The digestive tract is the most vulnerable site of pelvic and abdominal radiation. About 50% of pelvic radiotherapy patients have significant digestive symptoms that affect their quality of life, namely radiation enteritis. Radiation enteritis is an intestinal injury caused by radiotherapy for pelvic and abdominal malignancies, with anorexia, nausea, vomiting, abdominal pain, diarrhea, mucus stool, persistent blood in stool, urgency, perianal pain, and severe intestinal perforation as the main symptoms. Radiation enteritis can involve the small intestine, colon and rectum, and is divided into acute radiation enteritis and chronic radiation enteritis according to the pathological stage, characteristics and clinical manifestations, which are generally defined by 3-6 months. The clinical manifestations of acute radiation enteritis cover almost all possible GI signs and symptoms, while the main clinical manifestations of chronic radiation bowel injury are intestinal obstruction, intestinal fistula, diarrhea, GI bleeding, anemia, and malnutrition.
Intestinal obstruction is the most common clinical manifestation of chronic radiation enteritis, accounting for approximately 74.26% of cases. In 70% of all patients with radiation enteritis requiring surgery, the indication for surgery is small bowel obstruction.
The incidence of radiological bowel injury varies by site of bowel: rectum > sigmoid colon > transverse colon > ileum > jejunum > duodenum. Because gynecological and bladder tumors often require radiation therapy, and the rectum is close to the cervix and bladder, the incidence of radiation proctitis is higher. In addition, the terminal ileum and distal colon are closer to the pelvic floor, so the incidence of radiotherapy injury is also higher. When there is inflammation in the abdominal cavity or a history of abdominal surgery, part of the small intestine is often adherent to the pelvic floor, so the probability of radiation injury to this part of the intestine is also higher.
The typical pathological changes can be divided into 3 stages: (1) Acute stage: mainly affecting the mucosal layer, mostly manifested by degeneration and detachment of epithelial cells, thinning of the intestinal mucosa, shortening of the villi, dilatation of capillaries, congestion and edema of the intestinal wall mucosa, and local or diffuse ulceration.
(2) Subacute stage: It mainly manifests in the submucosa. There is varying degrees of regeneration and healing of the mucosa, but the small submucosal arterial endothelial cells swell to form occlusive vasculitis, and the occlusion of blood vessels leads to progressive ischemia of the intestinal wall.
(3) Chronic phase: It can affect the whole intestinal wall, with progressive occlusive endarteritis and interstitial fibrosis as its main pathological features. These pathological changes eventually lead to intestinal ischemia, resulting in atrophic thinning of the small intestinal mucosa, dense fibrosis of the submucosa, thickening of the plasma membrane fibrosis, irregular adhesions and atrophic stenosis of the small intestine to the point of intestinal obstruction, which significantly increases the difficulty of surgery for radiation enteritis.
Radiation bowel injury is important for prevention. The protection of normal tissues by precise radiotherapy has a greater advantage than conventional radiotherapy, which can relatively reduce the radiation dose received by the intestine. However, even in the era of precision radiotherapy, there is still a clinical need to face the issue of the trade-off between efficacy and injury, especially for complex, recurrent or advanced tumors. Overall, treatment decisions should be made with a focus on radiotherapy efficacy and prolonging patient survival, and consideration of how to reduce radiotherapy injury on this basis requires multidisciplinary consultation and mutual agreement with the patient and his or her family. Due to the difficulty and complexity of radiological intestinal injury treatment, prevention of radiological intestinal injury becomes very important, including the use of precise radiotherapy, avoiding giving too much dose to the intestine, avoiding irradiating the mucosa of the whole circumference; during and after radiotherapy also need to pay attention to the prevention of constipation, avoiding intestinal damage by dry and hard stools; and educating patients to pay attention to their diet, not to eat leftovers, cold dishes, salty dishes and other foods that can easily cause intestinal infection The patient should be educated to pay attention to diet and not to eat leftovers, cold dishes, salty dishes and other foods that may cause intestinal infection.
