31.1 Introduction

Radiation therapy is an important treatment option in patients with carcinoma of the cervix, uterus, ovaries, prostate, testicles, bladder, and rectum. ^{1 , 2 , 3 , 4} The injurious effects of X-rays on normal intestine were noted only 2 years after Roentgen’s discovery of X-rays, when Walsh ⁵ described the case of a coworker who developed bowel dysfunction while exposed to X-rays. The coworker’s symptoms cleared when he was kept from further exposure. Much has been written about the pathology and clinical symptomatology of radiation injury to individual organ systems. Some of the most serious injuries occur in the gastrointestinal tract, with damage to the small bowel, colon, and rectum. Despite improved technology and a better understanding of the effects of radiation on normal tissues, radiation injury is still a formidable problem. Many patients who are cured of carcinoma still suffer considerable morbidity and occasional mortality from the radiation itself.

31.2 Incidence and Clinical Manifestations

The true incidence of radiation injury is difficult to assess accurately. Most large series estimate the incidence of chronic radiation injury to be between 5 and 11%, with approximately 20% of these requiring an operation. ⁶ Krook et al ⁷ reported a 6.7% incidence of bowel complications in patients who received postoperative chemoradiation for rectal adenocarcinoma.

Although the acute effects of radiation begin within hours of the commencement of radiation therapy, most patients will not experience the symptoms of acute radiation injury until 3,000 to 4,000 cGy have been delivered. Acute colitis and proctitis are manifested by abdominal pain, diarrhea, tenesmus, and rectal bleeding. There is little value in pursuing an aggressive diagnostic evaluation in this clinical setting. Approximately 50 to 70% of all patients undergoing therapeutic pelvic irradiation will develop these symptoms. A decrease in the daily dosage of the radiation is usually successful, and it is distinctly uncommon to have to discontinue the therapy. ⁶

Late complications can lead to a multitude of clinical problems. Patients may present with bowel obstruction, stricture, fistula formation, perforation, hemorrhage, and malabsorption. They may also experience fecal incontinence, either because of direct radiation damage to the anal sphincter or as a consequence of late radiation effects on pelvic nerves. ⁸ One must keep in mind that patients who survive 5 or more years after their first malignancy may be at risk for the development of subsequent malignancies within the radiation fields. ⁶

Eighty-five percent of all patients who develop radiation injury present between 6 and 24 months after completion of radiation therapy. ^{9 , 10 , 11} The remaining 15% of patients may develop complications years or even decades after treatment. ¹² In general, patients with rectal ulceration or proctitis present somewhat earlier in their course than with strictures and fistulas. ^{13 , 14}

Damage to the small intestine is more serious and constitutes 30 to 50% of the radiation injuries severe enough to require operation. ^{15 , 16} Urinary tract complications, including ureteral obstruction secondary to fibrosis, cystitis, and fibrotic changes in the bladder (with bladder dysfunction and fistula formation), occur in up to 28% of patients having late gastrointestinal complications. ^{17 , 18}

Late complications can appear clinically as anorexia, malnourishment, colicky abdominal pain, bowel dysfunction (including diarrhea, obstipation, fecal urgency, and frequency of defecation with or without incontinence), rectal pain, rectal bleeding, dysuria, hematuria, chronic urinary tract infections, sepsis, and shock. Since many of these symptom complexes may also be seen in patients with recurrent malignancy, it is often difficult to distinguish late radiation injury from recurrent carcinoma.

A systemic review of 21 randomized controlled trials in 2015 evaluated the quality of toxicity information. ¹⁹ There was a lack of reporting standards, and studies that used patient-reported outcomes identified higher rates of toxicity symptoms than clinician-reported studies.

31.3 Mechanisms of Radiation Injury

Ionizing radiation injures cells by the transfer of energy to critical biologic macromolecules, including DNA, proteins, and membrane lipids. Some damage occurs directly from absorption of energy by the target molecules. Indirect damage is caused by diffusible oxygen-free radicals, highly reactive intermediates generated from the absorption of radiant energy by low-molecular-weight compounds. Water is, by far, the most abundant component of the cell, and the radiologic products of water are responsible largely for indirect, free radical damage. When target macromolecules are irradiated directly or react with high-energy free radical intermediates, the targets themselves become ionized or transformed into free radicals. Although radiation can exert its damaging effects by these two different mechanisms, the end result is the same. ²⁰

