Non‐surgical interventions for late rectal problems (proctopathy) of radiotherapy in people who have received radiotherapy to the pelvis

Fleur T van de Wetering; Leen Verleye; H. Jervoise N Andreyev; Jane Maher; Joan Vlayen; Bradley R Pieters; Geertjan van Tienhoven; Rob JPM Scholten

doi:10.1002/14651858.CD003455.pub2

Intervenciones no quirúrgicas para los problemas rectales tardíos (proctopatía) de la radioterapia en pacientes que han recibido radioterapia en la pelvis

Authors' declarations of interest

Version published: 25 April 2016 Version history

https://doi.org/10.1002/14651858.CD003455.pub2

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Resumen

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Antecedentes

Ésta es una actualización de una revisión Cochrane publicada por primera vez en 2002 y actualizada previamente en 2007. Los problemas rectales tardíos de la radiación (proctopatía) incluyen hemorragia, dolor, urgencia fecal e incontinencia y pueden desarrollarse después de un tratamiento de radioterapia pélvica para el cáncer.

Objetivos

Evaluar la efectividad y la seguridad de las intervenciones no quirúrgicas para el tratamiento de la proctopatía tardía por radiación.

Métodos de búsqueda

Se hicieron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL) (número 11, 2015); MEDLINE (Ovid); EMBASE (Ovid); CANCERCD; Science Citation Index; y CINAHL desde su inicio hasta noviembre de 2015.

Criterios de selección

Se incluyeron ensayos controlados aleatorizados (ECA) que comparaban intervenciones no quirúrgicas para el tratamiento de la proctopatía tardía por radiación en pacientes con cáncer que han recibido radioterapia pélvica para el cáncer. Los resultados primarios considerados fueron: episodios de actividad intestinal, hemorragia, dolor, tenesmo, urgencia y disfunción del esfínter.

Obtención y análisis de los datos

La selección de los estudios, la evaluación del "riesgo de sesgo" y la extracción de datos se realizaron por duplicado, y cualquier desacuerdo se resolvió involucrando a un tercer autor de la revisión.

Resultados principales

Se identificaron 1221 referencias únicas y 16 estudios con 993 participantes que cumplían los criterios de inclusión. Un estudio encontrado a través de la última actualización se trasladó a la sección "Estudios en espera de clasificación". No se agruparon los resultados para un metanálisis debido a la variación en las características de los estudios y las variables de evaluación entre los estudios incluidos.

Dado que la proctopatía por radiación es una afección con diversos síntomas o combinaciones de síntomas, los estudios fueron heterogéneos en cuanto a su efecto previsto. Algunos estudios investigaron tratamientos dirigidos a la hemorragia solamente (grupo 1), otros investigaron tratamientos dirigidos a una combinación de síntomas anorrectales, pero no un solo tratamiento (grupo 2). El tercer grupo se centró en el tratamiento de la colección de síntomas conocida como enfermedad pélvica por radiación. A fin de permitir cierta comparación de esta colección heterogénea de estudios, se describen los efectos en estos tres grupos por separado.

Nueve estudios evaluaron los tratamientos para la hemorragia rectal y fueron poco claros o con un alto riesgo de sesgo. Los únicos tratamientos que marcaron una diferencia significativa en los resultados primarios fueron la coagulación con plasma de argón (CPA) seguida de sucralfato oral versus CPA con placebo (puntuación endoscópica de 6 a 9 a favor de la CPA con placebo, riesgos relativos (RR) 2,26, intervalo de confianza (IC) del 95%: 1,12 a 4,55; un estudio, 122 participantes, evidencia de calidad baja a moderada); tratamiento con un toque de formalina (4%) versus enema de retención de esteroides de sucralfato (puntuación de los síntomas después del tratamiento calificada por la Radiation Proctopathy System Assessments Scale (RPSAS) y puntuación sigmoidoscópica a favor de la formalina (p = 0,001, efecto no cuantificado, un estudio, 102 participantes, evidencia de muy baja a baja calidad), y la irrigación colónica más ciprofloxacino y metronidazol versus la aplicación de formalina (4%) (hemorragia (p = 0,007, efecto no cuantificado), urgencia (p = 0,0004, efecto no cuantificado) y diarrea (p = 0,007, efecto no cuantificado) a favor de la irrigación colónica (un estudio, 50 participantes, evidencia de baja calidad).

Tres estudios, de riesgo de sesgo poco claro y alto, evaluaron tratamientos dirigidos a algo muy localizado pero no a una sola patología. No se identificaron diferencias significativas en los resultados primarios. Se calificaron todos los estudios como evidencia de muy baja calidad debido al riesgo poco claro de sesgo e imprecisión muy grave.

En cuatro estudios, de riesgo de sesgo incierto y alto, se evaluaron tratamientos dirigidos a más de un síntoma pero confinados a la región anorrectal. Los estudios que demostraron un efecto sobre los síntomas incluyeron: tratamiento basado en un algoritmo dirigido por el gastroenterólogo versus atención habitual (folleto detallado de autoayuda) (diferencia significativa a favor del tratamiento basado en un algoritmo dirigido por el gastroenterólogo sobre el cambio en la puntuación del Inflammatory Bowel Disease Questionnaire–Bowel (IBDQ‐B) a los seis meses, diferencia media (DM) 5,47, IC del 95% 1,14 a 9,81) y el tratamiento basado en un algoritmo dirigido por enfermeras versus la atención habitual (diferencia significativa a favor del tratamiento basado en un algoritmo dirigido por enfermeras en el cambio de la puntuación del IBDQ‐B a los seis meses, DM 4,12, IC del 95% 0,04 a 8,19) (un estudio, 218 participantes, evidencia de baja calidad); la oxigenoterapia hiperbárica (a 2,0 atmósferas absolutas) versus placebo (mejoría de la puntuación subjetiva, objetiva, de manejo, analítica ‐ efectos tardíos del tejido normal (SOMA‐LENT) a favor de la oxigenoterapia hiperbárica (HBOT), P = 0,0019) (un estudio, 150 participantes, evidencia de calidad moderada, palmitato de retinol versus placebo (mejoría en la SPRAS a favor del palmitato de retinol, p = 0,01) (un estudio, 19 participantes, evidencia de baja calidad) y medicina tradicional china integrada más medicina occidental versus medicina occidental (radioproctopatía de grado 0 a 1 después del tratamiento a favor de la medicina tradicional china integrada, RR 2,55; IC del 95%: 1,30 a 5,02) (un estudio, 58 participantes, evidencia de baja calidad).

El nivel de evidencia para la mayoría de los resultados se redujo usando GRADE a bajo o muy bajo, principalmente debido a la imprecisión y a las limitaciones de los estudios.

Conclusiones de los autores

Aunque algunas intervenciones para la proctopatía tardía por radiación parecen prometedoras (incluido el sucralfato rectal, el metronidazol añadido a un régimen antiinflamatorio y la terapia de oxígeno hiperbárico), los estudios únicos y pequeños aportan evidencia limitada. Además, no se registraron bien los resultados importantes para los pacientes con cáncer, como la calidad de vida y los efectos a largo plazo. La naturaleza episódica y variable de la proctopatía tardía por radiación requiere grandes ensayos multicéntricos controlados por placebo (ECA) para establecer si los tratamientos son efectivos. Los estudios futuros deben abordar la posibilidad de que se produzcan lesiones asociadas a otros órganos gastrointestinales, urinarios o sexuales, lo que se conoce como enfermedad pélvica por radiación. Las intervenciones, así como los parámetros de los resultados, deben ser más amplios e incluir los que son importantes para los pacientes con cáncer, como las evaluaciones de la calidad de vida.

