Intestinal Radiation Injury
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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.
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:
Previous surgery causes the development of adhesions that tend to fix the intestines, which may become involved in the radiation field.
Patients with hypertension, diabetes mellitus, and generalized atherosclerosis are at an increased risk for vascular occlusive disease.
Thin, elderly, and female individuals may have more small intestine lying in the pelvis and may be subject to more radiation exposure.
Hypoxic cells are less sensitive to radiation injury. Administering hyperbaric oxygen (HBO) at the time of radiation to increase tumor cell destruction also can increase damage to the healthy cells.
Certain chemotherapeutic agents (eg, Adriamycin, methotrexate, 5-fluorouracil, bleomycin) increase sensitivity to radiation.
Based on limited uncontrolled retrospective data, patients with underlying inflammatory bowel disease may be at a higher risk for severe toxicity.
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] :
Group I: Consisted of 44% of patients with the most favorable outcome; 70% achieved resolution in 18 months, 5% required surgery, and 15% died from complications.
Group II: Consisted of 36% of patients with a less favorable outcome and 25% mortality.
Group III: Consisted of 20% of patients with intractable bleeding, all of whom required surgery. The overall mortality was 41%.
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:
Small or large bowel obstruction
Small or large bowel bleeding
Fistulae: Rectovaginal, enterovesical, rectovesical, or enterocolic
Malabsorption, electrolyte abnormalities, and dehydration
Perforation
Urethral stenosis
Cystitis
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Rajeev Vasudeva, MD Clinical Professor of Medicine, Consultants in Gastroenterology, University of South Carolina School of Medicine
Rajeev Vasudeva, MD is a member of the following medical societies: American College of Gastroenterology, Columbia Medical Society, South Carolina Gastroenterology Association, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, South Carolina Medical Association
Disclosure: Received honoraria from Pricara for speaking and teaching; Received consulting fee from UCB for consulting.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Douglas M Heuman, MD, FACP, FACG, AGAF Chief of Hepatology, Hunter Holmes McGuire Department of Veterans Affairs Medical Center; Professor, Department of Internal Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine
Douglas M Heuman, MD, FACP, FACG, AGAF is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Physicians, American Gastroenterological Association
Disclosure: Received grant/research funds from Novartis for other; Received grant/research funds from Bayer for other; Received grant/research funds from Otsuka for none; Received grant/research funds from Bristol Myers Squibb for other; Received none from Scynexis for none; Received grant/research funds from Salix for other; Received grant/research funds from MannKind for other.
BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine
BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.
Anil Minocha, MD, FACP, FACG, AGAF, CPNSS Professor of Medicine, Director of Digestive Diseases, Medical Director of Nutrition Support, Medical Director of Gastrointestinal Endoscopy, Internal Medicine Department, University of Mississippi Medical Center; Clinical Professor, University of Mississippi School of Pharmacy
Anil Minocha, MD, FACP, FACG, AGAF, CPNSS is a member of the following medical societies: American Academy of Clinical Toxicology, American Society for Gastrointestinal Endoscopy, American Federation for Clinical Research, American Association for the Study of Liver Diseases, American College of Forensic Examiners Institute, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association
Disclosure: Nothing to disclose.
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