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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 2  |  Issue : 1  |  Page : 10-16

Progress in multidisciplinary treatment of hemorrhagic radiation proctitis


1 Department of Gynecology, Red Cross Hospital of Yulin, Yulin, Guangxi, China
2 Department of Pathology, Red Cross Hospital of Yulin, Yulin, Guangxi, China

Date of Submission01-Mar-2022
Date of Decision21-Apr-2022
Date of Acceptance22-Apr-2022
Date of Web Publication15-Jun-2022

Correspondence Address:
Prof. Guangjie Liao
Department of Pathology, Red Cross Hospital of Yulin, No. 1, Jin Wang Rd. Yuzhou, Yulin, Guangxi
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aort.aort_9_22

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  Abstract 


With the development and wide application of radiotherapy technology, the incidence of radiation proctitis (RP) caused by radiotherapy for pelvic malignant tumors tends to increase, especially the treatment of hemorrhagic RP (HRP) is very difficult. Complications such as intestinal necrosis and perforation cause great pain and inconvenience to patients. How to effectively and safely treat HRP is an urgent clinical problem to be solved. This article reviews the progress of multidisciplinary treatment of RP, especially HRP, in recent years, and focuses on the progress of formalin in the treatment of hemorrhagic radiation proctitis.

Keywords: Formalin, hemorrhagic radiation proctitis, radiation proctitis, review, treatment


How to cite this article:
Li Q, Liao G. Progress in multidisciplinary treatment of hemorrhagic radiation proctitis. Ann Oncol Res Ther 2022;2:10-6

How to cite this URL:
Li Q, Liao G. Progress in multidisciplinary treatment of hemorrhagic radiation proctitis. Ann Oncol Res Ther [serial online] 2022 [cited 2022 Nov 29];2:10-6. Available from: http://www.aort.com/text.asp?2022/2/1/10/347564


  Introduction Top


With the development of society and the improvement of the medical and health security system, the incidence and diagnosis rate of pelvic malignancies in China were gradually increasing.[1],[2] Radiation therapy had become an indispensable and effective method for the treatment of pelvic malignancies. While the treatment of pelvic malignancies had received good results, complications caused by radiotherapy were still inevitable, among which radiation proctitis (RP) was the most common and intractable complication.[3] It was characterized by secondary ionizing radiation therapy damage to the rectal epithelial cells. RP could be divided into two subtypes, acute RP (ARP) and chronic RP (CRP), according to the time from initiation of radiotherapy to the onset of signs and symptoms. ARP was usually self-healing with few complications. However, CRP tended to be more severe and was often associated with many complications. The treatment options available for CRP were limited, and most data on treatment strategies came from case reports or small sample researches.[3] Chronic bleeding was the main clinical manifestation of patients complicated with RP. The bleeding was extremely stubborn. Some patients might even cause severe anemia due to repeated bleeding. Repeated bleeding transfusions were required to continue treatment. At present, standard treatment strategies and procedures for CRP in China, especially for hemorrhagic RP (HRP) were still deficient. Although many treatment methods had shown effectiveness to a certain extent, most of them were small, single-center, nondouble-blind studies, lacking high-quality relevant research evidence to support. The current clinical treatment measures for HRP mainly included drug therapy, endoscopic therapy, and surgical therapy. The overall efficacy was poor or the equipment was expensive and technically complicated. It was particularly important to find a safe, cost-effective, and practical conservative treatment for patients with HRP. The Chinese experts formulated the first edition of “Expert Consensus on Diagnosis and Treatment of Radiation Proctitis in China”[1] in December 2018. The consensus pointed out that the main symptoms of RP could be relieved by nonsurgical treatment as much as possible to avoid the occurrence of serious complications. The release of the 2018 version of the “Consensus” has played a good guiding role in the clinical diagnosis and treatment of radiation rectal injury and promoted the development of scientific research in China. However, according to the recommendations of the consensus, there was still no preferred efficient, safe, and economical treatment for RP. With the emergence of many new research evidence, new technologies and new concepts, especially the multidisciplinary diagnosis and treatment models, more and more attention has been paid on RP. Under the joint promotion of the Colorectal Surgeons Committee and the Colorectal Cancer Professional Committee of the Chinese Anti-Cancer Association, the Chinese Expert Group on Diagnosis and Treatment of Radiation Intestinal Injury had formulated the “Chinese Expert Consensus on Multidisciplinary Diagnosis and Treatment of Radiation Rectal Injury (2021 Edition).”[2] The new version of the “Consensus” further standardized the definition of radiation rectal injury, and proposed the clinical classification of radiation rectal injury for the first time in the world. It advocated the concept of “integrated pelvic injury” and the importance of “multidisciplinary diagnosis and treatment,” and emphasized the important preventive effect of precise individualized radiotherapy technology on injury. In terms of treatment, it advocated individualized treatment according to the characteristics of disease classification, and also updated the recommendation level of previous nonsurgical treatment according to the latest research. At present, domestic and foreign literatures reported that formalin was effective in the treatment of HRP, but it still had some potential risks and adverse reactions. It was very important to master the precise positioning, concentration, treatment time control, and contraindications of formalin use. This article will focus on summarizing the relevant progress of formalin treatment under the precursor of reviewing the treatment progress of HRP.