PICOs

Population

Intervention

Comparison

Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Resumen en términos sencillos

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Intervenciones no quirúrgicas para las consecuencias rectales tardías de la radioterapia en pacientes que han recibido radioterapia radical en la pelvis

Antecedentes

La radioterapia se utiliza a menudo para tratar el cáncer en el área pélvica. Varios órganos de la pelvis, como el ano, el recto, la vejiga, la próstata, los órganos ginecológicos (útero , ovarios, cuello uterino y vagina), el intestino delgado y los huesos de la pelvis pueden estar expuestos a los efectos de la radioterapia, lo que puede provocar una enfermedad pélvica por radiación. Los síntomas de la enfermedad pélvica por radiación pueden aparecer alrededor del momento del tratamiento (efectos tempranos) o durante un período de tiempo, a menudo muchos años después del tratamiento (efectos tardíos) debido a cambios a largo plazo secundarios a la cicatrización (fibrosis), el estrechamiento (estenosis) y la hemorragia debido a la formación de nuevos vasos sanguíneos (telangiectasia). El daño en el recto (proctopatía por radiación) es el efecto tardío de la radiación en la pelvis que más se ha investigado, y que afecta a un grupo pequeño pero importante de pacientes que se someten a radioterapia pélvica. Los síntomas comunes son urgencia rectal, incontinencia rectal, dolor, secreción de moco y hemorragia rectal.

Objetivo de la revisión

El objetivo de esta revisión fue evaluar el efecto de los tratamientos no quirúrgicos sobre el daño rectal tardío.

Principales hallazgos

Se encontraron 16 ensayos controlados aleatorizados (cuasi) (ECA) que incluían a 993 participantes que evaluaban los tratamientos no quirúrgicos para la proctopatía por radiación. Aunque algunos tratamientos parecen prometedores (como el sucralfato rectal, la adición de metronidazol a un régimen antiinflamatorio y la terapia de oxígeno hiperbárico), la calidad de la evidencia fue de baja a muy baja. Además, en esos estudios, con frecuencia no se abordaron los resultados importantes para los pacientes con cáncer, incluida la calidad de vida y los efectos a largo plazo.

Conclusiones

Aunque algunas intervenciones para el daño rectal por radiación tardía son prometedoras, la evidencia fue de baja calidad y no se pueden extraer conclusiones firmes. No se pudieron combinar los datos de los estudios para comparar diferentes tratamientos, ya que los diseños de los ensayos y las medidas de resultado eran diferentes. La naturaleza episódica y variable de los daños tardíos del recto por radiación requiere ECA más amplios para establecer si los tratamientos son efectivos. Los estudios futuros deberían abordar la posibilidad de que se produzcan lesiones asociadas a otras estructuras pélvicas, lo que se conoce colectivamente como enfermedad pélvica por radiación. Lo ideal sería que las medidas de resultado se estandarizaran entre los estudios e incluyeran evaluaciones de la calidad de vida y otros resultados importantes para los pacientes con cáncer.

Calidad de la evidencia

La calidad de la evidencia de la mayoría de los resultados fue baja o muy baja, principalmente debido al pequeño tamaño de la mayoría de los estudios y a las limitaciones de los mismos.

Authors' conclusions

Implications for practice

One of the most commonly used treatments against rectal bleeding is argon plasma coagulation (APC). Though APC is very effective against rectal blood loss and considered standard, to our knowledge it had never been tested in a randomised fashion. APC works to reduce rectal blood loss but not other symptoms. The treatments tested in addition to APC showed no benefit. The significant results of formalin dab treatment (4%) versus sucralfate steroid retention enema and colonic irrigation plus ciprofloxacin and metronidazole versus formalin application (4%) are hampered by the fact that they were not compared to APC and may only be indicated in case of contraindications to APC. The same applies to the three studies investigating a broader spectrum of anorectal symptoms, one of which showed an advantage of adding metronidazole to mesalazine and betamethasone enema (only for the symptom rectal blood loss). The remaining four studies focused on the entire symptom complex that may be described as pelvic radiation disease. One of these (the largest) showed that specialistic care in the form of a gastroenterologist‐ or nurse‐led algorithm is better then a self help booklet. The remaining three studies showed a benefit from the investigated treatment, but two of these were very small. Only hyperbaric oxygen showed an advantage over placebo in a reasonably sized randomised study, hence this was the most convincing evidence.

Overall, we conclude for general practice that radiation proctopathy is more complex than rectal blood loss, which many studies focussed upon. The studies focusing only or mainly on rectal blood loss are hampered by the fact that the treatment considered standard for this condition was never investigated in a randomised manner. The broader radiation proctopathy and pelvic radiation disease likely require specialistic care, for instance in the form of a gastroenterologist‐led algorithm. The most convincing evidence for improvement of the symptom complex of radiation proctopathy was shown for hyperbaric oxygen therapy.

Implications for research

The evidence for the effectiveness of non‐surgical interventions for late radiation proctopathy is limited and hampered by a lack of common standards. Although certain interventions look promising, single small studies (even if well conducted) provide limited evidence. Some commonly used treatments have not been investigated in RCTs. This review is furthermore hampered by the inability to compare the different studies.

Pelvic radiation disease is often not confined to one organ, and symptomatology is based on physiological disorders. Radiation proctopathy, which was the focus of this review, is but one aspect of pelvic radiation disease. The true incidence of the disease is not clear. Before setting up future trials, a widely used uniform definition of this disorder is warranted to serve as a basis. Secondly, there is an urgent need to clearly define the endpoints to investigate and to use a unified grading system by which these endpoints can be categorised, such as the CTCAE or the LENT‐SOMA for late radiation effects, to our knowledge the most widely used and well‐validated classification system of (late) toxicity symptoms, which however is not as sensitive as some other scales (Khalid 2006; Olopade 2005). Without such a system, it is unlikely that meaningful randomised studies can be designed. Future RCTs should also include major important patient‐reported outcome measures’, such as long‐term effects and quality of life evaluations.

Background

This review is an update of the previously published Cochrane review 'Non‐surgical interventions for late radiation proctopathy in people who have received radical radiotherapy to the pelvis' (Denton 2002), which was last updated in 2007.