About 1/3 of patients with chronic radiation enteritis need surgery. The purpose of surgery for radiation enteritis secondary to intestinal obstruction is to relieve the obstruction, restore intestinal function, and prevent recurrence. Since chronic ischemia and fibrosis of the intestinal canal are irreversible, surgical resection of the diseased intestinal canal is the most desirable measure for the treatment of chronic radiation enteritis, but various short-circuit and palliative procedures were proposed in the early days due to the high incidence of complications such as postoperative anastomotic leakage and morbidity and mortality. The advantage of short-circuit anastomosis lies in its simplicity of operation and the low risk of intraoperative accidental injury and postoperative anastomotic leak. However, because the short-circuit procedure does not remove the diseased bowel, there is a risk of bleeding, fistula, obstruction, infection and blind collaterals syndrome in the diseased bowel, often requiring reoperative treatment, and the risk of reoperation will be significantly higher. The postoperative survival of patients with bowel resection is longer than that of patients with short-circuit surgery, and the complication rate of postoperative intestinal bleeding is lower. Therefore, the general principle of treatment of radiation enteritis combined with intestinal obstruction has transitioned to definitive resection of the diseased intestine and reconstructive surgery of the digestive tract, and palliative surgery is only applicable to some special patients, such as emergency surgery, surgery for acute radiation intestinal injury, or patients with severe malnutrition, abdominal infection, extensive radiation damage to the intestine, and abdominal adhesions that cannot be separated. This part of the patients either have complicated abdominal conditions that make surgery difficult, or face the risk of serious postoperative complications, or are in a state of severe stress and shock, and are not suitable for definitive resection.
In medical treatment, the basic treatment of radiation enteritis is mainly the following: (1) nutritional therapy: most patients with radiation enteritis are in a state of high consumption, poor intestinal digestion and absorption, a large number of nutrients are lost through the intestine, nutritional therapy is an indispensable therapeutic measure. A number of clinical studies such as over-consumption of poor blood in stool prove that appropriate nutritional support can benefit patients with radiation enteritis. Recently, some scholars have proposed that early start of enteral nutrition is beneficial to the growth of intestinal mucosal villi after radiation, recovery of intestinal barrier function and improvement of the body’s immune response.
(2) Probiotics: The disruption of intestinal mucosal barrier and inappropriate parenteral nutrition in patients with radiation enteritis can lead to intestinal microecological disorders and bacterial infections, and can promote the expression of cytokines (such as AIM2, ASC, Caspse-1) and promote the development of radiation enteritis. Positive effects of Lactobacillus acidophilus and Bifidobacterium bifidum on intestinal mucosa repair and relief of diarrhea and other symptoms in patients with radiation enteritis have been reported. They can be used clinically as single strains or in combination with multiple strains, but it has not been proven that the efficacy of the combination of multiple strains is higher than that of single strains.
(3) Antioxidants: In the pathogenesis of radiation enteritis, radiation can directly damage dsDNA, and can also induce intracellular oxygen radical generation and damage dsDNA. more clinically used antioxidants are reduced glutathione and vitamins, clinically proven effective vitamins mainly include vitamin C, vitamin E and carotene. Experiments have confirmed that 1,4-dihydropyridine (1,4-DHPs) is an effective antioxidant that can prevent cell damage by radiation, but it is difficult to reach effective concentrations in mitochondria.
(4) Mucosal protective agents: Mucosal protective agents have been used clinically for the treatment of radiation enteritis for a long time, the main drugs are: montelukast, aluminum thioglycollate, aluminum magnesium plus, etc. They can be used by oral or retention enema, retention enema is more effective than oral treatment.
(5) Glutamine: Glutamine (Glu) is the main energy substance for rapidly dividing cells (such as intestinal stem cells, vascular endothelial cells, etc.), and several studies in the past have concluded that GLu is beneficial to the repair of intestinal mucosa in RE and/or alleviates symptoms such as diarrhea and abdominal pain. However, recent studies have concluded that whether or not to take Glu did not significantly improve intestinal mucosal damage and symptoms in patients with radiation enteritis.
