signifi cant Therapy Study istration Treatment Up (n) Treatment Groups Effect Metronidazole Cavcic et al65 Oral 4 weeks 12 months 60 Oral metronidazole plus Reduction in the incidence oral 5-ASA and of rectal bleeding and betamethasone enema mucosal ulcers; versus identical 5-ASA decreased diarrhea and and betamethasone edema treatment without metronidazole Sucralfate Kochhar et al66 Enema 4 weeks 4 weeks 37 Oral sulfasalazine with Improved clinical response prednisolone enemas versus sulfate enemas and oral placebo Vitamin A Ehrenpreis Oral 90 days 90 days 19 Oral retinol palmitate Reduction of rectal et al67 versus placebo symptoms as measured by the Radiation Proctopathy System Assessments Scale Short-chain Pinto et al68 Enema 5 weeks 6 months 19 Short-chain fatty acid Decrease in number of fatty acids Vernia et al69 Enema 3 weeks 3 weeks 20 enemas versus placebo days of rectal bleeding; (butyrate) improved endoscopic score; higher hemoglo- bin values; remission of clinical symptoms

5-ASA = 5-aminosalicylic acid (mesalazine). injury, and the high oxygen pressure leads to the maturation as it is only offered in specialized centers; and its signifi cant of telangiectasias and has been shown to increase the expense. Additionally, the claustrophobic effect can be vascular density of soft tissues several-fold.64 It also reduces diffi cult for some patients, and potential side effects include damage secondary to free radicals, stimulates tissue regen- otic barotrauma and transient myopia, although these tend eration, and decreases fi brosis to improve the compliance to be mild and transient.43,78 of the bowel.5 The successful use of this therapy for treat- ment of radiation injury, specifi cally the treatment of severe Endoscopic Therapy hemorrhage secondary to radiation colitis, was reported in 1993.74 For a time, all the evidence supporting the use of this If medical manage- therapy was derived from impressive results from case ment fails, endoscopic series, such as an early report from 1997 of 14 patients therapy should be sug- treated in 100% oxygen at two atmospheres. Eight patients gested to address acute experienced complete resolution of symptoms, and another or clinically signifi cant reported substantial improvement.75 Larger case series bleeding or in the case of followed and also showed promising results, such as the unavailability of hyper- 2007 report of 65 patients with chronic radiation enteritis baric oxygen therapy. who were treated with hyperbaric oxygen.76 An overall Endoscopic therapy is response was demonstrated in 68% of patients, and 43% especially useful in con- showed a complete response. In 2008, a randomized trolling hemorrhage sec- controlled trial treated 150 patients with radiation proctitis ondary to telangiectasias as opposed to bleeding secondary refractory to other therapies with either hyperbaric oxygen to diffuse proctitis [see Figure 12].1 There are several possible treatment at 2.0 atmospheres absolute or sham treatment modalities, all of which are invasive and have the potential with air at 1.1 atmospheres absolute for 30 to 40 sessions. for serious procedure-related complications and side effects. Hyperbaric oxygen therapy led to a signifi cant improve- These risks should be thoroughly discussed with the patient, ment in patients’ radiation proctitis as graded by the LENT- and experienced practitioners should carry out endoscopic SOMA scoring system, an improvement in quality of life, therapy with caution.78 and an overall 32% absolute risk reduction between the groups with a number needed to treat of 3.77 Hyperbaric thermal coagulation oxygen is a safe, well-tolerated, noninvasive therapy that Thermal coagulation is one of the most common modali- also offers the advantages of possibly reversing progressive ties used and encompasses the use of argon plasma, laser changes and improving associated urinary problems. The coagulation, and bipolar probes. The common therapeutic disadvantages of hyperbaric oxygen therapy are the signifi - benefi t is the destruction of bleeding vessels, but the effect cant time commitment, as it can constitute up to 8 weeks of can also extend into the mucosa and submucosa, which can daily 90-minute treatment sessions; the limited availability, damage these already ischemic tissues and led to subsequent