Description of the condition

Radiotherapy is often used to treat cancer in the pelvic area. It can be used as single therapy or in combination with chemotherapy, as primary treatment or before or after surgery. Examples of cancer in the pelvis that can be treated with radiotherapy include prostate, bladder, cervix, endometrial, vaginal, rectal, and anal cancer. One drawback of radiotherapy is the development of late radiation toxicity. Several organs in the pelvis, including the anus, rectum, bladder, prostate, gynaecological organs, pelvic bones, and sometimes small bowel may be exposed to the effects of radiotherapy, which can lead to a variety of symptoms. The term 'pelvic radiation disease' has been proposed, defined as “transient or long term problems, ranging from mild to severe, arising in non‐cancerous tissues resulting from radiotherapy treatment to a tumour of pelvic origin” (Andreyev 2010; Denham 2002). If symptoms are confined to the rectum or the anorectal complex, we tend to speak of radiation‐associated proctopathy, or radiation‐induced proctopathy, formerly referred to as late radiation proctopathy. The current review, which is an update of a Cochrane review first published in 2002 and subsequently assessed as up to date in 2008, about the treatment of late radiation proctopathy is mainly focused on late radiation‐associated proctopathy, further referred to as radiation proctopathy, although more recent studies may examine treatment for pelvic radiation disease (Andreyev 2013). Radiation proctopathy is the most often investigated late‐radiation effect to the pelvis. The common symptoms are rectal urgency, rectal incontinence, pain, strictures, mucus discharge, and rectal bleeding.

There have been extensive investigations into the association between rectal dose and the occurrence of late radiation proctopathy when treating the prostate gland (Boersma 1998; Peeters 2006; Pollack 2002). Since several dose‐escalation studies found an improved biochemical control for prostate cancer at higher radiation doses, the standard care for treatment is a prescribed dose of at least 75 Gy (Peeters 2006b; Pollack 2002; Zietman 2005). However, in these dose‐escalation studies, an increase of radiation proctopathy was found with higher doses to the prostate (and therefore also to the rectum). It is reasonable to assume that the risk of radiation proctopathy also applies to other cancer sites in the same region that are being radiated. Toxic effects of radiotherapy are often graded according to the Radiotherapy Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG/EORTC) Late Radiation Morbidity Scoring Schema on a scale of 0 to 5 (www.rtog.org, Appendix 1). The Common Terminology Criteria for Adverse Events (CTCAE) and other adjusted local scorings schemas are also often used. Radiation proctopathy greater than grade 2 has been reported in 20% to 35% of men treated for prostate cancer (Al‐Mamgani 2008; Pollack 2002; Zietman 2005). However, these are physician‐reported outcomes. Patient‐reported outcomes (outcomes derived directly from people about how they function or feel in relation to a health condition and its therapy, without interpretation of the patient’s responses by a clinician) could be very different, and thus these toxicity outcomes could be underestimated (Higgins 2011).

The pathophysiology and symptomatology of radiation proctopathy are rather complex because different anorectal subregions can be involved (Heemsbergen 2005; Smeenk 2012b). For example, rectal incontinence and urgency are caused by reduced rectal capacity and tissue compliance resulting in impaired anal sphincter function (Kushwaha 2003; Smeenk 2012b; Yeoh 2009). Incontinence and urgency symptomatology originates from different muscle groups of the anorectal sphincter complex (Smeenk 2012). However, in this patient group incontinence can also be induced by loose stool consistency and speed of transit through the small bowel (Putta 2005). Rectal bleeding is usually the result of vulnerable mucosa combined with loss of submucosal capillaries, leading to new, but abnormal, blood vessels formation (teleangiectasia) in the rectal wall.

With modern radiotherapy techniques such as intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT), higher conformal dose distribution to the prostate gland is reached with consequently lower doses to the anorectal complex. Yet, even with IMRT radiation, proctopathy incidence is 5% to 65% (Bekelman 2011; De Meerleer 2007; Zelefsky 2008).

Description of the intervention

The medical treatment of radiation proctopathy is not clearly defined and in the absence of recommendations, management is often unsatisfactory. This is due in part to difficulties in recognising and establishing the diagnosis and also because a proportion of the biological changes are not reversible. At present there is no 'best' treatment for this clinical scenario, and the outcomes of both medical and surgical management can be disappointing. The literature suggests a number of treatment options, including low‐residue or elemental diets, pain control, and replacement transfusion. Other therapies are reported to be of variable benefit in controlling symptoms, with the option of surgery if medical management fails or is inappropriate (Babb 1996).

Current non‐surgical treatment options include:

Aminosalicylic acid derivatives: Anti‐inflammatory agents in this group, such as sulfasalazine and mesalazine, have been reported to have a role in the management of this condition (Baum 1989). Another agent with anti‐inflammatory properties is WF10 (Veerasarn 2006).
- Sulfasalazine is a prodrug that is composed of 5‐aminosalicylic acid (5‐ASA) and sulfapyridine. In the colon, sulfasalazine is divided by the bacterial enzyme azoreductase into the two components. 5‐ASA (mesalazine), the active component, is poorly absorbed from the colon and is largely secreted in the stool. Sulfapyridine is largely absorbed in the colon and is associated with many side effects. Sulfasalazine is available as an oral and as a topical (rectal) compound. Intake is distributed in two to three times over day. At the beginning of therapy, a dose of 2 g to 4 g a day is given, which can be lowered to 1 g to 2 g a day for maintainance. Sulfazalasine, 5‐ASA (mesalazine), is the active component against inflammatory bowel disease. The precise mechanism of action is not known, but is mainly attributed to anti‐inflammatory and immunosuppressive properties. The considered mechanisms of action are: inhibition of cytokine synthesis (Bantel 2000; Rousseaux 2005), inhibition of prostaglandin and leukotriene synthesis (Hawkey 1985), free radical scavenging (Ahnfelt‐Ronne 1990), immunosuppressive activity by inhibition of T‐cell and B‐cell activation (MacDermott 1989a; Stevens 1995), and impairement of white cell adhesion and function (Neal 1987).
- Mesalazine is the active component of sulfasalazine. It is rapidly absorbed in the jejunum. Several compounds are on the market with delayed release of mesalazine to increase the availability for the colon.
Short chain fatty acid (SCFA) preparations: SCFA enema is a solution of sodium acetate, sodium propionate, sodium n‐butyrate with additional sodium chloride. As butyrate is the most effective SCFA for colonic regeneration, an only‐butyrate enema as a 80 mmol solution is also effective (Hille 2008; Vernia 2000). This solution is placed endorectally once or twice a day. Vernia et al. found that an application course of three weeks or more is needed for optimal result (Vernia 2000). An improvement can be observed after four to six weeks (Cook 1998). SCFAs are organic fatty acids that are produced by colonic bacterial metabolism. SFCAs are produced predominantly in the colon by anaerobic bacterial fermentation of non‐absorbed carbohydrates. The majority is absorbed in the colon. When SCFA is absorbed by colonocytes, sodium and water absorption is stimulated. Besides this, SCFA dilates resistance arteries, increase mucosal blood flow and oxygen uptake, reduces mucosal permeability, and enhances production and release of mucus (Kvietys 1981; Mortensen 1990). SCFAs are necessary for optimal growth of the colonic mucosa and stimulate cell proliferation.
Sucralfate preparations: Sucralfate is an aluminium salt of sucrose octasulfate. It can be used twice a day in a 1 g to 2 g enema as a 10% suspension in water (Kochhar 1991; McElvanna 2014). Relief of symptoms can be expected after one to two weeks. Other possible suspensions are in propylcellulose or glycerine. The dose varies from 1 g to 10 g (Carling 1986; Kochhar 1988). Sucralfate works by a cytoprotective effect because of an adherent complex binding to tissue proteins of the mucosa and protecting the colonic mucosa. There is evidence for promoting angiogenesis and reduction of microvascular injury (O'Brien 1997). Another possible mechanism is because of lowering of prostaglandin‐E2 levels (Zahavi 1989).