Damage to lipid membranes results, in part, from lipid peroxidation. Functionally, these changes are expressed as altered membrane fluidity and increased permeability, which can trigger the release of potent physiologic mediators that enhance the damage. ²⁰

31.4 Pathology

The gastrointestinal tract is second only to the kidneys in radiosensitivity, and gastrointestinal tract injury is the major limiting factor affecting tolerance to radiation of the abdomen and pelvis. ^{21 , 22} Although the small intestine is more radiosensitive than the large intestine, it is injured less frequently because of its mobility within the abdominal cavity. The sites of most severe injury after pelvic irradiation are in the lower sigmoid colon and upper rectum, probably because of their proximity to the field of radiation. Overt injury to the small intestine is less common but, when it occurs, is usually situated 6 to 10 cm from the ileocecal valve. These areas show the most severe derangement of vascular architecture and maximum reduction in microvascular volume. ²³

At the cellular level, the injurious effect of radiation is still not fully understood. Ionizing radiation generates free radicals from intracellular water; they, in turn, can interact with DNA to block transcription and replication. Cells with a high proliferation rate such as those in the intestinal mucosa are more susceptible to such disruptions. ^{24 , 25} More latent effects can occur in the vascular connective tissue, giving rise to complications later. ²⁴

Grossly, early radiation injuries result in an edematous, thickened, and hyperemic mucosa. Areas of superficial ulceration or necrosis may also be present (▶ Fig. 31.1). ²⁶ In the small bowel, the villi become blunted, and in both the small and large bowels, the crypts become shortened, and cryptal microabscesses can form. Microscopically, the microvilli of the surface epithelium are shortened, prominent large nuclei are present, and the mitochondria and endoplasmic reticulum are dilated. ¹⁵ The submucosa may show some cytologic atypia with bizarre, enlarged fibroblasts that could be mistaken for malignant cells (▶ Fig. 31.2). A loss of the normal fibrillar pattern of collagen and the deposition of large amounts of hyalin may also be present in the submucosa. ²⁷ A hyalin-type substance thickens artery walls as well. ^{22 , 28} Spasm and thrombosis may occur in the arterioles (▶ Fig. 31.3), and vascular ectasias may develop. ^{22 , 28} Infiltration by leukocytes can be seen throughout the full thickness of the bowel wall.

Late injuries are characterized by a severe degree of fibrosis. Grossly, the bowel appears pale and opaque, and is usually shortened. The mesentery becomes thickened and may also be shortened. ¹⁵ Gross radiation changes may be indistinguishable from those of Crohn’s disease, but the fat does not generally extend over the surface of the bowel as it does in Crohn’s disease (▶ Fig. 31.4). ²⁹ Loops of small intestine may be fused with fibrous adhesions and normal tissue planes obliterated, giving rise to a “frozen pelvis” comparable to that seen with recurrent malignancy. ^{15 , 29} Strictures, generally long and tapered, may appear; ulcers may develop and can be deep and progress to a fistula or perforation. ^{29 , 30}

Histologically, the villi show thickening and flattening, with areas of atrophy and degeneration. There is a marked submucosal fibrosis with hyalinization. ¹⁴ Telangiectasias may be prominent in the submucosa but may also occur throughout the bowel wall (▶ Fig. 31.5). The arterioles show hyaline thickening of the media with intimal proliferation. ²⁷ Areas of venous and lymphatic sclerosis are noted, and venous and lymphatic ectasias can appear in the submucosa. ¹⁴ The smooth muscle of both the small and large intestines may become hypertrophic, and the ganglion cells in the rectum may also undergo hypertrophy and degenerate; the latter change can affect function. ^{8 , 16} The serosa and perirectal connective tissue usually show fibrosis with arterial hyalinization and intimal fibrosis. ²⁹

A microradiography study using barium sulfate infusion by Carr et al ²³ showed that in radiation-injured bowel that requires resection, alterations in microvascular architecture are present in all sections, but these appearances vary with the type of lesion. At the site of fully developed strictures, a reduction in vascularity affects all the layers of the intestinal wall. Histologically, these areas show pronounced fibrosis in the submucosa and muscularis propria together with severe vascular changes that consist of occlusive fibrin thrombi in capillaries and sometimes-occlusive intimal fibrosis in the small intramural arterial vessels. In sections taken from sites adjacent to perforations, avascularity zones are apparent. The mucosal vascular pattern is abnormal, and the severity of change parallels the reduction in vascularity in the remainder of the section. Capillary microthrombi are present in these mucosal vessels with or without accompanying mucosal necrosis.