  Overview of Radiation Proctitis Top


RP referred to the sequelae of radiation therapy in patients with pelvic malignancies such as cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, rectal cancer, and bladder cancer. RPs could be divided into ARP and CRP according to the onset time and course of the disease, and usually took 3 months course as the boundary between acute and CRP. ARP occured in more than 75% of patients receiving pelvic radiotherapy, while CRP occured in about 5% to 20% of the patients.[3] In fact, the incidence of CRP was very likely to be underestimated because not everyone who developed symptoms of proctitis seeked medical attention in a timely manner. Hematochezia was usually the main symptom diagnosed in patients with CRP,[2],[4],[5] which can be manifested as bloody stools, bloody stools with mucus, dripping blood after stools, and even worse bloody stools. These patients were often accompanied by pain, anal bulge, and other anal irritation symptoms. Under endoscopy, hyperemia, edema, ulcers, erosions, and perforations on the mucosal surface of the damaged intestinal segment could be seen, and it was easy to form bladder fistula or rectovaginal fistula.[6],[7] Patients with mild symptoms were relatively tolerable, while severe patients will maintain the symptoms of blood in the stool for a long time, which was induced by HRP.

Essentially, both direct and indirect mechanisms of radiation-induced tissue damage targeted cellular deoxyribonucleic acid (DNA), thereby inhibiting transcription and preventing cellular replication.[8] Through direct mechanisms, ionizing radiation directly damaged DNA or cell membranes. It could induce double-stranded DNA breaks, caused interstrand and intrastrand crosslinks, or DNA mutations, and might impair the rigidity of phospholipid bilayers and the electrical gradient of cell membranes.[9] An indirect mechanism involved the ionization of water molecules to generate free radicals, leading to oxidative stress damage.[10]

The main pathogenesis of ARP may be that the free radicals generated by radiation ionization leading to the inhibition of intestinal mucosal epithelial cell proliferation, which could recover spontaneously after radiotherapy. The pathological changes of chronic HRP (CHRP) included intestinal submucosal arterioles ischemia, hemorrhage, and chronic fibrosis of the intestinal wall. Under endoscopy, telangiectasia, intestinal stenosis, ulcers, and fistulas could be observed. Under the microscope, intimal fibrosis of small arteries could be seen.[11]

Once HRP occurred, most patients had persistent symptoms of blood in the stool. Some patients required repeated blood transfusions to correct anemia, which brought great pain to the patients.


  Treatment of Hemorrhagic Radiation Proctitis Top


Treatment overview of hemorrhagic radiation proctitis

At present, clinical exploration of multidisciplinary application of various methods for the treatment of CRP has achieved certain results, but there were still few literature reviews on the treatment progress of HRP. After reviewing the literatures and combining with “Expert Consensus on Diagnosis and Treatment of Radiation Proctitis in China” (2018 edition),[1] we summarize the main treatment methods for HRP as follows:

Antibiotics

Antibiotics such as metronidazole and ciprofloxacin were used to treat the bleeding and diarrhea symptoms of HRP. Radiation damage to the intestinal mucosal barrier might lead to the translocation of intestinal flora, the imbalance of the proportion of flora species, and the abnormal proliferation of flora. Currently, there were few clinical studies on antibiotics for the treatment of HRP. Cavcić et al.[12] found that when HRP patients took oral mesalazine (1 g, 3 times/day) and betamethasone enema (1 time/day), adding metronidazole orally (400 mg, 3 times/day) could improve the remission rate of blood in the stool and diarrhea and reduce the incidence of endoscopic mucosal edema and ulcers. Sahakitrungruang et al.[13] found that CHRP patients treated with enema (1 L tap water enema/day) plus oral antibiotics (ciprofloxacin 500 mg, 2 times/day + metronidazole 500 mg, 3 times/day) could improve symptoms such as blood stool and frequent stool. Symptoms such as diarrhea, urgency, and tenesmus could also be relieved. Although metronidazole and ciprofloxacin had certain effects in the treatment of in HRP, the treatment cycle was long, and they could not directly achieve hemostasis. It was not effective for patients who have a large amount of bleeding and need timely blood transfusion.

