In 1897, 2 years after the discovery of x-rays by Roentgen, radiation-induced intestinal injury was first reported.
Although toxicity was the limiting factor in the early years, advancements in technology made in delivering high doses of radiation possible to selected localized tissue targets, resulted in increased efficacy and increased utilization of radiation in the armamentarium of cancer therapy.
Many cancer patients receive some form of radiation as part of their cancer therapy; therefore, radiation-induced injury is likely to be a frequent occurrence despite improvements in radiation technology. In addition, events such as the explosions at Japan's Fukushima Daiichi nuclear power plant in March of 2011 ignite concerns of radiation exposure, which can lead to radiation-induced injury.
In a phase I/II dose-escalation trial of a 3-dimensional conformal radiation therapy (3DCRT; RTOG 9406) for prostate cancer, Michalski et al reported on the incidence of late toxicity and found tolerance to high-dose 3DCRT was excellent but that there was significantly more grade 2 or greater toxicity with a dose of 78 Gy at 2 Gy/fraction than with 68.4-79.2 Gy at 1.8 Gy/fraction and with 74 Gy at 2 Gy/fraction.[1] The patients were divided into 3 groups: Group I patients were treated at the prostate only; group 2 patients were treated at the prostate and at the seminal vesicles with a prostate boost; and group 3 patients were treated at the prostate and seminal vesicles.
When McCammon et al evaluated 30 patients with intermediate- to high-risk prostate cancer to determine the toxicity associated with pelvic intensity-modulated radiotherapy (IMRT) and hypofractionated simultaneous integrated boost (SIB), the investigators found that, at a median follow-up of 24 months, late toxicity that exceeded grade-2 severity was uncommon; there were 2 occurrences of grade-3 toxicity and 1 case of grade 4.[2] The patients had also received androgen suppression. The investigators used the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, to score toxicity.
Significant efforts have been made to develop methods to decrease or prevent radiation damage and to treat this dreadful complication.
Images of radiation-induced intestinal injuries are shown below.
View Image | Intestinal radiation injury. Note the characteristic mucosal changes observed in radiation proctitis with multiple telangiectasias. |
View Image | Intestinal radiation injury. Friability and oozing of blood from atrophic-appearing mucosa due to radiation can be seen. |
This article focuses specifically on the effects of radiation on the small intestine, the large intestine, and the rectum.
Understanding the basic principles of how radiation affects the intestinal tract at the cellular level is important.
The new accepted unit dose of radiation is the gray (Gy); 1 Gy is equivalent to 100 rads. Although radiation injury can occur at doses of less than 40 Gy, serious injury usually occurs at doses greater than 50 Gy. Minimal tolerance (TD 5/5) is the dose that causes 5% of patients to have radiation injury within 5 years. While maximal tolerance (TD 50/5) is the dose at which 25-50% of patients manifest injury in 5 years. This translates to 45-65 Gy for the small intestine, 45-60 Gy for the colon, and 55-80 Gy for the rectum. The window of safety is narrow or perhaps nonexistent because the doses that cause injury are very close to the doses needed for therapy.
Cells are most sensitive to radiation during the G2 and M stages of mitotic division; therefore, rest periods between radiation sessions are important for the recovery of tissues. The most rapidly dividing cells are the most radiosensitive.
Radiation-induced injury is best described in 2 ways. Acute injury is a function of fractionation of the dose, field size, type of radiation, and frequency of treatment. Acute injury is caused by injury to the mitotically active intestinal crypt cells. On the other hand, chronic radiation injury is caused by injury to the less mitotically active vascular endothelial and connective tissue cells. Chronic injury is a function of the total dose of radiation used. This accounts for the described biphasic radiation injury.
Radiation injury impairs the normal repopulation of surface epithelium with growing new cells from the epithelial crypt cells. Repopulation normally takes place in 5-6 days. This impairment leads to varying degrees of retraction of villous core cells and spreading out of the enlarged villous epithelial cells. The loss of absorptive surface leads to malabsorption manifesting as diarrhea. Depending on the degree of disruption to the mucosal barrier by injury to the surface cells, microulcerations may form. The microulcerations can coalesce to form gross lesions. Intercellular tight junctions are disrupted, permitting the passage of endotoxin-containing particles from the lumen into the plasma.
Impairment to the blood supply by injury to capillary endothelium also contributes to the disruption. Invasion of the mucosa by intestinal microbes and sepsis may occur. Usually, therapeutic doses do not produce these profound consequences, and radiation treatment should be suspended or reduced when symptoms become significant. Crypt mitosis returns to normal within 3 days. Complete histologic recovery takes as long as 6 months. Chronic effects usually manifest after 6-24 months and are caused mostly by obliterative arteritis and thromboses of vessels; the result is ischemia or necrosis.