31.5 Pathogenesis

Malabsorption with intractable diarrhea is one of the most serious consequences of radiation injury to the intestine. Several factors may be involved in the genesis of this problem, including increased bowel motility. ³¹ The change in motility may stem from increased prostaglandin release, which can stimulate the smooth muscle of the small bowel. ^{31 , 32} Loss of the brush border and its digestive enzymes may occur, causing a decrease in carbohydrate absorption and osmotic diarrhea. ²⁸ Bacterial overgrowth in the intestine can also cause malabsorption and subsequent diarrhea. ³³ Injury to the terminal ileum can cause a decrease in the absorption of bile salts, which has a dual effect. An increased bile salt load to the colon causes intraluminal sodium retention with an increase in intraluminal water retention. In addition, the bile salt pool decreases in size, with a decrease in the absorption of fats and the development of steatorrhea. ³³

Although injury to the small intestine is chiefly responsible for malabsorption and diarrhea, injury to the rectum is responsible for the development of incontinence and the frequency and urgency of defecation. Stenosis of the rectosigmoid area sometimes is severe enough to cause these symptoms. ²⁷ Anal manometric study in patients with radiation proctitis showed a decrease in rectal volume and compliance. The physiologic length of the internal sphincter decreased, while the squeeze pressure and external sphincter muscle function were normal. Rectosphincteric reflex was abnormal in several patients. ^{8 , 16} Correlating these findings with histologic studies showed hypertrophy of smooth muscle and abnormalities in the myenteric plexus, including hypertrophy of the nerve fibers and a decrease in the number of ganglion cells within the plexus of Auerbach. ³⁴ A similarity between these findings and those of Hirschsprung’s disease was apparent.

Another complication of intestinal radiation is the development of a primary carcinoma in the radiated tissue. This was first noted by Slaughter and Southwick ³⁵ in 1957. In 1965, Black and Ackerman ³⁶ developed criteria for the diagnosis of radiation-induced carcinoma. These criteria include a 10-year latency period from the time of radiation therapy and severe radiation changes in the adjacent tissues. Sandler and Sandler ³⁷ demonstrated that patients who have had radiation therapy have a relative risk for developing a primary carcinoma in the radiated field 2.0 to 3.6 times that of the normal population. Patients who have undergone radiation in the pelvic region have careful surveillance beginning 10 years after completion of radiation therapy. Most of these neoplasms are likely to arise in the rectum and, therefore, should be within reach of a rigid or flexible sigmoidoscope.

Although one would expect high-dose radiation to be essential for the induction of colorectal carcinoma, in fact, the opposite may be true. Palmer and Spratt ³⁸ found that patients who received low-dose radiation for benign gynecologic conditions had a greater chance (3.32%) of developing rectal carcinoma than those who received high-dose radiation (1.42%) to treat carcinoma of the cervix. Radiation-induced colorectal carcinomas were more often of mucinous histologic type (25–60% of cases) than carcinomas in nonradiated patients (10% of cases). ⁶ The fact that these carcinomas are of a different histologic type and that all colon carcinomas induced by radiation in rats are mucinous adenocarcinomas ³⁹ lends further support to the concept that these carcinomas are radiation induced.

Another pathologic process that can be confused with adenocarcinoma is colitis cystica profunda, which has been noted to occur in irradiated tissue. It is a rare condition characterized by the presence of epithelial mucous cysts that are generally deep to the mucosa. ^{40 , 41} Although the glandular elements in the submucosa and muscularis propria may appear as adenocarcinoma, cytologic evidence of malignancy must be present before the lesions may be called adenocarcinoma.

31.6 Predisposing Factors

The cumulative total dosage of radiation delivered to the tissues is an important determinant of any subsequent radiation damage. Strockbine et al ⁴² in a review of 831 patients noted no intestinal injuries when the total radiation dose was less than 3,000 rads but found an injury rate of 36% among patients receiving 7,000 rads. Assessment of the minimal and maximal tolerance doses for the gastrointestinal tract has shown that the small bowel is the most radiosensitive area.