Enema drugs

Topical drugs work primarily by local retention enemas which allowed adequate contact of the drug with the diseased rectum. Commonly used enema drugs include sucralfate, steroid hormones, short-chain fatty acids, metronidazole, and compound enema preparations. In an acidic environment, sucralfate can form a protective barrier on the surface of the intestinal mucosa.[14] However, the meta-analysis results of Hovdenak et al.[15] suggested that sucralfate could not prevent radiation enteritis and might aggravate diarrhea and bleeding, so it was not recommended. Gibson et al.[16] analyzed a large number of literatures on cancer patients who applied gastrointestinal mucosal protective drugs during radiation therapy, and they believed that the use of sucralfate was still not recommended for the prevention of CRP. The RCT study conducted by Kochhar et al.[17] found that after 4 weeks of oral sucralfate combined with prednisolone enema treatment, the symptoms of blood in the stool were significantly relieved, and the lesions were healed under endoscopy. However, the disadvantage of this program was that the treatment time was long, and the effect is not good for patients with a large amount of bleeding. Short-chain fatty acids played a key role in regulating the process of mucosal proliferation and repair, and it could provide more than half of the energy required for mucosal proliferation. Therefore, short-chain fatty acid enema therapy for patients with radiation enteritis was theoretically feasible. However, the results of the RCT study by Talley et al.[18] showed that short-chain fatty acid enema did not have a significant advantage over placebo. Compound enema preparation was a combination of sucralfate, steroid hormones, short-chain fatty acids, and metronidazole, which can treat mild to moderate HRP. Topical 4% formalin solution (formaldehyde) had been used for 20 years in the treatment of HRP and was considered to be an ideal treatment method. The mechanism was that formaldehyde played a role in hemostasis by coagulating proteins and generating thrombus in the mucosal neovascularization, and because the effect of formaldehyde in the mucosal layer was superficial and limited, it did not exceed the mucosal layer, and there were few side effects.

The latest research found that the treatment of HRP with aluminum-magnesium suspension combined with Kangfuxin liquid was better than aluminum-magnesium plus suspension combined with epidermal growth factor retention enema. It could improve the quality of life of patients while improving symptoms, which was worthy of clinical application.[19] Research[20] found that the traditional Chinese medicine scheme (acupoint injection of Fufang Kushen injection combined with “Yuchang Decoction” retention enema) had a good therapeutic effect on patients with ARP, and can effectively improve the quality of life of patients.

In the study of Xuefeng et al.,[21] HRP patients were randomly divided into formalin group and compound enema group (combined with metronidazole, sucralfate, dexamethasone, thrombin freeze-dried powder) for conservative enema, respectively. The results showed that the effective rate of the formalin group was 91%, and the effective rate of the compound enema group was 69%. The efficacy of the formalin group was significantly higher than that of the compound enema group.

Endoscopic argon-ion coagulation combined with epinephrine spraying therapy

This method could immediately stop bleeding of the lesion and accelerate the repair of damaged mucosa. It was one of the safe and effective endoscopic treatment measures, but it requires high hardware and software conditions. The operator must be proficient in the operation steps, and master the use method and characteristics of the argon knife, and these techniques need to be equipped with expensive-related equipment. At present, many hospitals do not have such equipment, and this technology is rarely carried out.[22]

Hyperbaric oxygen therapy

Hyperbaric oxygen therapy (HBOT) could improve tissue ischemia, hypoxia, and microcirculation disorders caused by vascular endothelial injury, increased blood oxygen partial pressure and blood oxygen content, accelerated ulcer healing, and promoted tissue repair in HRP patients. It was effective treatment for refractory HRP. At the same time, patients had good tolerance to HBOT and few adverse reactions. However, the high cost also limited its wide application to a certain extent, and there were few hospitals that carried out this treatment at present.

