Radiation enteritis is mostly caused by radiation damage to the small intestine and colorectum after radiotherapy for pelvic malignancies (e.g., rectal cancer, prostate cancer, cervical cancer, etc.). Prospective studies have shown that 90-95% of patients develop acute radiation reaction scale (RTOG / EORTC) 2 or more degrees of enteritis during pelvic radiotherapy. CRE occurs 12 to 24 months after the end of radiotherapy, and may occur years to decades after the end of radiotherapy, and can be divided into small bowel radiation and colorectal radiation. Radiation colitis is characterized by abdominal pain, abdominal distension and other obstructive symptoms, and in severe cases, complete intestinal obstruction, intestinal perforation and intestinal fistula. Blood in the stool is the main reason for most CRE patients to be seen.
At present, there is a lack of standard and standardized treatment measures for CRE. The main treatment measures for the common complications of CRE are as follows.
I. Treatment of blood in stool
1, drug therapy: more research is to retain the selection and application of enemas and drugs, the main role is to reduce inflammatory edema, rebuild the mucosal barrier, stimulate the regeneration of epidermal cells. There has been some evidence-based medical evidence proving the clinical value of metronidazole, aluminum thioglycollate, vitamin A, WF10 and hydrocortisone. Although steroids have been used to treat this disease for many years, there is a lack of large, well-designed studies with variable results. One RCT showed that hydrocortisone enemas were superior to betamethasone enemas in improving clinical symptoms, but there was no significant difference in endoscopic changes. NSAIDs, especially those used to treat inflammatory bowel disease, such as oral mesalazine, can reduce the inflammatory response and edema in radiation proctitis and rebuild the mucosal barrier in the area of inflammatory response. Aluminum thioglycollate and metronidazole have been shown to have definite benefits in improving the symptoms of radiation enteritis and increasing the efficiency of treatment. The highest quality study was a prospective double-blind randomized controlled study by Kochhar et al. in 1991, in which the authors compared the efficacy of oral sulfasalazine enemas with that of aluminum thioglycollate enemas plus oral placebo for 8 weeks of continuous treatment in patients with radiation enteritis and found a significant advantage of aluminum thioglycollate enemas over hormones and NSAIDs in improving clinical symptoms (94% versus 53 (94% vs. 53%). A subsequent RCT showed that a 4-week oral dose of metronidazole followed by an enema of aluminum thioglycollate improved the efficiency of treatment and other symptoms such as diarrhea and ulcers, with no significant adverse effects at long-term follow-up. However, there was no significant effect if aluminum thioglycollate was given orally.
Ehrenpreis et al. reported that oral vitamin A significantly improved rectal symptoms in patients with radiation enteritis, probably due to its mucosal healing effect. A phase II clinical study in 2006 suggested that WF10 could improve the clinical symptoms of CRE patients with no significant adverse effects in long-term follow-up.
Formaldehyde cautery: In 1976, Shrom et al. first used formaldehyde cautery for the treatment of radiation cystitis, and based on their successful experience, Rubinstein et al. first used it for the treatment of radiation proctitis in 1986. Since then, many small trials have reported the safety and efficacy of formaldehyde cautery in the treatment of radiation proctitis. Formaldehyde acts superficially by coagulating proteins and creating thrombi within the neovascularization of the mucosal layer, thereby providing hemostasis. Local application of formaldehyde is more effective in the treatment of persistent radiation proctitis bleeding, and has the advantages of low price, practicality, and repeated treatment if the effect is unsatisfactory. However, formaldehyde is also a fixative, highly irritating, and improper methods may cause acute colitis, fecal incontinence, rectal stricture and pain in the anal region.
In the case of low-level radiation proctitis, low-concentration (4%) formaldehyde can be applied locally to the wound for tens of seconds to 5 min under direct vision after dilation until the wound is white or bleeding stops, and in the case of higher-level radiation proctitis, it can be treated by local spraying under sigmoidoscopy or colonoscopy, but it must be operated by experienced personnel to prevent complications. Haas et al. treated 100 CRE patients with direct wound coverage using a 10% formaldehyde soaked dressing under direct vision with an efficiency of 93% and a serious adverse effect rate of 1%. Local formaldehyde cautery hemostasis is effective and can be used as first-line treatment for patients with intractable bleeding, but more RCT studies are needed to determine the optimal dose of formaldehyde and details of local application.