Coagulation therapy:
- Bipolar electrocoagulation: Coagulation is achieved with a probe by heating the contact tissue. Direct contact of the probe with the treated tissue is necessary. At the tip of the probe positive and negative electrodes are located that pass electricity through the tissue. Coagulation depth is controlled by probe size, duration of heating, and choice of energy. The applied current is locally between the electrodes of the probe. The coagulation is aimed at bleeding telangiectatic areas. At 70ºC tissue coagulation will occur and bleeding is stopped. Once the tissue is desiccated, tissue resistance increases and prevents deep coagulation. Bipolar electrocoagulation is effective for superficial lesions. Penetration depth can be regulated by the probe size, applied energy level, and pressure of the probe on tissue.
- Thermal coagulation therapy: The heater probe is a thermocouple to heat up the exposed tissue by cauterisation. At the tip of the probe there is a heat‐generating device that converts electric energy to heat energy (Protell 1978).
- Argon plasma coagulation uses ionised argon gas for a thermal reaction. A probe is introduced to the treatment area, and argon gas, which itself is non‐flammable, is sprayed on the surface to be treated and ionised by 6000 volts via electric wires in the probe. A high‐frequency current develops between the electrode and the underlying tissue, resulting in coagulation and desiccation. Desiccated tissue loses electric conductivity, prohibiting deep devitalization of the treated tissue. Coagulation is achieved by heating up the treated tissue. Heating is not influenced by tissue resistance, making deep coagulation possible. The mechanism of coagulation and desiccation of the treated tissue is by direct heat transfer.
Corticosteroids: Several steroid enemas are available for radiation proctopathy treatment. Hydrocortisone, prednisolone, and betamethasone were used in this review. The enema is introduced into the rectum for several minutes once a day. The treatment can be continued for 2 to 4 weeks. Hydrocortisone is available as, for example, 100 mg in a 60 ml aqueous solution. Betamethasone, which has a more powerful action than hydrocortisone, is available as, for example, 5 mg in a 100 ml aqueous solution. The working mechanism of topical corticosteroid application (steroid enema) is an anti‐inflammatory effect with the inhibition of prostaglandin synthesis.

Formalin applications: Formalin is applied topically in a 4% to 10% solution on the affected rectal mucosa. The application can be either by irrigation of the rectum or direct application with a soaked gauze. Formalin acts by hydrolysing proteins leading to chemical cauterisation. Another mechanism is by coagulation of the tissue (Haas 2007; Leiper 2007; Parikh 2003).
Pentoxyfilline: Pentoxyfilline is a xanthine derivative. It is almost completely resorbed by oral admission. It is also used for intermittent claudication and administered orally three times a day 400 mg. Pentoxifylline increases the deformability of erythrocytes, inhibits the aggregation of thrombocytes, and reduces fibrinogen level in plasma. In this way microvascular blood flow is enhanced.
Antibiotic treatment: Metronidazole is an antibiotic that is especially useful in the treatment of anaerobic infections. Metronidazole is effective against obligate anaerobes and against facultative anaerobes such as Helicobacter pylori and Gardnerella vaginalis. It is orally well absorbed and distributed evenly into body tissues. The dosage is dependent on the indication for treatment. Usual oral administration is 1 g to 2 g distributed in one to four intakes. The working mechanism of metronidazole is by its anti‐inflammatory action to improve mucosal healing in combination with other therapeutic measures.
Hyperbaric oxygen: Hyperbaric oxygen therapy is performed in specially designed chambers. One or more people are treated in the chamber with 100% oxygen. Pressure is increased to 25 x 10⁴ to 30 x 10⁴ Pa. Treatment duration is approximately 60 to 90 minutes, 5 to 7 days a week. Number of treatments varies with the degree of severity and response effect, usually 30 to 40 treatments. Plasma oxygen level increases by inhalation of 100% high‐pressure oxygen. As a result, tissue oxygenation will improve. Hyperbaric oxygen facilitates fibroblast proliferation, angiogenesis, and wound healing (Marx 1990; Roth 1994; Wattel 1998).
Retinol palmitate: Retinol palmitate, or vitamin A, is completely absorbed via the bowel. The recommended daily allowance for an adult male is 3000 IU (900 micrograms) and for an adult female 2300 IU (700 micrograms). Therapeutic dosage for retinol in case of deficiency is 25,000 to 50,000 IU per day for a limited period. The prophylactic dosage is 2500 to 5000 IU per day. Retinol palmitate increases fibroblast secretion of mucopolysaccharide and collagen and increases fibronectin synthesis. These mechanisms assist in wound healing (Hein 1984).
Chinese traditional medicine in combination with Western medicine: consists of Shen Ling Bai Zhu powders (herbal ingredients) and Western medicine (smectite powder 6 g, dexamethasone 5 mg, levofloxacin hydrochloride 0.2 g, anisodamine 10 mg, and physiological saline 100 ml).

How the intervention might work

See Description of the intervention

Why it is important to do this review

As described above, late radiation proctopathy is common, with incidence rates of 5% to 65% (Bekelman 2011; De Meerleer 2007; Zelefsky 2008), and potentially a major burden to people with cancer. The medical treatment of radiation proctopathy is not clearly defined, and in the absence of recommendations, management of the condition is often unsatisfactory. While the literature suggests a number of treatment options, there is no 'best' treatment choice. We are therefore assessing the effectiveness of various non‐surgical treatment options in managing late radiation proctopathy in this review.

Objectives

To assess the effectiveness and safety of non‐surgical interventions for managing late radiation proctopathy.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) or quasi‐RCTs, irrespective of language and publication status, that compared any non‐surgical intervention for late radiation proctopathy to no intervention, placebo, or any other intervention were eligible for inclusion. In previous versions of this review, non‐randomised studies were also eligible. For this update, as RCT data was available, we decided to focus on RCTs and quasi‐RCTs only, as non‐randomised studies suffer from high risk of bias.

Types of participants

People diagnosed with a pelvic malignancy, who had undergone pelvic radiotherapy as part of their treatment schedule (primary radiotherapy, pre‐ or postoperative radiotherapy, with or without chemotherapy, or as a palliative treatment) and subsequently developed late radiation proctopathy, defined as radiation proctopathy of any grade, continuing from completion of radiotherapy for more than three months, or occurring more than three months after completion of radiotherapy.

Types of interventions

Experimental: any non‐surgical intervention for late radiation proctopathy, such as:

Aminosalicylic acid derivatives
Short chain fatty acid (SCFA) preparations
Sucralfate preparations
Coagulation therapy
Corticosteroids
Formalin applications
Pentoxyfilline
Hyperbaric oxygen
Antibiotic treatment

Control: no intervention, placebo, or any other non‐surgical intervention.

Types of outcome measures

Primary outcomes

We determined primary outcome measures by the presenting symptoms as recorded retrospectively or prospectively with diaries and scoring systems, for example:

Episodes of bowel activity
Bleeding
Pain
Tenesmus
Urgency
Sphincter dysfunction

Secondary outcomes

Mortality
Morbidity
Quality of life (QoL): 12‐Item Short Form Health Survey (Ware 1996), Subjective, Objective, Management, Analytic ‐ Late Effects of Normal Tissue (SOMA‐LENT) score (Pavy 1995), Visual Analogue Scale, (Scott 1976), mean Inflammatory Bowel Disease Questionnaire–Bowel subset score (IBDQ‐B) (Cheung 2000)

Search methods for identification of studies

Electronic searches

The literature searches from inception to 2007 have been updated and were re‐run in November 2015.