Surgical treatment

In cases where conservative treatment of HRP was not ideal, the last treatment option to consider was surgery. Surgery was often required in patients with refractory bleeding, intestinal perforation, intestinal strictures, and fistula formation.[23],[24] Elective surgical methods included fecal diversion, resection and anastomosis of diseased bowel, and fistula repair, and so on. Surgery also carried risks. Due to the vesicles and fibrosis of the intestinal tissue within the field of radiotherapy, the postoperative bowel had a high risk of perforation, and the incidence of anastomotic leakage could also be as high as 65%.[25] Therefore, it was necessary to ensure anastomosis with unirradiated healthy tissue to restore the continuity of the intestine.[26],[27]

Radiation therapy and physical position strategy

In radiation therapy, the radiation dose, the size of the treatment field and the volume of the irradiated intestine directly affected the toxicity of intestinal radiation. Intensity-modulated radiotherapy can reduced the toxicity of normal tissue associated with radiotherapy due to the variety of treatment shapes, the steep dose gradient, and the use of a large number of small beams with nonuniform intensity.[28] During radiotherapy, the incidence of radiation enteritis could be reduced by adjusting the position of radiotherapy and the time of radiotherapy. Systematic studies suggested that keeping the patient in the prone position, compressing the lower abdominal wall, and using positioning devices such as abdominal plates during radiation therapy might reduce the volume of the irradiated bowel,[29],[30],[31] thereby reducing the incidence of radiation enteritis. The results of a retrospective study in China showed that the protective effect of the prone position on the damaged organs was better than that of the supine position. The possible mechanism was that under the action of gravity, the prone position caused the damaged organs to sag naturally.[32] Shukla et al.[33] in a prospective randomized controlled study of 229 patients with cervical cancer who required radiotherapy showed that the probability of grade III and IV mucositis in patients who received radiotherapy in the morning was significantly higher than that in patients who received radiotherapy in the evening. Therefore, in clinical treatment, the occurrence of radiation enteritis could be reduced by adjusting the radiotherapy time of patients.

Maintaining bladder capacity

The reduction of bladder capacity would increase the intestinal volume of the exposed area to a certain extent, and increase the radiation toxicity effect on normal organs and tissues. Maintaining good bladder capacity during radiation therapy can reduce radiation enteritis. Shukla et al.[33] found that a larger initial bladder volume during radiotherapy reduced the incidence of enteritis from 22% to 5%. Bandanatham et al.[34] conducted a prospective study of the association of pelvic radiotherapy with colitis. Patients were assessed weekly for the highest grade of radiation colitis, and the mean bladder volume at the end of treatment was significantly reduced at the end of treatment, while the grade of colitis increased. Therefore, during radiotherapy, patients were instructed to drink more water and keep their bladder full, so that only the received radiation dose reached the bowel and reduced radiation damage to normal mucosa.

Formalin topical treatment of hemorrhagic radiation proctitis

Formalin solution has been used for the treatment of HRP for more than 30 years. In 1986, Rubinstein successfully applied formalin for the first time in the treatment of CHRP.[35] Since then, the use of formalin solution for hemostasis had become a very effective method. In recent years, several studies have shown that the success rate of formalin in the treatment of CHRP varies from 60% to 100%.[36]

The mechanism of formalin in the treatment of chronic hemorrhagic radiation proctitis

The mechanism of formalin in the treatment of HRP was that formaldehyde could form thrombus in blood vessels by coagulating blood and stop bleeding at the bleeding site by chemically cauterizing new capillaries induced by radiation. The site of action was superficial and did not extend beyond the mucosal layer.[36],[37]

The “Chinese Expert Consensus on the Diagnosis and Treatment of Radiation Proctitis”[1] recommended the use of formaldehyde for topical treatment of hemorrhagic radiation enteritis. The specific methods included formaldehyde retention enema, gauze infiltration, and local perfusion. However, these treatment methods were likely to cause adverse reactions such as tenesmus, anal pain, anal ulcers, anal stenosis, and difficulty in defecation. Severe cases could cause perforation and fistula formation.[38] Therefore, experts recommended that for patients with rectal stenosis, ulcers, anal incontinence and anal cancer, the topical treatment of CRP with formaldehyde should be very cautious.[2],[38]

Research progress on the use of formalin in the treatment of chronic hemorrhagic radiation proctitis and the selection of therapeutic concentration