The combination of acute and chronic radiation injury can result in varying degrees of inflammation, thickening, collagen deposition, and fibrosis of the bowel, as well as impairment of the mucosal and motor functions.[3]
Although radiation obviously is responsible for the radiation-induced intestinal injury, certain predisposing factors increase the risk of radiation injury, as follows:
Although the exact incidence remains controversial, radiation enteritis is increasing and has been estimated to occur in 2-5% of patients receiving abdominal or pelvic radiotherapy.[4, 5] This incidence is expected to continue increasing.
Some investigators have report a much higher incidence of radiation enteritis, which may be explained by the extent of the radiation field, the technique, and the dosage of radiation used.
The prevalence has been underestimated largely due to the lack of clinical recognition, and it varies from 0.5% to 37%, depending on the radiation technique.
No predilection exists for any racial or age group, nor for either sex. However, because most malignancies occur in older individuals, one expects this entity to be less of a problem in children.
The natural history of radiation enteritis is hard to ascertain due to the lack of follow-up information in these patients. Often, these patients succumb to their original malignancy. Reports exist that 50% of patients with radiation-induced enteritis who survived more than 3 months after surgery and who were observed for as long as 12 years did well, while the remainder had persistent symptoms, developed complications, or both. The 5-year survival rate for the entire group was 40%.
In terms of radiation proctitis, Gilinsky et al developed the following classification system based on outcome[6] :
The cumulative 10-year incidence of moderate injuries is estimated at 8%, and that of severe injuries is estimated at 3%, including bleeding and obstruction, stenosis and fistulization, and malabsorption and peritonitis.
Complications of intestinal radiation injury include the following:
Symptoms can appear early, within hours of the first treatment session; very shortly after therapy; or months to years after the treatment has ended.
In most situations, patients experience acute symptoms 2-3 weeks into the treatment. Symptoms usually resolve in 2-6 months. Symptoms tend to be self-limited and mild in severity, requiring predominantly symptomatic therapy. The correlation between the severity of mucosal damage and the severity of symptoms appears to be poor.
Symptoms include the following:
Symptoms generally are insidious and develop months to years after therapy has ended. Many patients with chronic radiation enteritis may not have a prior history of acute radiation injury. Note the following:
Physical examination findings vary, and they can be normal or abnormal depending on the presence or absence of an underlying complication. Note the following potential findings:
Obtain the following laboratory studies:
Flat and upright radiographs are usually nonspecific. During the early phase, the radiographs may show findings consistent with an ileus. Findings may also may show dilated loops with air fluid levels in the event of a bowel obstruction.
The presence of thumb printing may be due to mucosal edema.
Barium studies are better than plain radiographs, because they provide better mucosal detail and document the presence of fistulae. Usual findings include separation of loops, narrowed fixed loops with poor distension, absent haustral markings, diffuse mucosal ulceration, or a single ulcer. The single ulcer usually is located on the anterior wall of the rectum.
Abdominal and pelvic CT imaging is an excellent study to confirm bowel obstruction and its possible location. This imaging modality can rule out the possibility of an abscess, and it may help in further delineation of fistulae.
Video capsule endoscopy has been utilized for diagnosing radiation enteritis in anecdotal reports.[7, 8] However, clinicians must exercise caution due to a potentially increased risk of bowel obstruction at the site of fibrotic strictures.
Endoscopy has several advantages over radiologic studies. Endoscopic biopsies may reveal classic histologic changes consistent with radiation injury. Endoscopic therapy also can be provided in the same setting, as necessary.
Endoscopic findings vary depending on the timing of the procedure (ie, acute setting versus chronic setting).
Colonoscopy may be dangerous depending on the stage of irritation and injury of the colon. Colonoscopy needs to be performed cautiously in the acute setting.
Acute setting
Initial changes reveal a friable edematous mucosa, whereas later changes reveal duskiness, edema, and inflammation.
Ulceration is infrequent but may occur later as the cumulative dose of radiation increases. In this case, the results would show necrotic mucosa with patchy areas of superficial ulceration.
Chronic setting
Fibrosis of the bowel wall may appear as smooth and symmetric strictures.
The mucosa may appear granular, friable, edematous, and pale, with prominent submucosal telangiectatic vasculature.
This procedure can potentially detect strictures or a source of bleeding in the small bowel in difficult to diagnose cases.