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Figure 12 Endoscopic view of actively bleeding telangiectasia. Figure 13 Bleeding rectal telangiectasia status following argon plasma coagulation with hemostasis achieved. ulceration in up to 50% of patients in one study.79 Ulcer- of formalin, such as enemas, application via endoscopy ations do have the potential to cause pain, to inhibit healing, or transanal examination under anesthesia is less likely to and to lead to stricturing that can affect bowel function. cause burns.2 Other potential side effects include worsened bleeding, bloating, cramping, tenesmus, fi stulae formation, and perfo- cryoablation ration. The reported effi cacy is high, however, at between 76 Endoscopic cryoablation is a newer technique with an and 100%, and it is a widely used therapy.78 effi cacy of 70 to 100% reported in pilot studies.78 Observed Bipolar diathermy places two electrodes across a mucosal therapeutic effects include clinical improvement as mea- bleeding point and uses the tissue as a conductor. It has been sured by the Radiation Proctitis Severity Assessment Scale successfully used, but its continuous use is impeded by char (RPSAS) and decreased density of rectal telangiectasias.83 formation on the tips of the electrodes.80 Argon plasma Side effects include rectal ulceration as well as perforation. coagulation (APC) avoids this issue by avoiding physical Cryoablation is not yet widely used and is still being contact between the electrode and the patient. It is the most investigated. widely used thermal coagulation technique and is generally considered the safest and the cheapest.1 It coagulates to a depth of 0.5 to 3 mm and generally requires two or three Endoscopic radiofrequency ablation (RFA) for the treat- treatments for maximum benefi t [see Figure 13]. Adverse ment of radiation injury is being explored in the context of effects occur in up to 18% of patients and tend to be mild. clinical trials. Previous studies have demonstrated its effi - In addition to improving rectal bleeding, patients can also cacy for mucosal ablation of the , and case reports experience improvement in other symptoms, including and small case series have reported effi cacy in the treatment urgency and diarrhea.2 Laser therapy, generally with a of chronic radiation proctitis by way of reepithelialization of neodymium:yttrium-aluminum-garnet (Nd:YAG) laser, is squamous mucosa over areas of hemorrhage without any another option for endoscopic coagulation but is infrequentl y adverse side effects observed.84–86 Although this technique is used because of the greater cost and safety risk, especially in promising, more studies are needed before it can be widely terms of ocular hazards, when compared with APC.2 recommended. formalin application Surgical Therapy The application of 4 to 10% formalin solution to the bowel mucosa causes cauterization of newly formed blood Surgical management vessels to prevent further bleeding. Reported effi cacy varies of this patient popula- between 48 and 100%, and similar to thermal coagulation, it tion is very high risk, can cause pain, ulceration, stricturing, and perforation, as and even when carried well as formalin-associated colitis and serum sickness.78,81 out at specialized One small randomized trial comparing APC and topical tertiar y or quaternary formalin treatment demonstrated comparable effi cacy in care centers, operative controlling rectal bleeding following radiation for prostate morbidity and mortality cancer.82 Although there are other options for the application are signifi cant. Surgery

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04/15 gastro acute and chronic radiation injury to the lower gastrointestinal tract — 12 should be considered only in patients who are reasonably 2. Johnston MJ, Robertson GM, Frizelle FA. Management of fi t and have a realistic life expectancy. The most common late complications of pelvic radiation in the rectum and operative complications include anastomotic leakage, if an anus: a review. Dis Colon Rectum 2003;46:247–59. anastomosis is created, and fi stula formation. Complications 3. Denham JW, Hauer-Jensen M. The radiotherapeutic occur in up to 30% of patients, and between 40 and 60% will injury—a complex ‘wound.’ Radiother Oncol 2002;63: require multiple laparotomies for management.2,9 Subse- 129–45. quent intestinal failure can result, which leads to in-hospital 4. Syndikus I, Morgan RC, Sydes MR, et al, MRC RT01 death in up to one third of patients.87 Indications for surgery Collaborators. 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