Digestive endoscopy might play an important role in the diagnosis and treatment of RP, especially in terms of precise positioning and reducing complications. However, there were very few domestic and foreign literatures on this treatment method, and the above domestic consensus also did not introduce. Huang Kun et al.[38] retrospectively analyzed 10 patients with HRP treated by spraying 4% formalin under direct vision through endoscope. The specific operation was as follows. First, the Japanese Olympus CF260 electronic colonoscope was used for examination, and the bleeding diseases caused by polyps, tumors, and vascular malformations should be excluded. Then found the bleeding site, and changed the patient's position to obtain the best position to observe the bleeding point. After that, injected 4% formalin through the spray tube to cover the bleeding point for about 2 min. When the intestinal mucosa turned white or the bleeding was stopped, the formalin should be exhausted immediately, and the residual formaldehyde should be washed out repeatedly by normal saline. In this retrospective study, the total effective rate of formalin treatment was 100%. Some patients had mild adverse reactions such as abdominal distension, abdominal pain and anal bulging feeling, and the symptoms were relieved after symptomatic treatment, none of the patients developed anus after operation. No patient had adverse reactions and complications such as anal ulcer, anal stenosis, difficulty in defecation, perforation or fistula formation after operation. There were two patients with recurrent hemorrhage within 1 year, both of which were patients with Sherman grade III under endoscopy, which may be related to the heavier lesions before treatment. This study suggested that the application of formalin spraying under digestive endoscopy in the treatment of HRP could better distinguish rectal stenosis, ulcers, and anal canal cancer compared with other methods such as formalin retention enema and formalin gauze infiltration. This method could better grasp the contraindications of treatment. And formaldehyde could be more accurately applied to the lesion, thereby improving the safety of the treatment and reducing the occurrence of complications such as postoperative stricture, difficulty in defecation, and perforation. This was just a retrospective analysis of a certain study, the sample size was small, and there were very few domestic literatures on this type of endoscopic spraying treatment. This study is only a retrospective analysis, the sample size was small, and the literature of this type of endoscopic spraying of formaldehyde in the treatment of HRP was rare. The specific clinical application, practical effects, and side effects need to be further confirmed, and the number of samples needs to be increased for reliability.

The mechanism of action of formalin in the treatment of HRP suggested that theoretically, formaldehyde might still damage the rectal mucosa.[39] The “Expert Consensus on Diagnosis and Treatment of Radiation Proctitis in China”[1] proposed that a series of complications such as anal pain, rectal necrosis, and sepsis might occur in the treatment of RP with formaldehyde. Therefore, in addition to paying attention to precise positioning and spraying of drugs, grasping contraindications, and shortening the mucosal contact time of formaldehyde, it was also necessary to focus on the degree of mucosal damage caused by the concentration of formalin. Most studies showed that the use of formaldehyde solution in the treatment of RP was effective and safe. It has been reported in the literature[4] that the applicable concentration range of formaldehyde in the treatment of hemorrhagic radiation enteritis is 3.6%–10%. Some scholars have tried 10% formaldehyde to treat HRP, and the effective rate of treatment is higher than that of 4% solution.[7] In the clinical trial of Shanji,[40] 124 cases of HRP were treated with 4% and 10% formalin, both of which were effective, and there was no statistical difference. However, the adverse reactions of patients in the 4% group were significantly smaller, so the authors believed that the 4% formaldehyde concentration was more suitable for clinical use. The same conclusion was also obtained in the study of Yongyi et al.[41] Raman[42] used 2% formaldehyde to enema with a curative effect of 78.2%, and some patients experienced adverse reactions such as diarrhea, abdominal pain, tenesmus, fever, and vomiting. The above studies suggested that 4% formaldehyde might be the optimal therapeutic concentration.


  Outlook Top


In conclusion, HRP was a common complication in radiotherapy patients with malignant pelvic tumor, which seriously affected the efficacy and reduced the quality of life of patients. At present, there was no efficient, safe and economical treatment method for HRP. Therefore, it is particularly important to find a safe, cost-effective, and practical conservative treatment method for patients with HRP. Comprehensive literature showed that formalin had a significant effect in the treatment of HRP. At present, formaldehyde retention enema and formaldehyde liquid gauze infiltration were mainly used. While achieving remarkable results, some serious complications might also occur. The literature suggested that endoscopic spraying of 4% formalin in the treatment of HRP was cost-effective and accurate, and could significantly reduce the above-mentioned complications. However, there were very few reports on this method at home and abroad, and the related studies were only retrospectively analyzed, and the sample size was small. Therefore, the specific clinical practice effects and complications need to be further confirmed by more large-sample studies.

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.



 
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Introduction
Overview of Radi...
Treatment of Hem...
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