Intrarectal formalin treatment for haemorrhagic radiation induced proctopathy: efficacy and safety

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Total doses exceeding 60Gy are associated with a higher risk of rectal bleeding. If radiation induced chronic haemorrhagic proctopathy (RHP) is severe and/or causes iron-deficiency anaemia, treatment should be offered. Aim of this prospective study was to evaluate efficacy and safety of intrarectal formalin treatment for haemorrhagic RHP at the Royal Marsden Hospital. Methods Adult patients who received pelvic radiotherapy were enrolled. Haemoglobin was evaluated before the first and after the last formalin treatment. Antiplatelet, anticoagulation treatment and administration of transfusion (indication: RHP) were recorded. Interval between the completion of radiotherapy and the first intrarectal 5% formalin treatment was assessed; dose of radiotherapy was evaluated. Clinical assessment of frequency & amount of rectal bleeding (rectal bleeding score: 1-6) and endoscopic appearance (score: 0-3) were classified. Complications were recorded. Results Nineteen patients were enrolled: 13 males (68%) and 6 females. Mean age was 75±9 years. Median time between completion of radiotherapy and the first formalin treatment was 20 months, inter-quartile range (IQR): 15. Median dose of radiotherapy was 68Gy, IQR: 14. Thirty-two procedures were performed (1.7 per patient). In total, 9/19 (47%) patients were receiving anticoagulation and/or antiplatelet medication. Five patients (5/19, 26%) received transfusion. Mean value of haemoglobin before the first formalin treatment was 110±18g/l, after the last treatment 123±16g/l; p=0.022. Median of rectal bleeding score before the first formalin treatment was 6 (IQR: 0), after the last treatment 2 (IQR: 1-4); p˂0.001. Median of endoscopy score on the day of the first treatment was 3 (IQR: 0); on the day of the last treatment 1 (IQR: 1-2); p˂0.001. The median follow-up was 6 months (IQR: 4-16). One female patient with a persistent rectal ulcer which healed eventually (18 months of healing) developed a recto-vaginal fistula subsequently (complication rate: 1/19: 5%). Conclusions Treatment with intrarectal formalin in RHP is effective and safe. Radiotherapy chronic radiation proctopathy bleeding formalin Figures Figure 1 Figure 2 Figure 3 Introduction Radiotherapy is a widely used curative treatment option for localized malignancies, nevertheless it is limited by the dose dependent toxicity to the surrounding organs. Consequences of radiotherapy towards the gastrointestinal (GI) tract are observed frequently and at least one third of patients who had received treatment for pelvic malignancy will suffer from chronic GI symptoms [ 1 , 2 ]. The maximum dose of radiation tolerated by the colon and the rectum is between 60 and 80 Gy [ 3 ]. Among the gastrointestinal organs, rectum is the most frequently affected organ despite the rectal mucosa is more resistant when compared to the colon and small bowel. There are two reasons for it: 1) the proximity of the rectum to the irradiated pelvic organs; 2) its fixed position within the field of radiation [ 4 ]. Total doses of radiation exceeding 60Gy are associated with a higher risk of rectal toxicity and rectal bleeding [ 5 ]. Further factors influencing toxicity towards the rectum include technique of radiotherapy (external beam radiation therapy (intensity-modulated radiation therapy), brachytherapy (anterior wall of the rectum receives high dose of radiation), stereotactic radiotherapy), concomitant chemotherapy, precision of planning, position during the treatment (supine position), comorbidities (including inflammatory bowel disease, connective tissue disease, obesity, diabetes mellitus, HIV) and smoking [ 1 , 6 – 13 ]. Acute radiation proctitis develops within three months from completion of radiotherapy [ 14 ], is highly dose dependent and has been observed in up to 75% of patients. The most typical symptoms are diarrhoea, mucus discharge, abdominal cramps and bloating, rectal urgencies, tenesmus, incontinence and minor rectal bleeding [ 1 , 15 , 16 ]. Chronic radiation proctopathy has been reported in up to one fifth of patients who had received pelvic radiotherapy and can develop without previous history of acute radiation proctitis [ 1 , 15 ]. The onset is delayed, at least 3 months after completion of radiotherapy, the usual median of onset is 8–12 months [ 17 ]). Patients can have symptoms similar to acute proctitis, however full-thickness bowel ischaemia and fibrotic changes contribute to additional symptoms / complications including severe rectal bleeding, formation of fistulas, strictures or perforations [ 16 ]. Neovascularization and formation of teleangiectasias are responsible for rectal bleeding [ 18 ]. In our clinical practice, we use a stool bulking agent for optimization of stool consistency and frequency in a patient with radiation induced chronic haemorrhagic proctopathy (RHP) in the first instance. The second line treatment are sucralfate enemas; sucralfate, complex of aluminium hydroxide and sulphated sucrose, adheres to mucosal cells and provides a cytoprotective effect, further, it stimulates prostaglandin synthesis [ 1 , 19 ]. If rectal bleeding does not improve after sucralfate enema 2g administered locally twice a day for several weeks, we proceed to an endoscopic intervention: either treatment with argon plasma coagulation (in cases of a few bleeding teleangiectasias) is used [ 18 , 20 ] or installation of intrarectal formalin (if there are widespread teleangiectasias in the rectum) is opted [ 20 , 21 ]. Aim of this prospective study was to evaluate efficacy and safety of intrarectal formalin treatment for RHP at the Royal Marsden Hospital, NHS Foundation Trust, London. Methods Adult patients with RHP, in whom previous conservative treatment (optimization of stool consistency & frequency and/or sucralfate enemas) failed, were enrolled into the study between March 2018 and October 2021 (43 months). The contraindications to treatment with intrarectal formalin were other chronic consequences of radiotherapy towards the GI tract including presence of ulcers, fistulas and strictures. All patients had haemoglobin evaluated before the first and after the last treatment with formalin. Antiplatelet and anticoagulation treatment were recorded as well as previous administration of transfusion from indication of RHP. Interval between the completion of radiotherapy and the first intrarectal formalin treatment was assessed; dose of radiotherapy delivered was evaluated. Patients received full bowel preparation for majority of treatments, however if individuals were poorly and if they came for repeat formalin treatment, preparation with phosphate enema was used exceptionally. Clinical assessment of frequency and amount of rectal bleeding (rectal bleeding score) was adapted from the classification used by Takemoto et al. [ 22 ], Table 1. Table 1 Clinical Assessment Of Rectal Bleeding (Adapted From Takemoto Et Al., 22) The frequency of bleeding: Score 3: 3 or more episodes of bleeding per week Score 2: 1 to 2 episodes of bleeding per week Score 1: less than 1 episode of bleeding in 2 weeks The amount of bleeding: Score 3: severe (reddened toilet bowl) Score 2: moderate (blood on stool surface) Score 1: mild (blood spot on paper) Score 0: no bleeding for at least 3 months Therefore, the rectal bleeding score (as sum of frequency and amount of bleeding) can be 1–6. Endoscopic