A retrospective review of 31 patients by Yang et al suggested that capsule endoscopy may be safe and effective in visually identifying the etiology of subacute small bowel obstruction, particularly in cases of suspected intestinal tumors or Crohn disease not found with routine studies.[9] Of the 31 cases, capsule endoscopy provided a definitive diagnosis in 12 (38.7%): 4 Crohn disease, 2 carcinomas, and 1 each of intestinal tuberculosis, ischemic enteritis, abdominal cocoon, intestinal duplication, diverticulum, and ileal polypoid tumor. There were no cases of acute small bowel obstruction, but the capsule was retained in 3 (9.7%) patients either due to Crohn disease (n = 2) or tumor (n = 1).[9]
Histologic changes vary depending on the timing of presentation. Acute changes include hyperemia, edema, and inflammatory cell infiltration of the mucosa, with villous shortening, crypt abscesses, thinning of the mucosa, and ulceration.
During the subacute and chronic stages, some mucosal regeneration may occur. The endothelial cells may degenerate, and fibrin plugs may form. Large foam cells beneath the intima are considered pathognomonic for radiation injury. Submucosal fibrosis and obliteration of small blood vessels result in ischemia, which is progressive and irreversible. Ischemia initially involves the mucosa and gradually progresses to involve the submucosa and serosa. Ischemic necrosis and ulceration may lead to fistula formation.
In general, the correlation between pathologic and physiologic changes in the intestines is poor.
The treatment of acute injury varies depending on the symptoms, and the treatment of chronic injury varies depending on the location of injury.
For symptom control, consider antidiarrheals, bile-sequestering agents, antiemetics, 5-aminosalicylic acid (5-ASA) moieties, and sucralfate. Simple iron supplementation may suffice in some individuals with low-grade bleeding leading to mild anemia.
Consider topical steroids and sucralfate enemas if symptoms are related to rectal involvement. 5-ASA enemas have not been found to be very helpful.
Consider formalin instillation of the rectum and therapeutic endoscopic interventions (eg, ablation with argon, Nd:YAG laser, bipolar circumactive probe [BICAP], argon plasma coagulator). A retrospective study compared formalin instillation with Argon Plasma Coagulator (APC) in a small number of patients and suggested that APC was more effective and safer than formalin in controlling hematochezia and resulted in higher hemoglobin levels.[10]
Hyperbaric oxygen (HBO) therapy may be considered in intractable radiation proctitis before surgical intervention.
Surgical intervention usually is required as a last resort or in the case of complications (eg, perforation, obstruction, abscess drainage, fistulae, local wound infections). The surgical approach should be as conservative as possible.
Abdominopelvic operations are best avoided in patients who have received high-dose radiation to the pelvis. Resection of the rectum carries an operative morbidity rate of 12-65% and a mortality rate of 0-13%.
Resection of the diseased bowel can be difficult because identifying the affected loops at laparotomy may be problematic. Doppler viewing of the bowel and intraoperative frozen sections have not been helpful.
An intestinal bypass procedure may be necessary depending on the surgical findings and technical difficulties. Although resection has been shown to cause a higher incidence of leakage and mortality than bypass, the diseased bowel left behind also can cause more bleeding and can result in perforation and fistulization.
Several techniques have been described for resection with primary anastomosis, or secondary anastomosis with diversion colostomy or ileostomy.
When at least one end of a primary anastomosis is healthy bowel, reports exist that leakage is reduced significantly.
Dilation of strictures may be required. Perforation risk is significant if the strictures are long.
Rectovaginal fistulae may close spontaneously or after diversion colostomy. Other fistulae usually require surgical repair.
Presacral sympathectomy has been used for amelioration of severe pain.
A team approach is extremely important to treat these patients. The team may include a radiation oncologist, a medical oncologist, a gastroenterologist, a nutritionist, and, possibly, a surgeon.
The services of a pain specialist may be necessary if the pain is intractable and severe.
Also, the services of a physician experienced with hyperbaric oxygen (HBO) therapy may be necessary if this modality is considered in intractable proctitis.
Although no restriction on activity is necessary, on the basis of animal studies, a low-fat diet is recommended, with the intention of reducing pancreatic and biliary secretions to decrease radiation damage. A low-fat, low-residue, and lactose-free diet has been tried with some suggested success. Elimination of insoluble fiber from the diet with the substitution of soluble fiber has been tried.
Findings from animal studies suggest that glutamine-supplemented diets (eg, polymeric, elemental) may be protective against radiation injury.
Consider an elemental diet or the use of total parenteral nutrition as the clinical situation demands. A recent Italian retrospective study in patients with mechanical bowel obstruction due to chronic radiation enteritis showed that initial treatment with bowel rest and home parenteral nutrition was superior to initial surgical intervention in long-term survival and nutrition autonomy.
Note the following:
A number of promising innovative pharmacologic therapies are being studied.[11, 12, 13] Unfortunately, most of the data are from animal studies, and trials in humans are lacking. These agents include antioxidants in the form of vitamin E and vitamin E-like compounds, as well as the lazaroids (ie, 21-amino steroids) and, more recently, octreotide.