The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11, 2015) (Appendix 2)
MEDLINE (Ovid) (April 2007 to Nov week 1 2015) (Appendix 3)
EMBASE (Ovid) (April 2007 to 2015 week 45) (Appendix 4)

We did not apply a search filter due to the range of interventions searched for. This basic strategy was expanded for text and MeSH terms before being applied to the described databases.

Searching other resources

In addition, we searched the prospective trial register ClinicalTrials.gov with the key words 'proctitis' AND 'radiation' and 'proctopathy' AND 'radiation', and checked reference lists.

Data collection and analysis

We downloaded all titles and abstracts retrieved by the electronic searches to a reference management database (Reference Manager) and removed duplicate references. Two pairs of review authors (FW and RS; LV and JV) independently examined the remaining references. We excluded those studies that clearly did not meet the inclusion criteria, and we obtained copies of the full text of potentially relevant references. Two pairs of review authors (FW and RS; LV and JV) independently assessed the eligibility of the retrieved reports/publications. We resolved any disagreements through discussion or, if required, by consulting a third review author (RS). We identified and excluded duplicates. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram and Characteristics of excluded studies table.

Data extraction and management

We (FW, LV, JV) independently abstracted the data using a pre‐designed data abstraction form (Appendix 5). A second review author (LV, JV, or RS) checked data abstraction for accuracy. One review author (FW) transferred data into the RevMan 5 file (Review Manager 2014). We double‐checked that data was entered correctly by comparing the data presented in the systematic review with the study reports.

Assessment of risk of bias in included studies

Two review authors (FW, RS) independently assessed the risk of bias of all included studies according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We grouped outcomes as ‘subjective’ and ‘objective’ for the purposes of assessing blinding and incomplete outcome data. We resolved disagreements through consensus. For each relevant comparison we summarised the evidence per outcome in an additional table. We allocated the level of evidence using the the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system (GRADEpro 2014).

Measures of treatment effect

We described dichotomous data using the risk ratio (RR) with 95% confidence interval (CI). We expressed continuous data, that is symptom scores, as mean differences (MDs).

Dealing with missing data

If outcome data were missing, we planned to contact trial authors.

Assessment of heterogeneity

We planned to formally test statistical heterogeneity using the natural approximate Chi² test, which provides evidence of variation in effect estimates beyond that of chance. Since the Chi² test has low power to assess heterogeneity where a small number of participants or trials are included, we planned to set the P value conservatively at 0.1. We planned to test heterogeneity using the I² statistic, which calculates the percentage of variability due to heterogeneity rather than chance.

We planned to interpret the I² statistics in relation to the size of the included studies. We used the following interpretation as a rough guide:

0% to 40%: might not be important;
30% to 60%: may represent moderate heterogeneity;
50% to 90%: may represent substantial heterogeneity;
75% to 100%: considerable heterogeneity.

We planned to examine potential sources of clinical heterogeneity through the use of analyses as specified above. We planned to examine potential sources of methodological heterogeneity through the use of sensitivity analyses (Sensitivity analysis).

Assessment of reporting biases

If more than 10 included studies were available, we planned to use funnel plots to assess the potential for small‐study effects such as selective publication.

Data synthesis

We had planned to pool outcome data from studies that were sufficiently similar in participant characteristics and methodology followed (length of follow‐up, diagnostic criteria) and to use the random‐effects model for meta‐analysis, as we expected diversity in cancer types, interventions, and definitions of radiation proctopathy across included studies. However, due to the heterogeneous nature of the included studies, this was not feasible for this update but may be implemented in the future.

Subgroup analysis and investigation of heterogeneity

We planned to conduct subgroup analyses to investigate possible differences between groups, considering factors such as age, stage, type of intervention, and length of follow‐up in interpreting any heterogeneity.

Sensitivity analysis

We planned sensitivity analyses by excluding studies with high risk of bias. However as no meta‐analyses were performed, no sensitivity analyses were undertaken.

Results

Description of studies

Results of the search

In the previous version of this review (Denton 2002), which was assessed as up to date in 2008, seven trials were included (Cavcic 2000; Ehrenpreis 2005; Jensen 1997; Kochhar 1991; Pinto 1999; Rougier 1992; Talley 1997). Through the update, we found a total of 1443 trials as a result of the literature search. After we removed duplicates, 1221 were left for evaluation. We (FW, LV, JV) identified a total of 48 potential titles and abstracts for full‐text evaluation. After review of full text and discussion (FW, LV, JV, RS), we excluded a further 31 trials (Characteristics of excluded studies). We (FW, LV, JV, RS) eventually decided to include an additional nine trials (Figure 1), increasing the total number of included trials to 16 (including 993 participants). One eligible study found through the last update was moved to the Studies awaiting classification section (Guo 2015). Details of the participants, interventions, and outcomes in these trials are in the Characteristics of included studies table.

Figure 1

Study flow diagram.

Included studies

Study design

Five trials were placebo controlled (Chruscielewska 2012; Clarke 2008; Ehrenpreis 2005; Pinto 1999; Talley 1997), three trials assessed the effect of the addition of one intervention to another intervention, (Cavcic 2000; Kochhar 1991; Venkitaraman 2008) and eight trials compared two or more active interventions (Andreyev 2013; Jensen 1997; Lenz 2010; Nelamangala 2012; Rougier 1992; Sahakitrungruang 2012; Tian 2008; Yeoh 2013). All but two trials addressed single comparisons (Pinto 1999; Talley 1997).

Types of interventions

Four trials compared different types of anti‐inflammatory agents as a treatment for late radiation proctopathy (Cavcic 2000; Kochhar 1991; Rougier 1992; Venkitaraman 2008). In two trials, short‐chain fatty acids (SCFA) enemas were compared to placebo (Pinto 1999; Talley 1997). Three trials assessed the effects of sucralfate compared to either anti‐inflammatory agents (Kochhar 1991), formalin therapy (Nelamangala 2012), or placebo (Chruscielewska 2012). Another three trials assessed the effects of formalin therapy compared to colonic irrigation (Sahakitrungruang 2012), sucralfate steriod (Nelamangala 2012), or argon plasma coagulation (Yeoh 2013). Two trials assessed the effect of thermal coagulation therapy to either heater probe, in Jensen 1997, or bipolar coagulation, in Lenz 2010. One trial assessed the effect of hyperbaric oxygen therapy versus placebo (Clarke 2008), and three trials assessed other interventions: integrated Chinese traditional medicine (Tian 2008), retinol palmitate (Ehrenpreis 2005), and a gastroenterologist‐led algorithm‐based treatment with a nurse‐led algorithm‐based treatment or with usual care (Andreyev 2013).