classification followed the classification used by Chi et al. [ 23 ], Table 2. Table 2 Endoscopic assessment (according to Chi et al., 23) Grade 0: no teleangiectasias (normal mucosa) Grade 1: <10 discrete teleangiectasias Grade 2: single coalescing patch of teleangiectasias and/or ≥ 10 discrete teleangiectasias Grade 3: presence of 2 or more coalescing teleangiectasia patches Intrarectal formalin treatment was performed by one operator in an outpatient setting. Patients received between 1–3 sessions of formalin depending on the effect after each treatment. Each treatment sessions were 6 weeks apart. In the beginning of the procedure, patients were positioned on the left side. Rectum and the distal sigmoid were cleared from blood clots and from mucus. The severity of proctopathy was assessed and after the exclusion of any other complicating findings (ulcers, fistulas, strictures, neoplasias, associated inflammation), patient was put to the prone position. One of the assisting nurses took special care of anal and perianal area when a wet cloth was applied peri-anally with the aim to avoid any leakage of formalin from the rectum. A 5% solution of formalin was administered via the spray catheter (MTW spray catheter, diameter: 2.3mm, length: 215cm) which was positioned via the channel of the paediatric colonoscope (Image 1). Administration of formalin was aimed at the bleeding teleangiectasias; after these were covered by formalin adequately, the remaining air from the rectum was aspirated so that a good contact of formalin and bleeding teleangiectasias was achieved. Volume of 15-50ml of 5% formalin was used for individual treatments. Duration of application was between 60-180s. Majority of procedures were performed without sedation and/or analgesia as we wanted to achieve optimal collaboration and feedback from the patients during the treatment so that acute and/or chronic complications could be avoided. After maximum duration of 180s of treatment, formalin was aspirated and the rectum was rinsed with water. In the end, good care of anal and peri-anal area was taken again. Complications of the formalin treatment were recorded. Obtained data were treated statistically by means of descriptive statistics, Wilcoxon test and paired t-test using Statistica software, version 13, 2013, Tulsa, OK, USA. All patients enrolled into the study were adequately informed, supplied and signed an informed consent. The study was approved by the Royal Marsden NHS Trust committee for clinical research as a service evaluation (Ref. SE 1170). Results Nineteen patients were enrolled into the study, 13 males (68%) and 6 females. All male patients received radiotherapy for prostate cancer, two females received radiotherapy for endometrial carcinoma, two women for anal carcinoma, one for carcinoma of the cervix and one for rectal adenocarcinoma. Mean age of enrolled individuals was 75 ± 9 years. After exclusion of one outlier, the median time between completion of radiotherapy and the first formalin treatment was 20 months, inter-quartile range (IQR) was 15 months. The median dose of radiotherapy delivered was 68 Gray, IQR: 14 Gray. In total, 12/19 (63%) patients had been treated with Sucralfate enemas, but this treatment failed. The median of daily bowel movements was 2, IQR: 2. Normacol (sterculia, bulk forming laxative), was used in 68% of patients (13/19). One patient (1/19; 5%) had diabetes mellitus (type 2). The median volume of formalin for a single treatment was 35ml, IQR: 10ml; (min.: 15ml, max.: 60ml). The median duration of a single formalin treatment was 180s, IQR: 150-180s; (min.: 60s, max.: 180s). In total, thirty-two procedures with formalin administration were performed (1.7 procedure per patient in average). Nine patients had a single formalin treatment, seven patients required two formalin treatments (6 weeks apart) and three patients required three treatments. Twenty-one (21/32; 65%) procedures were performed without sedation and/or analgesia. Four formalin treatment were performed after pan-colonoscopy and therefore these patients received sedation (midazolam) and analgesia (fentanyl). Seven patients received minimal dose of sedation and or analgesia purely for formalin treatment (those who were significantly anxious and/or had significant perianal/perirectal pain: 50ug of fentanyl was used on three occasions, 1mg of midazolam and 25ug of fentanyl were administered on three occasions, 2mg of midazolam and 50ug of fentanyl were used on one occasion). In regards of anticoagulation and/or antiplatelet medication, three patients were treated with Rivaroxaban, one patient with Apixaban, one patient with Warfarin; one individual was receiving Apixaban and Clopidogrel, one patient Clopidogrel. During the treatment sessions with formalin, one patient was switched from Aspirin to Clopidogrel and one individual was started on Aspirin. In total, 9/19 (47%) were receiving anticoagulation and/or antiplatelet medication before the last formalin treatment. In total, five patients (5/19, 26%) received transfusion for anaemia caused by RHP. Image 2a, 2b, 2c. Haemoglobin was recorded before the first and after the last formalin treatment. Two patients were excluded from the analysis, as one suffered from myelodysplastic syndrome/leukaemia and one from multiple myeloma. The mean value of haemoglobin before the first formalin treatment was 110 ± 18g/l; (min.: 64g/l, max.: 142g/l), the mean value after the last formalin treatment was 123 ± 16g/l; (min.: 83g/l, max.: 143g/l); p = 0.022 (paired t-test), Graph 1. The median of rectal bleeding score (as the sum of frequency and amount of bleeding; 1–6) before the first formalin treatment was 6 (IQR: 0) and after the last formalin treatment was 2 (IQR: 1–4); p˂0.001 (Wilcoxon test), Graph 2. Median of endoscopy score (0–3) on the day of the first formalin treatment was 3 (IQR: 0); median of endoscopy score on the day of the last formalin treatment was 1 (IQR: 1–2); p˂0.001 (Wilcoxon test), Graph 3. Two patients were excluded from the analysis as they have not had a follow up endoscopy (one patient died, one patient improved clinically and did not wish to have a follow-up endoscopy; impact of formalin treatment was assessed based on the clinical symptoms - severity and frequency of bleeding in both cases). One patient was diagnosed with a persistent rectal ulcer (after a single formalin treatment, Image 3 ), which healed eventually (18 months after it had been first diagnosed; this was treated with 5-ASA locally and orally). This female patient developed subsequently (5 months after the healing was confirmed) a recto-vaginal fistula at the site where the original ulcer was. Complication rate was therefore 1/19, 5%. The median follow-up was 6 months (IQR: 4–16 months). Discussion Our study looked at the efficacy and safety of intrarectal formalin treatment in severe RHP. The first formalin treatment performed in a 71-year-old male patient for RHP, one year after the pelvic radiation for bladder cancer, was reported by Rubinstein in 1986. All previous conservative treatments including performing a colostomy failed to control the rectal bleeding in this patient. Rectum was irrigated with a solution of formalin, rectal bleeding stopped and no recurrence was observed within the subsequent fourteen months [ 24 ]. Majority of studies evaluating the formalin treatment are smaller in size: eight patients [ 25 ], thirteen patients [ 26 ], five patients [ 27 ], twenty patients [ 28 ], twenty-one