Although nonsteroidal anti-inflammatory drugs have shown some promise in animal studies, the results with a prostaglandin analogue, misoprostol, have been less than satisfactory.
Other emerging therapies include intravenous and intra-arterial vasopressin, epidermal growth factor, growth hormone, and nitric oxide (NO) inhibitors.
Sucralfate therapy in doses varying from 1 g every 4-6 hours during treatment and for another 3-4 weeks thereafter has been shown to be effective during pelvic irradiation. However, a more recent study showed that oral sucralfate was not effective in preventing late rectal injury in patients with prostate cancer.
The US Food and Drug Administration (FDA) approved the use of IV amifostine (Ethyol) as a radioprotectant agent. Administered as a daily dose, amifostine is to be used in the prevention of radiation-induced xerostomia in the postoperative setting. Its efficacy in the prevention of radiation intestinal injuries has yet to be established. Concern about tumor protection appears to be unwarranted. Adverse effects, such as nausea and hypotension, the need for daily injections, and cost concerns may limit its wide acceptance.
Animal studies
A murine study by Qiu et al described a novel molecular mechanism of growth factors in suppressing p53 upregulated modulator of apoptosis (PUMA) in acute radiation-induced gastrointestinal damage and gastrointestinal syndrome through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/p53 axis in the intestinal stem cells.[14]
In a different murine study, Cheng et al reported novel functions for receptor for activated C kinase 1 (Rack1) in regulating crypt cell proliferation and regeneration, promoting differentiation and apoptosis, and repressing development of neoplasia.[15]
In a murine and rat study, Valuckaite et al investigated the ability of a high-molecular-weight polyethylene glycol-based copolymer, PEG 15-20, to protect the intestine against the early and late effects of radiation as well as assessed its mechanism of action in cultured rat intestinal epithelia.[16]
PEG 15-20 was able to prevent radiation-induced intestinal injury in the rats, as well as prevent apoptosis and lethal sepsis attributable to Pseudomonas aeruginosa in mice. In addition, the cultured intestinal epithelial cells were protected from apoptosis and microbial adherence and possible invasion.[6] The investigators noted that PEG 15-20 exerted a protective effect by preventing coalescence of lipid rafts by binding them.[16]
There have been some promising reports in animal studies that probiotics may be helpful in preventing radiation induced intestinal damage.[16, 17, 18, 19] It remains to be seen whether this intervention turns out to be a preventative or therapeutic tool in human subjects.
In a more recent murine study, the antineoplastic small molecular agent BCN057 induced intestinal stem cell repair and mitigated radiation-induced intestinal injury.[20]
Another murine study indicated that the combination of podophyllotoxin and rutin (G-003M) improved survival of mice after lethal radiation intestinal injury by preventing oxidative stress-mediated cell death and promoting structural and functional regeneration in intestinal tissue.[21]
As noted above, the most important aspect of intestinal radiation injury is prevention; therefore, a number of innovative prophylactic surgical therapies have been proposed, and include the following:
The treatment of acute injury varies depending on the symptoms, and treatment of chronic injury varies depending on the location of the injury.
Clinical Context: Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin), and complete body radiotherapy. Also beneficial in reducing the frequency of diarrhea by delaying intestinal transit.
Clinical Context: Acts on intestinal muscles to inhibit peristalsis and slow intestinal motility. Prolongs the movement of electrolytes and fluid through the bowel lumen and increases viscosity and loss of fluids and electrolytes.
Clinical Context: Drug combination that consists of diphenoxylate, which is a constipating meperidine congener and a subtherapeutic dose of atropine to discourage misuse. Inhibits excessive GI propulsion and motility.
Clinical Context: Forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts. Decreases diarrhea by preventing bile salt malabsorption.
Clinical Context: An aluminum-hydroxide complex of sulfated sucrose, which forms a protective barrier at the site of ulceration due to radiation. Binds bile acids and helps to treat diarrhea from secondary bile acid malabsorption. Effective when administered PO as a prophylactic agent in preventing acute and chronic radiation injury. Studies using enemas for the treatment of radiation proctitis have shown promising short-term results. No dosing standards exist, and doses used in studies vary from 1 g PO q4-6h during treatment and for another 3-4 wk thereafter.
Clinical Context: Retention enema. An adrenocorticosteroid derivative suitable for application to skin or external mucous membranes. Has mineralocorticoid and glucocorticoid effects resulting in anti-inflammatory activity. Used for its anti-inflammatory properties and is effective in radiation proctitis.
Clinical Context: Direct mucosal contact allows rectal bleeding to cease.