Participant characteristics

Three trials included participants with prostate cancer (Cavcic 2000; Venkitaraman 2008; Yeoh 2013), one trial included participants with cervical cancer (Nelamangala 2012), seven trials included a mixed population of participants with prostate, cervical, endometrial, uterine, vaginal, or rectal cancer (Andreyev 2013; Chruscielewska 2012; Jensen 1997; Kochhar 1991; Lenz 2010; Sahakitrungruang 2012; Talley 1997), and five trials did not specify cancer types of their participants (Clarke 2008; Ehrenpreis 2005; Pinto 1999; Rougier 1992; Tian 2008).

Fourteen trials were published in English, one was published in French, and one in Chinese.

In addition, we searched the prospective trial register ClinicalTrials.gov with the key words 'proctitis' AND 'radiation' and 'proctopathy' AND 'radiation' and found four potentially relevant registered trials that are ongoing (Characteristics of ongoing studies).

Excluded studies

A total of 47 titles and abstracts seemed to fulfil our inclusion criteria and required further discussion. Through discussion we excluded 31 of these studies (Characteristics of excluded studies). We excluded 11 studies because of their design (no randomised studies), 10 studies because the population did not fulfil our inclusion criteria (no late rectal consequences of radiotherapy), 9 studies as they were prevention studies, and 1 study because the intervention did not fulfil our inclusion criteria.

Risk of bias in included studies

The results of the 'Risk of bias' assessment of the included studies are presented in the Characteristics of included studies tables and summarised in Figure 2 and Figure 3.

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Appropriate sequence generation to ensure randomisation seemed likely in eight studies (Andreyev 2013; Chruscielewska 2012; Clarke 2008; Ehrenpreis 2005; Nelamangala 2012; Sahakitrungruang 2012; Venkitaraman 2008; Yeoh 2013). Cavcic 2000 and Tian 2008 had a high‐risk score as they were quasi‐randomised trials (treatment was allocated according to the date on which their treatment began, in Cavcic 2000, and according to treatment order, in Tian 2008). The remaining six studies did not adequately describe the method of randomisation, and thus were judged to be of unclear risk of selection bias (Jensen 1997; Kochhar 1991; Lenz 2010; Pinto 1999; Rougier 1992; Talley 1997).

Allocation concealment was adequate in six studies (Andreyev 2013; Chruscielewska 2012; Clarke 2008; Ehrenpreis 2005; Lenz 2010; Yeoh 2013; ). We judged the method of allocation concealment to be inappropriate, resulting in a high risk of bias, in three studies, as two used quasi‐randomisation (Cavcic 2000; Tian 2008), and one used an open list of random numbers (Nelamangala 2012). The method of allocation concealment was not clearly described in the remaining seven studies.

Blinding

The participants and personnel were not blinded in six studies (Andreyev 2013; Cavcic 2000; Nelamangala 2012; Sahakitrungruang 2012; Venkitaraman 2008; Yeoh 2013), which we therefore judged as having a high risk of performance bias. Participants and personnel were adequately blinded in eight studies (Chruscielewska 2012; Clarke 2008; Ehrenpreis 2005; Jensen 1997; Kochhar 1991; Lenz 2010; Pinto 1999; Talley 1997). For the remaining two studies, insufficient information was provided to judge the potential risk of performance bias and we therefore considered them to be at an unclear risk of bias.

Outcome assessors for subjective outcomes were not blinded in six studies (Andreyev 2013; Cavcic 2000; Nelamangala 2012; Sahakitrungruang 2012; Venkitaraman 2008; Yeoh 2013), and blinded in eight studies (Chruscielewska 2012; Clarke 2008; Ehrenpreis 2005; Jensen 1997; Kochhar 1991; Lenz 2010; Pinto 1999; Talley 1997). In the remaining two studies, the risk of bias on this item was unclear due to insufficient information.

As for the objective outcomes, the outcome assessors were blinded in seven studies (Cavcic 2000; Clarke 2008; Ehrenpreis 2005; Lenz 2010; Nelamangala 2012; Pinto 1999; Sahakitrungruang 2012;). In six studies the risk of bias on this item was again unclear due to insufficient information, and three studies did not assess objective outcomes (Andreyev 2013; Chruscielewska 2012; Yeoh 2013).

Incomplete outcome data

For subjective outcomes, we judged eight studies as at low risk of attrition bias (Chruscielewska 2012; Ehrenpreis 2005; Jensen 1997; Lenz 2010; Nelamangala 2012; Pinto 1999; Sahakitrungruang 2012; Tian 2008). We scored one study as at high risk of attrition bias, as a substantial number of participants (25% after three months, 40% after one year, 52% after two years) dropped out of the study for unknown reasons (Cavcic 2000). For the remaining seven studies, insufficient information was provided to draw a safe conclusion.

As for the objective outcomes, we judged six studies as at low risk of attrition bias (Ehrenpreis 2005; Jensen 1997; Lenz 2010; Nelamangala 2012; Sahakitrungruang 2012; Tian 2008). We scored one study as at high risk for attrition bias because the number of dropouts was not evenly distributed between the two groups (at three months: 10% versus 40%; after one year: 20% versus 60%; after two years: 37% versus 67%), and reasons for lost to follow‐up were not reported (Cavcic 2000). In three studies (Andreyev 2013; Chruscielewska 2012; Yeoh 2013), objective outcomes were not assessed. The remaining six studies provided insufficient information to draw a safe conclusion and we therefore judged them as at unclear risk of bias.

Selective reporting

We judged only two studies to be at low risk of selective reporting bias (Andreyev 2013; Lenz 2010). We judged two studies to be at high risk of reporting bias (Rougier 1992; Sahakitrungruang 2012). In the remaining studies no protocol was available, and we therefore judged the risk of bias on this item as unclear.

Other potential sources of bias

We judged all but two of the studies to be at low risk of other bias. In one study there were substantial differences in baseline characteristics (more aggressive grade of disease in the betamethasone group), resulting in a high risk of bias (Rougier 1992). We judged a second study to be at unclear risk of bias, as they failed to achieve the expected rate of enrolment, which may have influenced the results (Venkitaraman 2008).

Effects of interventions

Since radiation proctopathy is a condition with various symptoms or combinations of symptoms, the studies are heterogeneous in their intended effect. Some studies investigated treatments targeted at bleeding only (group 1), some investigated treatments targeted at a combination of anorectal symptoms, but not a single treatment (group 2). The third group focused on the treatment of the collection of symptoms referred to as pelvic radiation disease. In order to enable some comparison of this heterogeneous collection of studies, we described the effects in these three groups separately.