patients [ 29 ], thirteen patients (randomized study comparing efficacy of formalin treatment versus APC treatment in 14 patients [ 20 ]), twenty-nine patients [ 21 ]. Yet, the efficacy and safety profile are encouraging. A larger study performed by Haas et al included 100 patients [ 30 ]. American Society of Colon and Rectal Surgeons advocates for formalin treatment (strong recommendation based on moderate quality evidence) [ 31 ]. Median time of 20 months between the completion of radiotherapy and the first formalin treatment in our study is consistent with other literature [ 28 , 30 ]. Two thirds of our patients had been treated with Sucralfate enemas before the formalin. Sucralfate enemas seem to be moderately effective in the treatment of RHP [ 31 , 32 ] and therefore we may have delayed the time of indication for formalin treatment. The median dose of radiotherapy which had been delivered in our patients with subsequent RHP was 68 Gy. This is in agreement with study published by Michalski et al: doses of radiation exceeding 60Gy are associated with a higher rectal toxicity and rectal bleeding [ 5 ]. Different techniques of intrarectal formalin treatment have been reported, including application of formalin-soaked sponge stick, pieces of cotton soaked with formaldehyde solution, administration of cotton tip applicators with formalin via a proctoscope, or irrigation of the rectum through the colonoscope / proctoscope when formalin is applied directly at the rectal mucosa through the water channel of the endoscope/proctoscope or via the catheter [ 20 , 21 , 26 , 29 , 30 ]. The very important requirement is to protect the perianal area / perineum during the application of formalin. This is of the utmost importance as formalin can cause severe side effects towards this very fine area. Leakage of formalin perianally can occur especially in patients who have faecal incontinence. In our clinical practice, we apply wet cloths around the anus and one nurse is responsible for the prevention of formalin leakage. In the study performed by Chautems et al the protection of perineum was achieved by application of several layers of fatty ointment [ 26 ]. After we remove formalin from the rectum (via the water channel of the endoscope), we irrigate the rectum / rectosigmoid with a substantial amount of water, which is in agreement with other studies [ 20 , 29 ]. Between 1–4 sessions of formalin treatment have been reported [ 26 ]. Majority of patients responded after one treatment in some studies [ 26 , 27 , 29 ], Dziki et al reported a complete resolution of bleeding in 50% patients (10/20) after the first treatment [ 28 ]. Haas et al concluded that 93% patients stopped bleeding after an average of 3.5 formalin applications [ 30 ]. Importantly, patients who were taking aspirin, required additional 1.5 treatments in average [ 30 ]. Sharma et al confirmed that 19/29 patients (66%) required two applications of formalin to control the symptoms [ 21 ]. We performed 32 procedures with formalin administration in our patients (1.7 procedure per patient in average). A single formalin treatment was sufficient in 9 patients (47%), two treatments were required in 7 patients (37%) and three patients (16%) required three formalin treatments in our study. Two patients who received three sessions of formalin were treated with aspirin and clopidogrel & Apixaban. Formalin concentration between 4%-10% have been used in the treatment of RHP within the last few decades [ 32 , 33 ]; majority of studies used a 4% formalin [ 21 , 26 – 29 ]. Haas et al used a 10% concentration of formalin and reported a low complication rate of 1.1% [ 30 ]. Guo et al showed in his randomized study, that symptoms and rectoscopy scores of patients who received 10% formalin as well as those who were treated with 4% formalin improved significantly, however significantly more patients in the 10% group suffered treatment related complications compared to those in the 4% group [ 34 ]. We used 5% concentration of formalin and taking into account our results, we would not recommend increasing the concentration, which is in agreement with Guo et al [ 34 ]. The duration of formalin application differs between studies, however different techniques and different concentrations of formalin used can play an important role in the efficacy as well as in the complication rate. The usual interval between the formalin sessions were 4 weeks [ 20 , 21 ] or 2–4 weeks [ 30 ]. We believe that a longer interval may be better as we observe the main clinical effect after an approximately one month from the procedure. Also, small rectal ulcers / erosions caused by formalin may require more time to heal before the next treatment is considered. Therefore, the interval between the individual treatments were 6 weeks in our study. For the clinical practice as well as for the study purposes, the two used scoring systems [ 22 , 23 ] as well as serum value of haemoglobin are simple and clear tools how to assess the severity of the condition as well as its improvement after the treatment. Reported complications of intrarectal formalin treatment include: perianal/anal/rectal pain [ 27 , 29 , 35 , 36 ], anal fissure [ 35 ], new onset or aggravated faecal incontinence [ 27 , 29 , 36 ], acute colitis [ 29 , 36 ], mild stenosis of the anus and the rectum [ 26 , 37 ], persistent rectal ulcer [ 37 ], rectosigmoid necrosis [ 38 ] and rectovaginal fistula [ 38 ]. In our study, one patient had a persistent rectal ulcer which got healed eventually, however it highly likely contributed to the development of a subsequent recto-vaginal fistula (orifice into the fistula originated at the site of the previously healed ulcer). This female patient had a single formalin treatment and the complication was not predictable. Conclusions Our study has confirmed high efficacy of formalin treatment in RHP and a low rate of complications. Indication and contraindications have to be followed strictly. Abbreviations RHP radiation induced chronic haemorrhagic proctopathy GI gastrointestinal Declarations Ethics approval and consent to participate All patients enrolled into the study were adequately informed, supplied and signed an informed consent. The study was approved by the Royal Marsden NHS Trust committee for clinical research as a service evaluation (Ref. SE 1170). Research has been performed in accordance with the Declaration of Helsinki. Availability of data and materials All data generated or analysed during this study are included in this published article. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author´s contributions Darina Kohoutova – guarantor of integrity of the entire study, study concept and design, statistical analysis, manuscript preparation Caroline Gee – data collection and data analysis Ana Wilson – literature research and manuscript preparation Ramy Elhusseiny – data collection Linda Wanders – data collection and data analysis David Cunningham – manuscript preparation and manuscript editing Acknowledgement Professor D Cunningham is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Trust and The Institute of Cancer Research. 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Am J Surg. 1999;177(5):396–8. Luna-Pérez P, Rodríguez-Ramírez SE. Formalin instillation for refractory radiation-induced hemorrhagic proctitis. J Surg Oncol. 