(6) Hyperbaric oxygenation of the irradiated intestinal tube, mucosal and vascular endothelial damage, vascular endothelial swelling lumen narrowing and thrombosis cause intestinal ischemia and hypoxia. In recent years, hyperbaric oxygen has been used to treat radiation-related diseases such as: radioactive cystitis, radioactive enteritis, etc.
(7) Anti-inflammatory drugs: salicylates: such as salazosulfapyridine and mesalazine for the treatment of radiation enteritis in China for more than ten years, and related reports mostly consider salicylates anti-inflammatory drugs to be effective, but there is a lack of objective and systematic clinical data. Glucocorticoid drugs for the treatment of radiation enteritis are mainly: such as trimethoprim and budesonide, etc., which have achieved good efficacy in clinical trials, but most of them are in the stage of clinical exploration.
In 2018, the American College of Colorectal Surgeons released the world’s first Guidelines for the Diagnosis and Treatment of Radiation Proctitis; subsequently, China also released the Expert Consensus on the Diagnosis and Treatment of Radiation Proctitis in China (2018 edition) and the Expert Consensus on the Surgical Treatment of Chronic Radiation Bowel Injury (2019 edition). These guidelines have played a positive role in standardizing the clinical diagnosis and treatment of radiation enteritis. In the US guidelines, the recommended therapeutic measures for radiation enteritis mainly include formalin topical therapy, aluminum thioglycollate retention enema, endoscopic therapy, and hyperbaric oxygen therapy, and short-chain fatty acid enemas, ozone therapy, and metronidazole therapy are not recommended; however, the quality of evidence for these recommendations is average. In contrast, in our guidelines, psychotherapy and surgical treatment were added to the treatment section of radiation enteritis, and NSAIDs, glucocorticoids, antibiotics, probiotics, antioxidants, and growth inhibitors were added to the drug treatment section. Among them, our guidelines recommend steroid hormone enemas for the treatment of hemorrhagic radiation proctitis (recommendation level: 1A), but the American guidelines do not make relevant recommendations. The different recommendations of domestic and foreign guidelines are mainly due to the unclear mechanism of glucocorticoids for the treatment of radiation enteritis and the lack of evidence from high-quality studies.
Radiation enteritis is not clearly documented in ancient Chinese medical literature, but its clinical symptoms are very similar to those of intestinal disease, diarrhea and dysentery in ancient Chinese medicine. The Suwen – Taiyin Yangming Lun” that “food and drink is not restrained to live from time to time, Yin suffer from the …… Yin suffer from it into the five viscera …… into the five viscera is full of blockage, down for the drainage of the lower, a long time for the intestinal gas.” The evidence of the treatment of Huixin – dysentery “said:” stagnant down, dampness stagnation in the lower jiao, intestinal gas, said damp heat accumulation in the intestines, that is, today’s dysentery. Therefore, it is said that no accumulation of dysentery, dysentery is wet, heat, food accumulation of three”.
In recent years, the clinical research on the treatment of radiation enteritis in Chinese medicine, although the doctors in the treatment of radiation enteritis used different formulas, drugs, but in the etiology of the pathogenesis, treatment principles still coincide: that is, the essence of the pathogenesis of the deficiency of the real, deficiency and mixed with the real; treatment should be complementary diarrhea, cold and warm. However, there is still no unified standard for the specific operation of herbal enema, such as the depth of tube insertion, speed and temperature of medicine. However, there is still no uniform standard for the specific operation of Chinese medicine enema, such as the depth of cannula, speed and temperature of medicine, etc. There are relatively few studies on the internal treatment of radiation enteritis, and most of them have not been analyzed by evidence type, but only clinical trials of simple experimental prescriptions or ancient prescriptions.