Although total dosage is an important etiologic factor in the development of radiation injuries, patients receiving low-dose radiation can still suffer radiation damage to normal tissues. ^{11 , 27} This damage can occur because cell injury is also dependent on the rate at which the radiation is delivered. Malignant cells do not self-repair as well as normal cells between doses of radiation; so malignant cells do not repopulate between doses as well as normal cells. Consequently, the normal cell population is better able to tolerate radiation that is given more frequently, especially when smaller doses are used. ^{24 , 43} Doses of less than 200 rads per day comprise the regimen usually given for external beam radiation. Dosage rates are especially important when intracavitary radiation is used. Lee et al ⁴⁴ have shown that dosage rates greater than 60 rads per hour are associated with a higher incidence of bladder and rectal injuries.

It has long been known that some patients tolerate radiotherapy better than others. One important predisposing factor is existing vascular damage from hypertension, diabetes mellitus, collagen vascular disease, and atherosclerosis. ^{1 , 10 , 19 , 28 , 45 , 46 , 47 , 48 , 49} Second is a previous abdominal or pelvic operation that led to adhesions that immobilize the small bowel such that the same segment receives radiation with each treatment. ^{20 , 50} A thin habitus has also been associated with a greater frequency of chronic radiation damage. ⁴⁸

A strong correlation has also been made between radiation injury and various chemotherapeutic agents. Doxorubicin (Adriamycin), actimycin, bleomycin, and 5-fluorouracil (5-FU) enhance cell injury in the gastrointestinal tract; this necessitates reduction in radiation dosage when these agents are being used. ^{51 , 52} Olsalazine is contraindicated during pelvis radiation therapy because it increases the risk of proctitis. ⁵³ Animal studies have shown that intraluminal contents, including pancreatic secretions, can predispose the patient to radiation injuries. ⁵⁴

31.7 Small Intestine Injuries

31.7.1 Diagnosis

Injuries to the small bowel are not readily identified as it is the most difficult part of the gastrointestinal tract to study radiographically and it cannot be reached readily endoscopically. Small bowel studies are notoriously inexact; extensive narrowing may be present with normal radiologic findings. Positive findings, when present, are generally those of ischemia with “‘thumbprinting,”’ nodular filling defects, and separation of loops secondary to edema and/or fibrosis (▶ Fig. 31.6). ⁵⁵ Strictures and fistulas also can be seen, but fistulograms are often necessary to localize enterocutaneous fistulas. The recent progress in CT enterography will lead to its replacing other radiologic tests for evaluating the small intestine. ^{56 , 57} Radiation-induced lesions may be especially difficult to distinguish from neoplastic invasion on X-ray studies. Most lesions secondary to radiation appear in the terminal ileum, whereas 58% of those caused by malignancy occur in the duodenum or jejunum. ⁵⁸ Angiography can help distinguish the two entities. Characteristic findings of radiation injury include arterial stenosis, decreased vascularity, luminal irregularities, and stenosis in the veins, with a decrease in the capillary phase in the bowel wall. In contrast, arteries supplying a malignancy tend to be dilated and are associated with a large number of tiny “tumor” vessels within the carcinoma during the capillary phase. ⁵⁹ The recent progress of technology using integrated PET-CT imaging is valuable for the differentiation of posttreatment changes from recurrent carcinoma. ⁶⁰

The clinical manifestation of radiation damage to the small bowel can be divided into two groups according to the time of appearance. Acute enteral complications of radiation therapy occur either during or immediately following a course of radiation therapy. Nausea, vomiting, cramps, and intermittent diarrhea are all symptoms of acute radiation enteritis. Such symptoms are probably caused by a breakdown in the intestinal mucosa that is no longer able to absorb the usual fluids and nutrients. The mucosa is also unable to prevent the efflux of fluids from the underlying supporting stroma. These changes in the intestinal epithelium result in disorders of motility and transport of fluid and solutes. ^{24 , 61}

Long-term complications of radiation therapy are usually manifestations of progressive vasculitis and interstitial fibrosis initiated by radiation therapy, often delivered many years before clinical signs develop. Partial or complete intestinal obstruction due to strictures or decreased motility, intestinal perforation, gastrointestinal bleeding, and malabsorption and enteric fistulas are all long-term enteral complications of patients treated with abdominal or pelvic radiation therapy. ^{24 , 61}

31.7.3 Surgical Management

Selection of appropriate procedures should consider general as well as local aspects. Literature data indicate that over 40% of patients with radiation enteritis will not survive 2 years following operation, and over 60% of the deceased succumb to their primary malignancy. ⁷⁴ Operation is clearly indicated for obstruction, perforation, fistula that is unresponsive to TPN, abscess, and intractable bleeding or diarrhea. Although the number of patients requiring operation is small, the morbidity rate has been reported to be as high as 65% ⁷³ and the mortality rate as high as 45%. ⁷⁵ Decisions concerning timing of operation and type of operation can be critical.