2002;80(1):41–4. Graphs Graphs 1-3 are available in the Supplemental Files section. Additional Declarations No competing interests reported. Supplementary Files Graph13.docx Cite Share Download PDF Status: Published Journal Publication published 22 Mar, 2024 Read the published version in Colorectal Disease → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2058308","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":140537388,"identity":"58b30950-0736-45f1-90be-41349eb2e964","order_by":0,"name":"Darina Kohoutova","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABE0lEQVRIie2RMUvEMBTHXxDq0tL1lRv8Ci2COFT6Va4E3i0VHDM4FIRO4q0d/BCCUB17BOpg1LWggy6dFcFRTGl0kBzn6JAfPEJe8kv+IQAOxz8k09Xqyks0nRDAM03PqiTltMoBzb6o3KDE7TTSj6I7G5Sbuxd5dAxFODvpZq9C7uw+3tIzu37KAGluVdQilnUHIjrvCFslk+b+8CpmatCvo9YejED6Hoi4L/ZwVRFrVNAgq+QccFFalYdBK59QfCvZ5emkZGuVXt8SVEBGSfMLf1LYumBJrW8JzpBHNfF9pVJej8HySuaVP1ifn4W09e5/pPkS+aoXAg+WY7A3HSzcptimGPDXfDze/isOh8Ph+AtforVl23zWim4AAAAASUVORK5CYII=","orcid":"","institution":"The Royal Marsden Hospital NHS Foundation Trust","correspondingAuthor":true,"prefix":"","firstName":"Darina","middleName":"","lastName":"Kohoutova","suffix":""},{"id":140537390,"identity":"6f0d843e-d05b-4be8-be2e-e35784f17027","order_by":1,"name":"Caroline Gee","email":"","orcid":"","institution":"The Royal Marsden Hospital NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Caroline","middleName":"","lastName":"Gee","suffix":""},{"id":140537392,"identity":"aa329526-54dc-4fc8-8f0d-ba01904eb303","order_by":2,"name":"Ana Wilson","email":"","orcid":"","institution":"St Mark´s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"","lastName":"Wilson","suffix":""},{"id":140537394,"identity":"d87b822e-c7f5-4a65-8ea6-bae7b93b32fc","order_by":3,"name":"Ramy Elhusseiny","email":"","orcid":"","institution":"The Royal Marsden Hospital NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Ramy","middleName":"","lastName":"Elhusseiny","suffix":""},{"id":140537396,"identity":"ae19c885-6d14-49bc-af1b-d9d06396a82e","order_by":4,"name":"Linda Wanders","email":"","orcid":"","institution":"VU University Medical Centre","correspondingAuthor":false,"prefix":"","firstName":"Linda","middleName":"","lastName":"Wanders","suffix":""},{"id":140537398,"identity":"5da01250-fed0-495a-bcde-90e1bbf8ff05","order_by":5,"name":"David Cunningham","email":"","orcid":"","institution":"The Royal Marsden Hospital NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Cunningham","suffix":""}],"badges":[],"createdAt":"2022-09-12 22:29:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2058308/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2058308/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1111/codi.16956","type":"published","date":"2024-03-22T04:50:14+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":27390882,"identity":"d44bb172-ea1a-4648-8762-1a0c894da9d1","added_by":"auto","created_at":"2022-10-05 19:24:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":421244,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImage 1 High resolution white light endoscopy: retroversion in the rectum. Formalin applied via the catheter.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"F1.png","url":"https://assets-eu.researchsquare.com/files/rs-2058308/v1/0a9e3c33b7e02aa0c56a64b9.png"},{"id":27391775,"identity":"5d15b29f-2df0-460d-bdda-6eff7c6447fa","added_by":"auto","created_at":"2022-10-05 19:34:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1186240,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImage 2 Endoscopic situation in a male patient with severe RHP, transfusion dependent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2a: Endoscopic image before the first formalin treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2b: Endoscopic image after the first formalin treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2c: Endoscopic image after the third (last) formalin treatment\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"F2.png","url":"https://assets-eu.researchsquare.com/files/rs-2058308/v1/20c0179a7e69f98c3232ed68.png"},{"id":27390879,"identity":"e6f90d07-66aa-47a1-a285-cfbbd1cddcb5","added_by":"auto","created_at":"2022-10-05 19:24:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":495801,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImage 3: Post-formalin rectal ulceration. This healed eventually, but recto-vaginal fistula developed at the site of the previous ulcer subsequently.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"F3.png","url":"https://assets-eu.researchsquare.com/files/rs-2058308/v1/22d4f81707229a83ad67343b.png"},{"id":57121165,"identity":"6ea09a97-d933-4d15-b76e-5a18329eae74","added_by":"auto","created_at":"2024-05-25 04:50:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2695897,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2058308/v1/72b5cf62-a2a4-427e-9ef2-0967b497582f.pdf"},{"id":27391421,"identity":"f1ada725-3daa-48d4-a9a8-f64538d80cad","added_by":"auto","created_at":"2022-10-05 19:29:24","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":61425,"visible":true,"origin":"","legend":"","description":"","filename":"Graph13.docx","url":"https://assets-eu.researchsquare.com/files/rs-2058308/v1/eea68f040117960a3d46e674.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Intrarectal formalin treatment for haemorrhagic radiation induced proctopathy: efficacy and safety","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRadiotherapy is a widely used curative treatment option for localized malignancies, nevertheless it is limited by the dose dependent toxicity to the surrounding organs. Consequences of radiotherapy towards the gastrointestinal (GI) tract are observed frequently and at least one third of patients who had received treatment for pelvic malignancy will suffer from chronic GI symptoms [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe maximum dose of radiation tolerated by the colon and the rectum is between 60 and 80 Gy [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Among the gastrointestinal organs, rectum is the most frequently affected organ despite the rectal mucosa is more resistant when compared to the colon and small bowel. There are two reasons for it: 1) the proximity of the rectum to the irradiated pelvic organs; 2) its fixed position within the field of radiation [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Total doses of radiation exceeding 60Gy are associated with a higher risk of rectal toxicity and rectal bleeding [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurther factors influencing toxicity towards the rectum include technique of radiotherapy (external beam radiation therapy (intensity-modulated radiation therapy), brachytherapy (anterior wall of the rectum receives high dose of radiation), stereotactic radiotherapy), concomitant chemotherapy, precision of planning, position during the treatment (supine position), comorbidities (including inflammatory bowel disease, connective tissue disease, obesity, diabetes mellitus, HIV) and smoking [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11 CR12\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAcute radiation proctitis develops within three months from completion of radiotherapy [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], is highly dose dependent and has been observed in up to 75% of patients. The most typical symptoms are diarrhoea, mucus discharge, abdominal cramps and bloating, rectal urgencies, tenesmus, incontinence and minor rectal bleeding [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eChronic radiation proctopathy has been reported in up to one fifth