3.Endoscopic treatment: Endoscopic treatment includes 3 methods: laser treatment, argon coagulation (APC) and formaldehyde coagulation treatment. The early laser treatment is neodymium-doped yttrium aluminum garnet laser (Ng: YAG Laser), because its treatment depth is not easy to control has been replaced by potassium titanium phosphate laser therapy (KTP Laser). The argon ion beam can be automatically directed to the surface of the tissue to be treated, providing a comprehensive treatment of the lesion. In a meta-analysis of selected studies on APC, Andreyev found an overall complication rate of 25.7% in 338 patients, including 5 rectal strictures, 3 ulcers, 3 blasts, 2 perforations, 2 rebleeds, 1 rectovaginal fistula, 6 fistulas, and 1 fistula. 1 rectovaginal fistula, and 6 cases of prolonged pain. Therefore, APC is currently considered to be a safe and effective treatment modality. The results of endoscopic formaldehyde treatment for CRE were described previously.
Comparing the three treatment methods, KTP Laser, APC and formaldehyde, some studies have concluded that they are similar in terms of efficiency and safety, but some studies have also concluded that APC is the best endoscopic treatment for CRE.
Hyperbaric oxygen therapy: Hyperbaric oxygen therapy (HBO) can improve tissue ischemia, hypoxia and microcirculatory failure due to vascular endothelial injury in radiation enteritis, increase partial pressure of blood oxygen and blood oxygen content, reduce tissue damage, accelerate ulcer healing and promote tissue repair. Two RCT studies have confirmed that HBO can significantly improve mucosal healing in CRE. The disadvantage of treatment is that it requires special equipment and is expensive.
II. Treatment of diarrhea
The mechanism of diarrhea caused by pelvic radiotherapy is not fully understood, but there are at least 13 mechanisms, such as intestinal bacterial overgrowth, bile salt malabsorption, and altered intestinal dynamics. The use of appropriate laboratory tests such as breath test, culture of intestinal contents, and blood bile salt product testing can help to identify the cause of diarrhea and thus guide the appropriate treatment. At present, except for opioid blockers, which are considered to have a clear role in the treatment of diarrhea, other drugs such as antibiotics, biliary amines and anticholinergics are mostly studied in small, single-center studies.
III. Treatment of anal incontinence
Among the many symptoms of CRE, anal incontinence is the most frustrating for patients. For patients with anal incontinence after pelvic radiotherapy, colonoscopy, rectal ultrasound, and anorectal manometry can help to clarify the cause of the disease. A retrospective analysis showed that topical application of phenylephrine can have an efficiency of about 75%, which is one of the means that is still supported by evidence.
IV. Treatment of abdominal pain and anal and perineal pain
After pelvic radiotherapy, about 30% of patients have different degrees of abdominal pain or pain in the anus and perineum, and the related mechanism is less studied. Local physiotherapy, analgesic drugs and antidepressant drugs have certain effects.
V. Treatment of late complications
Late complications mainly include intestinal obstruction, intestinal perforation, intestinal fistula and intestinal hemorrhage, which are a great pain for patients and a great challenge for clinicians. Currently, surgery is considered necessary in approximately 30% of CRE patients. Indications for surgery include severe complications such as intestinal obstruction, intestinal perforation, intestinal fistula, intestinal hemorrhage, or intractable symptoms that have failed repeated conservative treatment. The principle of surgery should be to solve the clinical symptoms as the primary goal, carefully choose the timing and surgical method, minimize the mortality and complication rate of surgery, and improve the prognosis and long-term quality of life of patients.
There are two types of surgical treatment: one-stage bowel resection and anastomosis, and conservative surgery such as short-circuiting and stoma. The main disadvantage is anastomotic fistula, which is closely related to the location of the anastomotic intestinal tube. If the intraoperative anastomosis is unsatisfactory or the distal intestine is stenosed, an enterostomy should be performed proximal to the anastomosis. If the patient’s general condition is poor or if extensive intraoperative adhesions or “frozen pelvis” are seen, conservative surgery should be performed, which has the advantage of simplicity and few surgical complications; the disadvantage is the risk of bleeding, perforation, infection and blind collaterals syndrome in the open lesion, which often requires secondary or emergency surgery, and the risk of surgery will be greatly increased. Regimbeau et al. conducted a multicenter follow-up study of 109 patients with chronic radiation enteritis who underwent surgery for a mean of 40 months and found that the rate of secondary surgery was higher in the conservative surgery group than in the bowel resection group (50% vs. 34%), and the rate of death was significantly higher in the emergency surgery than in the plain surgery (11% vs. 1%).
In addition to the treatment of symptoms and complications, the treatment of CRP should also focus on the improvement of long-term quality of life. At present, although various treatments have demonstrated their effectiveness to some extent, there is not much evidence to support them, and we urgently need more large and well-designed RCTs with long-term follow-up to provide more therapeutic evidence to establish a standardized treatment strategy for radiation enteritis.