Often it is impossible to distinguish radiation injury from recurrent malignancy, thus influencing surgical decision-making. Walsh and Schofield ⁷⁶ reported on 53 patients with small bowel obstruction who underwent exploratory laparotomy and found that 17 of the 53 patients had recurrent malignancy, whereas the others had obstruction from other causes. Most of the patients with malignancy received good palliation from the operation, and the authors concluded that operation should not be denied solely because of concern about recurrent carcinoma.

The most controversial issue relating to the surgical management of patients with small bowel radiation injury is whether to bypass or resect the abnormal bowel. The argument against resection with primary anastomosis is that dividing the mesenteric vessels will further jeopardize an already compromised bowel and that dissection around adhesions increases the risk of subsequent fistula formation. ⁷³ On the other hand, bypassing an irradiated segment leaves behind a diseased portion of bowel with the potential for fistula formation and the development of a blind-loop syndrome. ^{77 , 78}

Surgical decision-making was influenced by a retrospective multicenter study with literature meta-analysis published in 1976, ⁷² which rather indiscriminately compared the surgical outcome of resection versus bypass, that is, without consideration of the intestinal segment involved. The conclusion that bypass was superior to resection in terms of surgical complication and operative mortality had substantial impact for more than a decade. ⁷⁴

Overall, an individualized approach selectively using bypass and resection is probably the safest course. For those cases in which most of the small bowel is involved and dense adhesions have formed in the pelvis, dissection should be avoided and a bypass procedure performed instead. On the other hand, resection is preferable if disease is confined to a short segment of small intestine or if wide resection and ileocolic anastomosis to the colon can be done. In the latter cases, frozen-section biopsy of the grossly normal colon segment can be helpful to rule out fibrosis, obliteration of vessels, or other evidence of significant radiation injury. ^{28 , 62 , 79}

Strictureplasty is not recommended as a primary procedure for radiation strictures. However, in patients with limited intestinal reserve where strictures are located within long segments of diseased bowel which, if resected or bypassed, would have significant nutritional or metabolic consequences, strictureplasty may be an effective and safe tool to conserve intestinal length. ⁸⁰

Despite high initial mortality and morbidity rates, life expectancy in patients with chronic radiation enteritis without recurrence of their primary neoplastic disease is good. Resection seems to provide a lower reoperative rate and a better 5-year survival and better quality of life than bypass procedure. ^{81 , 82}

Regardless of the procedure, special mention must be made of enterolysis. A high incidence of fistula formation and perforation has been reported after enterolysis because of either ischemia or small enterotomies made during the procedure. ^{1 , 10} Enterolysis should be undertaken with great caution and generally only if the surgeon is willing to resect the involved bowel if necessary.

The management of small bowel fistulas can be particularly difficult. The fistula may be due to recurrent malignancy as well as radiation injury. It is useful to divide the management of patients with enteric fistulas into three phases: (1) stabilization, (2) definition of the fistula, and (3) definitive therapy. ⁸³ Stabilization of the patient includes fluid and electrolyte resuscitation, control of fistula output, and nutritional repletion of the chronically debilitated patient. To define the extent of the fistula, contrast studies, including large and small bowel X-ray films and fistulograms, are employed. Every effort is made to ascertain the full extent of the often-complex small bowel fistulas encountered. Despite prolonged TPN, no radiation-induced small bowel fistula has ever closed with conservative management alone. However, TPN with gut rest may be a valuable initial treatment. Poor results have been obtained with attempts at resection of the fistula or partial bypass; the best results have followed total exclusion of the involved segment of bowel. ^{73 , 83 , 84} Smith et al ⁸³ reported a 92% success rate of total exclusion, bringing out one end of the excluded segment as a mucous fistula (▶ Fig. 31.7). This compares favorably with a 67% success rate with resection and a 69% success rate with partial bypass.

Related posts:

18 Rectal Prolapse 19 Benign Neoplasms of the Colon and Rectum 27 Diverticular Disease of the Colon 21 Colon Carcinoma: Epidemiology, Etiology, Pathology, and Diagnosis 33 Constipation 32 Intestinal Stomas

Stay updated, free articles. Join our Telegram channel

Join