of patients who had received pelvic radiotherapy and can develop without previous history of acute radiation proctitis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The onset is delayed, at least 3 months after completion of radiotherapy, the usual median of onset is 8\u0026ndash;12 months [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]). Patients can have symptoms similar to acute proctitis, however full-thickness bowel ischaemia and fibrotic changes contribute to additional symptoms / complications including severe rectal bleeding, formation of fistulas, strictures or perforations [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Neovascularization and formation of teleangiectasias are responsible for rectal bleeding [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our clinical practice, we use a stool bulking agent for optimization of stool consistency and frequency in a patient with radiation induced chronic haemorrhagic proctopathy (RHP) in the first instance. The second line treatment are sucralfate enemas; sucralfate, complex of aluminium hydroxide and sulphated sucrose, adheres to mucosal cells and provides a cytoprotective effect, further, it stimulates prostaglandin synthesis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. If rectal bleeding does not improve after sucralfate enema 2g administered locally twice a day for several weeks, we proceed to an endoscopic intervention: either treatment with argon plasma coagulation (in cases of a few bleeding teleangiectasias) is used [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] or installation of intrarectal formalin (if there are widespread teleangiectasias in the rectum) is opted [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAim of this prospective study was to evaluate efficacy and safety of intrarectal formalin treatment for RHP at the Royal Marsden Hospital, NHS Foundation Trust, London.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eAdult patients with RHP, in whom previous conservative treatment (optimization of stool consistency \u0026amp; frequency and/or sucralfate enemas) failed, were enrolled into the study between March 2018 and October 2021 (43 months).\u003c/p\u003e\n\u003cp\u003eThe contraindications to treatment with intrarectal formalin were other chronic consequences of radiotherapy towards the GI tract including presence of ulcers, fistulas and strictures.\u003c/p\u003e\n\u003cp\u003eAll patients had haemoglobin evaluated before the first and after the last treatment with formalin. Antiplatelet and anticoagulation treatment were recorded as well as previous administration of transfusion from indication of RHP.\u003c/p\u003e\n\u003cp\u003eInterval between the completion of radiotherapy and the first intrarectal formalin treatment was assessed; dose of radiotherapy delivered was evaluated.\u003c/p\u003e\n\u003cp\u003ePatients received full bowel preparation for majority of treatments, however if individuals were poorly and if they came for repeat formalin treatment, preparation with phosphate enema was used exceptionally.\u003c/p\u003e\n\u003cp\u003eClinical assessment of frequency and amount of rectal bleeding (rectal bleeding score) was adapted from the classification used by Takemoto et al. [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e], \u003cstrong\u003eTable\u0026nbsp;1.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;1\u003c/strong\u003e\u003c/p\u003e\n\u003ch3\u003eClinical Assessment Of Rectal Bleeding (Adapted From Takemoto Et Al., 22)\u003c/h3\u003e\n\u003cp\u003eThe frequency of bleeding:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eScore 3: 3 or more episodes of bleeding per week\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eScore 2: 1 to 2 episodes of bleeding per week\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eScore 1: less than 1 episode of bleeding in 2 weeks\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe amount of bleeding:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eScore 3: severe (reddened toilet bowl)\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eScore 2: moderate (blood on stool surface)\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eScore 1: mild (blood spot on paper)\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eScore 0: no bleeding for at least 3 months\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eTherefore, the rectal bleeding score (as sum of frequency and amount of bleeding) can be 1\u0026ndash;6.\u003c/p\u003e\n\u003cp\u003eEndoscopic classification followed the classification used by Chi et al. [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e], \u003cstrong\u003eTable\u0026nbsp;2.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEndoscopic assessment (according to Chi et al., 23)\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eGrade 0: no teleangiectasias (normal mucosa)\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eGrade 1: \u0026lt;10 discrete teleangiectasias\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eGrade 2: single coalescing patch of teleangiectasias and/or \u0026ge;\u0026thinsp;10 discrete teleangiectasias\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eGrade 3: presence of 2 or more coalescing teleangiectasia patches\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eIntrarectal formalin treatment was performed by one operator in an outpatient setting. Patients received between 1\u0026ndash;3 sessions of formalin depending on the effect after each treatment. Each treatment sessions were 6 weeks apart.\u003c/p\u003e\n\u003cp\u003eIn the beginning of the procedure, patients were positioned on the left side. Rectum and the distal sigmoid were cleared from blood clots and from mucus. The severity of proctopathy was assessed and after the exclusion of any other complicating findings (ulcers, fistulas, strictures, neoplasias, associated inflammation), patient was put to the prone position. One of the assisting nurses took special care of anal and perianal area when a wet cloth was applied peri-anally with the aim to avoid any leakage of formalin from the rectum. A 5% solution of formalin was administered via the spray catheter (MTW spray catheter, diameter: 2.3mm, length: 215cm) which was positioned via the channel of the paediatric colonoscope \u003cstrong\u003e(Image 1).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdministration of formalin was aimed at the bleeding teleangiectasias; after these were covered by formalin adequately, the remaining air from the rectum was aspirated so that a good contact of formalin and bleeding teleangiectasias was achieved. Volume of 15-50ml of 5% formalin was used for individual treatments. Duration of application was between 60-180s.\u003c/p\u003e\n\u003cp\u003eMajority of procedures were performed without sedation and/or analgesia as we wanted to achieve optimal collaboration and feedback from the patients during the treatment so that acute and/or chronic complications could be avoided.\u003c/p\u003e\n\u003cp\u003eAfter maximum duration of 180s of treatment, formalin was aspirated and the rectum was rinsed with water. In the end, good care of anal and peri-anal area was taken again.\u003c/p\u003e\n\u003cp\u003eComplications of the formalin treatment were recorded.\u003c/p\u003e\n\u003cp\u003eObtained data were treated statistically by means of descriptive statistics, Wilcoxon test and paired t-test using Statistica software, version 13, 2013, Tulsa, OK, USA.