1. Treatments for rectal bleeding

(see Table 1)

Open in table viewer

Table 1. Treatment for bleeding only

Study ID	Participant characteristics	Intervention(s)	Results	Level of evidence (GRADE)
Chruscielewska 2012	Adults with chronic radiation proctopathy or proctosigmoiditis were included if all of the following criteria were met: radiotherapy for a pelvic tumour completed at least 3 months before enrolment, the presence of rectal bleeding, radiation‐induced telangiectasia in the rectum and/or sigmoid colon on endoscopy, informed written consent by the person to participate in the study	Endoscopic APC followed by oral sucralfate (6 g twice daily) for 4 weeks (n = 60) versus APC with placebo administration for 4 weeks (n = 62)	Changes in chronic radiation proctopathy severity score (based on scales previously proposed by Chutkan et al. and Kochhar et al., median (interquartile range)) Overall severity score Week 8: 2 (1.3) versus 2 (1.3) Week 16: 2 (1.3) versus 2 (1.3) Week 52: 1 (1.2) versus (1.2) P > 0.05 for all between‐group comparisons	Moderate due to imprecision (precision not quantified)
			Diarrhoea score Week 8: 1 (1.1) versus 1 (1.1) Week 16: 1 (1.1) versus 1 (1.1) Week 52: 1 (1.1) versus 1 (1.1) P > 0.05 for all between‐group comparisons	Moderate due to imprecision (precision not quantified)
			Bleeding score Week 8: 1 (0.1) versus 0 (0.1) Week 16: 0 (0.1) versus 0 (0.1) Week 52: 0 (0.1) versus 0 (0.0) P > 0.05 for all between‐group comparisons	Moderate due to imprecision (precision not quantified)
			Tenesmus ⁄ rectal pain score Week 8: 0 (0.1) versus 0 (0.1) Week 16: 0 (0.0) versus 0 (0.1) Week 52: 0 (0.0) versus 0 (0.0) P > 0.05 for all between‐group comparisons	Moderate due to imprecision (precision not quantified)
			Endoscopy scores (graded according to the Gilinsky scale as endoscopic severity score) Score 6 to 9: Week 8: 20 to 59 versus 9 to 60 (RR 2.26, 95% CI 1.12 to 4.55) Week 16: 10 to 57 versus 8 to 60 (RR 1.32, 95% CI 0.56 to 3.10)	‐
			Complications Number (%) of people with complications: 38/60 (63%) versus 36/62 (58%) (RR 1.09, 95% CI 0.82 to 1.45)	Moderate due to imprecision (CI includes both benefits and harms)
			APC‐related complications Asymptomatic rectal ulcer: 30 versus 30 Symptomatic rectal ulcers: 7 versus 5 Rectovaginal fistula: 2 versus 0 Adynamic ileus: 0 versus 1	Low due to very serious limitations for imprecision (CI includes both benefits and harms)
			Other complications Severe constipation: 4 versus 0 Urticaria: 1 versus 0	‐
			Complication severity (APC‐related) Severe + fatal: 2/60 versus 0/62 (RR 5.17, 95% CI 0.25 to 105.4) P > 0.05 for all between‐group comparisons regarding complications	Low due to very serious imprecision (CI includes both benefits and harms)
Jensen 1997	People being considered for surgery, having failed 1 year of medical therapy, pelvic radiotherapy for a cancer at least 2 years earlier, rectal bleeds at least 3 times per week, anaemia, and a life expectancy of at least 2 years	Bipolar electrocoagulation (n = 12) versus Heater probe (n = 9)	Severe bleeding episodes after 1 year (measured by participant interview) 3/12 (33%) versus 1/9 (11%) (RR 2.25, 95% CI 0.28 to 18.22)	Low due to very serious imprecision (CI includes both benefits and harms)
			Mean number of severe bleeds after 1 year, mean (SD) (measured by participant interview) 0.3 (0.3) versus 0.4 (0.9) (MD ‐0.10, 95% CI ‐0.71 to 0.51)	Low due to very serious imprecision (CI includes both benefits and harms)
			Mean haematocrits after 1 year, mean (SD) 38.2 (4.8) versus 37.6 (3.0) (MD 0.60, 95% ‐2.75 to 3.95)	Low due to very serious imprecision (CI includes both benefits and harms)
			Mean units of red blood cells transfused after 1 year, mean (SD) 0.0 (0.0) versus 0.2 (0.6) (MD not estimable)	Low due to very serious imprecision (OIS not reached)
			Complications No major complications occurred
			QoL QoL informally assessed with participant responses, which improved with treatment
Kochhar 1991	Symptomatic radiation‐induced proctosigmoiditis	Oral sulfasalazine (500 mg tds) + rectal prednisolone (20 mg bd) for 4 weeks (n = 8) versus Oral placebo + rectal sucralfate suspension (2 g bd) for 4 weeks (n = 19)	Clinical improvement at 4 weeks (an in‐house scoring system was used measuring diarrhoea, bleeding per rectum, bleeding requiring blood transfusion, and tenesmus) 8 to 15 versus 16 to 17 (RR 0.57, 95% CI 0.35 to 0.92)	Low due to unclear RoB and imprecision (OIS not reached)
			Endoscopic improvement at 4 weeks (injury was graded according to the criteria of Gilinsky et al.) 7 to 15 versus 12 to 17 (RR 0.66, 95% CI 0.35 to 1.23)	Very low due to unclear RoB and very serious imprecision (CI includes both benefits and harms)
			Side effects at 4 weeks (participants were questioned and examined for any side effects of the medication) 2 participants in the sulfasalazine group did not tolerate the drugs due to myalgia, nausea, and headaches	Very low due to unclear RoB and very serious imprecision (very small sample size)
Lenz 2010	Recurrent rectal bleeding, started 6 months after radiotherapy with at least 1 bleeding episode in the week before and endoscopically confirmed radiation telangiectasias	APC (n = 15) versus Bipolar electrocoagulation (n = 15)	Eradication of all telangiectasias at 1 year 12/15 versus 14/15 (RR 0.86, 95% CI 0.64 to 1.14)	Low due to indirectness and imprecision (CI includes both benefits and harms)
			Complications Minor: 5/15 versus 10/15 (RR 0.50, 95% CI 0.22 to 1.11) Major: 1/15 versus 5/15 (RR 0.20, 95% CI 0.03 to 1.51)	Low due to very serious imprecision (CI includes both benefits)
			Relapse 1/12 versus 2/14 (RR 0.58, 95% CI 0.06 to 5.66)	Low due to very serious imprecision (CI includes both benefits and harms)
Nelamangala 2012	Rectal bleeding as a result of chronic haemorrhagic radiation proctopathy, following radiotherapy for carcinoma of the cervix	Formalin dab treatment (4%) as an outpatient procedure (formalin applied directly to each lesion via a rigid sigmoidoscope or a proctoscope under local anaesthesia. Under direct vision, a small piece of gauze soaked in 4% formalin was applied to the haemorrhagic areas for 2 min until the mucosa turned pale) (n = 51) versus Sucralfate steroid retention enema (100 mg of prednisolone and 1 g of sucralfate in 100 ml of normal saline), twice daily for 7 to 10 days (n = 51)	Symptom score after treatment (graded by the RPSAS), median (range) 9 (6 to 24) versus 13 (8 to 27) (P < 0.001)	Low due to high risk of bias and imprecision (OIS not reached)
			Sigmoidoscopic score (median (range) after treatment) 1 (0 to 3) versus 2 (0 to 3) (P < 0.001)	Very low due to high risk of bias, imprecision and indirectness (OIS not reached)
			Adverse events “Mild pain occurred in 33.3% patients in Group 1 during the application of formalin but this subsided within 1 day. There were no complications in Group 2.”	Low due to high risk of bias and imprecision (OIS not reached)
Pinto 1999	Clinical and histological diagnosis of chronic radioproctitis: Grade III Pourquier classification with rectal bleeding at least once a week, persistent symptoms for a minimum of 12 months (except 1 participant)	SCFA enema (as per Harig preparation 60 ml bd 5 weeks) (n = 10) versus Placebo: identically appearing enemas containing saline isotonic solution, bd 5 weeks (n = 9)	Mean endoscopic score after 5 weeks, mean (SD) 2.6 (1.8) versus 1.6 (4.2) (MD 1.00, 95% CI ‐2.33 to 4.33)	Low due to indirectness and imprecision (CI includes both benefits and harms)
			Number of days of rectal bleeding at the end of treatment (after 5 weeks), mean (SD) (participant diary) 1.4 (2.2) versus 3.4 (2.6) (MD ‐2.00, 95% CI ‐4.40 to 0.40)	Low due to very serious imprecision (CI includes both benefits and harms)
			Haemoglobin levels after 5 weeks, mean (SD) 13.1 ± 0.9 g/dl versus 10.7 ± 2.1 g/dl (MD 2.40, 95% CI 0.74 to 4.06)	Low due to imprecision (very small sample size)
Rougier 1992	Chronic radiation proctopathy confirmed and graded on sigmoidoscopy	Hydrocortisone acetate mousse 90 mg bd for 4 weeks (n = 16) versus Betamethasone lavage 5 mg od for 4 weeks (n = 16)	Improvement of endoscopic appearance 12/16 versus 5/14 (RR 2.10, 95% CI 0.98 to 4.48)	Very low due to high RoB, indirectness, and imprecision (CI includes both benefits and harms)
			Reduction of degree of bleeding (an in‐house scoring system was used) 6/16 versus 3/14 (RR 1.75, 95% CI 0.53 to 5.73)	Very low due to high RoB and very serious imprecision (CI includes both benefits and harms)
			Poor tolerance of enema 2/16 versus 10/14 (RR 0.17, 95% CI 0.05 to 0.67)	Low due to high RoB and imprecision (OIS not reached)
Sahakitrungruang 2012	Symptomatic haemorrhagic radiation proctopathy for more than 6 months without complications of rectal stricture, deep ulceration, fistula formation, or sepsis	Colonic irrigation (with 1000 ml of tap water via a 20F Foley catheter) plus ciprofloxacin (500 mg twice daily) and metronidazole (500 mg 3 times daily) by mouth for 1 week (n = 25) versus Formalin application in an office setting (4% formalin‐soaked gauze applied for 3 minutes under direct vision by using proctoscopy followed by immediate cleansing with water irrigation) (n = 25)	Comparison between the 2 treatment groups after 8 wks of treatment (measured by participant survey) Bleeding (days/week) median (min,max) ‐5 (‐7,0) versus ‐2 (‐7,4) (P = 0.007)	Low due to high RoB and imprecision (OIS not reached)
			Frequency (times/day) ‐2 (‐8,2) versus ‐2 (‐4,2) (P = 0.09)	Low due to high RoB and imprecision (OIS not reached)
			Urgency (days/week) ‐2 (‐7,3) versus 0 (‐2,7) (P = 0.0004)	Low due to high RoB and imprecision (OIS not reached)
			Diarrhoea (days/week) ‐2 (‐6,0) versus 0 (‐7,2) (P = 0.007)	Low due to high RoB and imprecision (OIS not reached)
			Tenesmus (days/week) ‐2 (‐7,0) versus 0 (‐4,4) (P = 0.07)	Low due to high RoB and imprecision (OIS not reached)
			Haematocrit (mg/dL) 0 (‐9,10) versus 0 (‐7,18) (P = 0.86)	Low due to high RoB and imprecision (OIS not reached)
			Vienna rectoscopy score after 8 wks of treatment No significant differences between groups (P = 0.78)	Low due to high RoB and imprecision (OIS not reached)
			Adverse events after 8 wks of treatment "There were no serious adverse drug reactions." "Four patients in the irrigation group and 8 patients in the formalin group required blood transfusion during the study, but this finding did not reach the statistic difference."	Low due to high RoB and imprecision (OIS not reached)
			Patient satisfaction 20/24 versus 10/23 (RR 1.92, 95% CI 1.16 to 3.16)	Low due to high RoB and imprecision (OIS not reached)
Venkitaraman 2008	Symptomatic late morbidity with at least 1 episode of rectal bleeding more than 6 months since pelvic radiotherapy	Standard therapies for late radiation‐induced bleeding plus oral pentoxifylline (400 mg) 3 times daily for 6 months (n = 20) versus Standard treatment for late radiation‐induced bleeding (n = 20)	Cessation of rectal bleeding (measured using a daily participant symptom diary) 16/20 versus 12/20 (RR 1.33, 95% CI 0.88 to 2.03)	Very low due to high RoB and very serious imprecision (CI includes both benefits and harms)
			Median time to cessation of bleeding (measured using a daily participant symptom diary) 22 days (range 1 to 119 days) versus 95 days (range 13 to 172) (P = 0.12) “However, at least one episode of recurrent bleeding occurred in 14 of the 16 patients in the study group and in all the 12 patients who had cessation of bleeding in the control group.”	Low due to high RoB and imprecision (OIS not reached)
			The median duration of freedom from bleeding (measured using a daily participant symptom diary) 12 days (range 8 to 290) versus 11 days (range 7 to 133)	Very low due to high RoB and very serious imprecision (precision not quantified; very small sample size)
			Adverse events “Pentoxifylline was well tolerated with minor side‐effects and the compliance rate was satisfactory. Seven patients required a dose reduction or temporary discontinuation of pentoxifylline, due to dyspepsia in five patients and rashes and chest pain in one patient each, whereas one patient required permanent discontinuation of pentoxifylline due to dyspepsia. Contrary to expectations, one patient had a transient, but significant, increase in serum fibrinogen levels.”	Very low due to high RoB and very serious imprecision (OIS not reached)