\u003c/p\u003e\n\u003cp\u003eAll patients enrolled into the study were adequately informed, supplied and signed an informed consent. The study was approved by the Royal Marsden NHS Trust committee for clinical research as a service evaluation (Ref. SE 1170).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eNineteen patients were enrolled into the study, 13 males (68%) and 6 females. All male patients received radiotherapy for prostate cancer, two females received radiotherapy for endometrial carcinoma, two women for anal carcinoma, one for carcinoma of the cervix and one for rectal adenocarcinoma.\u003c/p\u003e\n\u003cp\u003eMean age of enrolled individuals was 75\u0026thinsp;\u0026plusmn;\u0026thinsp;9 years. After exclusion of one outlier, the median time between completion of radiotherapy and the first formalin treatment was 20 months, inter-quartile range (IQR) was 15 months. The median dose of radiotherapy delivered was 68 Gray, IQR: 14 Gray.\u003c/p\u003e\n\u003cp\u003eIn total, 12/19 (63%) patients had been treated with Sucralfate enemas, but this treatment failed. The median of daily bowel movements was 2, IQR: 2. Normacol (sterculia, bulk forming laxative), was used in 68% of patients (13/19). One patient (1/19; 5%) had diabetes mellitus (type 2).\u003c/p\u003e\n\u003cp\u003eThe median volume of formalin for a single treatment was 35ml, IQR: 10ml; (min.: 15ml, max.: 60ml). The median duration of a single formalin treatment was 180s, IQR: 150-180s; (min.: 60s, max.: 180s). In total, thirty-two procedures with formalin administration were performed (1.7 procedure per patient in average). Nine patients had a single formalin treatment, seven patients required two formalin treatments (6 weeks apart) and three patients required three treatments.\u003c/p\u003e\n\u003cp\u003eTwenty-one (21/32; 65%) procedures were performed without sedation and/or analgesia. Four formalin treatment were performed after pan-colonoscopy and therefore these patients received sedation (midazolam) and analgesia (fentanyl). Seven patients received minimal dose of sedation and or analgesia purely for formalin treatment (those who were significantly anxious and/or had significant perianal/perirectal pain: 50ug of fentanyl was used on three occasions, 1mg of midazolam and 25ug of fentanyl were administered on three occasions, 2mg of midazolam and 50ug of fentanyl were used on one occasion).\u003c/p\u003e\n\u003cp\u003eIn regards of anticoagulation and/or antiplatelet medication, three patients were treated with Rivaroxaban, one patient with Apixaban, one patient with Warfarin; one individual was receiving Apixaban and Clopidogrel, one patient Clopidogrel. During the treatment sessions with formalin, one patient was switched from Aspirin to Clopidogrel and one individual was started on Aspirin. In total, 9/19 (47%) were receiving anticoagulation and/or antiplatelet medication before the last formalin treatment.\u003c/p\u003e\n\u003cp\u003eIn total, five patients (5/19, 26%) received transfusion for anaemia caused by RHP. \u003cstrong\u003eImage 2a, 2b, 2c.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHaemoglobin was recorded before the first and after the last formalin treatment. Two patients were excluded from the analysis, as one suffered from myelodysplastic syndrome/leukaemia and one from multiple myeloma. The mean value of haemoglobin before the first formalin treatment was 110\u0026thinsp;\u0026plusmn;\u0026thinsp;18g/l; (min.: 64g/l, max.: 142g/l), the mean value after the last formalin treatment was 123\u0026thinsp;\u0026plusmn;\u0026thinsp;16g/l; (min.: 83g/l, max.: 143g/l); p\u0026thinsp;=\u0026thinsp;0.022 (paired t-test), \u003cstrong\u003eGraph 1.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median of rectal bleeding score (as the sum of frequency and amount of bleeding; 1\u0026ndash;6) before the first formalin treatment was 6 (IQR: 0) and after the last formalin treatment was 2 (IQR: 1\u0026ndash;4); p˂0.001 (Wilcoxon test), \u003cstrong\u003eGraph 2.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMedian of endoscopy score (0\u0026ndash;3) on the day of the first formalin treatment was 3 (IQR: 0); median of endoscopy score on the day of the last formalin treatment was 1 (IQR: 1\u0026ndash;2); p˂0.001 (Wilcoxon test), \u003cstrong\u003eGraph 3.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo patients were excluded from the analysis as they have not had a follow up endoscopy (one patient died, one patient improved clinically and did not wish to have a follow-up endoscopy; impact of formalin treatment was assessed based on the clinical symptoms - severity and frequency of bleeding in both cases).\u003c/p\u003e\n\u003cp\u003eOne patient was diagnosed with a persistent rectal ulcer (after a single formalin treatment, \u003cstrong\u003eImage 3\u003c/strong\u003e), which healed eventually (18 months after it had been first diagnosed; this was treated with 5-ASA locally and orally). This female patient developed subsequently (5 months after the healing was confirmed) a recto-vaginal fistula at the site where the original ulcer was. Complication rate was therefore 1/19, 5%.\u003c/p\u003e\n\u003cp\u003eThe median follow-up was 6 months (IQR: 4\u0026ndash;16 months).\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study looked at the efficacy and safety of intrarectal formalin treatment in severe RHP.\u003c/p\u003e \u003cp\u003eThe first formalin treatment performed in a 71-year-old male patient for RHP, one year after the pelvic radiation for bladder cancer, was reported by Rubinstein in 1986. All previous conservative treatments including performing a colostomy failed to control the rectal bleeding in this patient. Rectum was irrigated with a solution of formalin, rectal bleeding stopped and no recurrence was observed within the subsequent fourteen months [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMajority of studies evaluating the formalin treatment are smaller in size: eight patients [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], thirteen patients [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], five patients [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], twenty patients [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], twenty-one patients [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], thirteen patients (randomized study comparing efficacy of formalin treatment versus APC treatment in 14 patients [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]), twenty-nine patients [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Yet, the efficacy and safety profile are encouraging. A larger study performed by Haas et al included 100 patients [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. American Society of Colon and Rectal Surgeons advocates for formalin treatment (strong recommendation based on moderate quality evidence) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMedian time of 20 months between the completion of radiotherapy and the first formalin treatment in our study is consistent with other literature [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Two thirds of our patients had been treated with Sucralfate enemas before the formalin. Sucralfate enemas seem to be moderately effective in the treatment of RHP [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] and therefore we may have delayed the time of indication for formalin treatment.\u003c/p\u003e \u003cp\u003eThe median dose of radiotherapy which had been delivered in our patients with subsequent RHP was 68 Gy. This is in agreement with study published by Michalski et al: doses of radiation exceeding 60Gy are associated with a higher rectal toxicity and rectal bleeding [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDifferent techniques of intrarectal formalin treatment have been reported, including application of formalin-soaked sponge stick, pieces of cotton soaked with formaldehyde solution, administration of cotton tip applicators with formalin via a proctoscope, or irrigation of the rectum through the colonoscope / proctoscope when formalin is applied directly at the rectal mucosa through the water channel of the endoscope/proctoscope or via the catheter [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe very important requirement is to protect the perianal area / perineum during the application of formalin. This is of the utmost importance as formalin can cause severe side effects towards this very fine area. Leakage of formalin perianally can occur especially in patients who have faecal incontinence. In our clinical practice, we apply wet cloths around the anus and one nurse is responsible for the prevention of formalin leakage. In the study performed by Chautems et al the protection of perineum was achieved by application of several layers of fatty ointment [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. After we remove formalin from the rectum (via the water channel of the endoscope), we irrigate the rectum / rectosigmoid with a substantial amount of water, which is in agreement with other studies [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBetween 1\u0026ndash;4 sessions of formalin treatment have been reported [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Majority of patients responded after one treatment in some studies [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], Dziki et al reported a complete resolution of bleeding in 50% patients (10/20) after the first treatment [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Haas et al concluded that 93% patients stopped bleeding after an average of 3.5 formalin applications [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Importantly, patients who were taking aspirin, required additional 1.5 treatments in average [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Sharma et al confirmed that 19/29 patients (66%) required two applications of formalin to control the symptoms [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe performed 32 procedures with formalin administration in our patients (1.7 procedure per patient in average). A single formalin treatment was sufficient in 9 patients (47%), two treatments were required in 7 patients (37%) and three patients (16%) required three formalin treatments in our study. Two patients who received three sessions of formalin were treated with aspirin and clopidogrel \u0026amp; Apixaban.\u003c/p\u003e \u003cp\u003eFormalin concentration between 4%-10% have been used in the treatment of RHP within the last few decades [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]; majority of studies used a 4% formalin [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan additionalcitationids=\"CR27 CR28\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Haas et al used a 10% concentration of formalin and reported a low complication rate of 1.1% [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Guo et al showed in his randomized study, that symptoms and rectoscopy scores of patients who received 10% formalin as well as those who were treated with 4% formalin improved significantly, however significantly more patients in the 10% group suffered treatment related complications compared to those in the 4% group [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. We used 5% concentration of formalin and taking into account our results, we would not recommend increasing the concentration, which is in agreement with Guo et al [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe duration of formalin application differs between studies, however different techniques and different concentrations of formalin used can play an important role in the efficacy as well as in the complication rate.\u003c/p\u003e \u003cp\u003eThe usual interval between the formalin sessions were 4 weeks [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] or 2\u0026ndash;4 weeks [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. We believe that a longer interval may be better as we observe the main clinical effect after an approximately one month from the procedure. Also, small rectal ulcers / erosions caused by formalin may require more time to heal before the next treatment is considered. Therefore, the interval between the individual treatments were 6 weeks in our study.\u003c/p\u003e \u003cp\u003eFor the clinical practice as well as for the study purposes, the two used scoring systems [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] as well as serum value of haemoglobin are simple and clear tools how to assess the severity of the condition as well as its improvement after the treatment.\u003c/p\u003e \u003cp\u003eReported complications of intrarectal formalin treatment include: perianal/anal/rectal pain [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], anal fissure [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], new onset or aggravated faecal incontinence [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], acute colitis [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], mild stenosis of the anus and the rectum [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], persistent rectal ulcer [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], rectosigmoid necrosis [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] and rectovaginal fistula [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. In our study, one patient had a persistent rectal ulcer which got healed eventually, however it highly likely contributed to the development of a subsequent recto-vaginal fistula (orifice into the fistula originated at the site of the previously healed ulcer). This female patient had a single formalin treatment and the complication was not predictable.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur study has confirmed high efficacy of formalin treatment in RHP and a low rate of complications. Indication and contraindications have to be followed strictly.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRHP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eradiation induced chronic haemorrhagic proctopathy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egastrointestinal\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients enrolled into the study were adequately informed, supplied and signed an informed consent. The study was approved by the Royal Marsden NHS Trust committee for clinical research as a service evaluation (Ref. SE 1170). Research has been performed in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;All data generated or analysed during this study are included in this published article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026acute;s contributions\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDarina Kohoutova \u0026ndash; guarantor of integrity of the entire study, study concept and design, statistical analysis, manuscript preparation\u003c/p\u003e\n\u003cp\u003eCaroline\u0026nbsp;Gee \u0026ndash; data collection and data analysis\u003c/p\u003e\n\u003cp\u003eAna Wilson \u0026ndash; literature research and manuscript preparation\u003c/p\u003e\n\u003cp\u003eRamy Elhusseiny \u0026ndash; data collection \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLinda Wanders \u0026ndash; data collection and data analysis\u003c/p\u003e\n\u003cp\u003eDavid Cunningham \u0026ndash; manuscript preparation and manuscript editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProfessor D Cunningham is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Trust and The Institute of Cancer Research.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGrodsky MB, Sidani SM. 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Treatment and prognosis of patients with late rectal bleeding after intensity-modulated radiation therapy for prostate cancer. Radiat Oncol. 2012;7:87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChi KD, Ehrenpreis ED, Jani AB. Accuracy and reliability of the endoscopic classification of chronic radiation-induced proctopathy using a novel grading method. J Clin Gastroenterol. 2005;39(1):42\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRubinstein E, Ibsen T, Rasmussen RB, Reimer E, S\u0026oslash;rensen BL. Formalin treatment of radiation-induced hemorrhagic proctitis. Am J Gastroenterol. 1986;81(1):44\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeow-Choen F, Goh HS, Eu KW, Ho YH, Tay SK. A simple and effective treatment for hemorrhagic radiation proctitis using formalin. 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Surg Innov. 2005;12(2):123\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaas EM, Bailey HR, Faragher I. Application of 10 percent formalin for the treatment of radiation-induced hemorrhagic proctitis. Dis Colon Rectum. 2007;50(2):213\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaquette IM, Vogel JD, Abbas MA, Feingold DL, Steele SR, Clinical Practice Guidelines Committee of The American Society of Colon and Rectal Surgeons. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Treatment of Chronic Radiation Proctitis. Dis Colon Rectum. 2018;61(10):1135\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNelamangala Ramakrishnaiah VP, Javali TD, Dharanipragada K, Reddy KS, Krishnamachari S. Formalin dab, the effective way of treating haemorrhagic radiation proctitis: a randomized trial from a tertiary care hospital in South India. Colorectal Dis. 2012;14(7):876\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDahiya DS, Kichloo A, Tuma F, Albosta M, Wani F. Radiation Proctitis and Management Strategies. Clin Endosc. 2022;55(1):22\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo GH, Yu FY, Wang XJ, Lu F. A randomized controlled clinical trial of formalin for treatment of chronic hemorrhagic radiation proctopathy in cervical carcinoma patients. Support Care Cancer. 2015;23(2):441\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaclarides TJ, King DG, Franklin JL, Doolas A. Formalin instillation for refractory radiation-induced hemorrhagic proctitis. Report of 16 patients. Dis Colon Rectum. 1996;39(2):196\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePikarsky AJ, Belin B, Efron J, Weiss EG, Nogueras JJ, Wexner SD. Complications following formalin installation in the treatment of radiation induced proctitis. Int J Colorectal Dis. 2000;15(2):96\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCounter SF, Froese DP, Hart MJ. Prospective evaluation of formalin therapy for radiation proctitis. Am J Surg. 1999;177(5):396\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuna-P\u0026eacute;rez P, Rodr\u0026iacute;guez-Ram\u0026iacute;rez SE. Formalin instillation for refractory radiation-induced hemorrhagic proctitis. J Surg Oncol. 2002;80(1):41\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Graphs","content":"\u003cp\u003eGraphs 1-3 are available in the Supplemental Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Radiotherapy, chronic radiation proctopathy, bleeding, formalin \t","lastPublishedDoi":"10.21203/rs.3.rs-2058308/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2058308/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePelvic radiotherapy is limited by a dose dependent toxicity to the surrounding organs. Total doses exceeding 60Gy are associated with a higher risk of rectal bleeding. If radiation induced chronic haemorrhagic proctopathy (RHP) is severe and/or causes iron-deficiency anaemia, treatment should be offered. Aim of this prospective study was to evaluate efficacy and safety of intrarectal formalin treatment for haemorrhagic RHP at the Royal Marsden Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdult patients who received pelvic radiotherapy were enrolled. Haemoglobin was evaluated before the first and after the last formalin treatment. Antiplatelet, anticoagulation treatment and administration of transfusion (indication: RHP) were recorded. Interval between the completion of radiotherapy and the first intrarectal 5% formalin treatment was assessed; dose of radiotherapy was evaluated. Clinical assessment of frequency \u0026amp; amount of rectal bleeding (rectal bleeding score: 1-6) and endoscopic appearance (score: 0-3) were classified. Complications were recorded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNineteen patients were enrolled: 13 males (68%) and 6 females. Mean age was 75±9 years. Median time between completion of radiotherapy and the first formalin treatment was 20 months, inter-quartile range (IQR): 15. Median dose of radiotherapy was 68Gy, IQR: 14. Thirty-two procedures were performed (1.7 per patient). In total, 9/19 (47%) patients were receiving anticoagulation and/or antiplatelet medication. Five patients (5/19, 26%) received transfusion. Mean value of haemoglobin before the first formalin treatment was 110±18g/l, after the last treatment 123±16g/l; p=0.022. Median of rectal bleeding score before the first formalin treatment was 6 (IQR: 0), after the last treatment 2 (IQR: 1-4); p˂0.001. Median of endoscopy score on the day of the first treatment was 3 (IQR: 0); on the day of the last treatment 1 (IQR: 1-2); p˂0.001. The median follow-up was 6 months (IQR: 4-16). One female patient with a persistent rectal ulcer which healed eventually (18 months of healing) developed a recto-vaginal fistula subsequently (complication rate: 1/19: 5%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTreatment with intrarectal formalin in RHP is effective and safe.\u003c/p\u003e","manuscriptTitle":"Intrarectal formalin treatment for haemorrhagic radiation induced proctopathy: efficacy and safety","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-10-05 19:24:22","doi":"10.21203/rs.3.rs-2058308/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e349123d-60e8-4d88-a1f2-6afd060bec67","owner":[],"postedDate":"October 5th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-05-25T04:50:14+00:00","versionOfRecord":{"articleIdentity":"rs-2058308","link":"https://doi.org/10.1111/codi.16956","journal":{"identity":"colorectal-disease","isVorOnly":true,"title":"Colorectal Disease"},"publishedOn":"2024-03-22 04:50:14","publishedOnDateReadable":"March 22nd, 2024"},"versionCreatedAt":"2022-10-05 19:24:22","video":"","vorDoi":"10.1111/codi.16956","vorDoiUrl":"https://doi.org/10.1111/codi.16956","workflowStages":[]},"version":"v1","identity":"rs-2058308","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2058308","identity":"rs-2058308","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}