APC: argon plasma coagulation
bd: 2 times a day
CI: confidence interval
MD: mean difference
od: once a day
QoL: quality of life
RoB: risk of bias
RPSAS: Radiation Proctopathy System Assessments Scale
RR: risk ratio
SCFA: short chain fatty acid
SD: standard deviation
tds: 3 times a day
OIS: Optimal Information Size

Short‐chain fatty acid (SCFA) versus placebo

One study randomised 19 participants with late radiation proctopathy (grade III of the Pourquier classification and with persistent symptoms for a minimum of 12 months) to SCFA enema (60 ml twice a day for 5 weeks) or a placebo (Pinto 1999). We considered the risk of bias of this study to be unclear. At the end of the treatment period, the difference in reduction in endoscopic score was 1 (95% confidence interval (CI) ‐2.33 to 4.33) (Analysis 1.1), and the difference between the mean number of days of rectal bleeding per week was ‐2 (95% CI ‐4.4 to 0.4) (Analysis 1.2), but this was not statistically significant. In long‐term follow‐up, two people were dropped from the placebo group because of severe bleeding, presumably representing treatment failures. At the end of the six months, the mean number of days of rectal bleeding per week and the endoscopic score was similar in the two groups.

Sucralfate versus placebo following argon plasma coagulation

One study compared the efficacy of sucralfate with placebo following argon plasma coagulation (APC) for late haemorrhagic radiation proctopathy (Chruscielewska 2012). This study included 122 participants with haemorrhagic late radiation proctopathy after irradiation for prostate, uterine, cervix, rectal, or vaginal cancer. All participants received APC, and were then randomised to oral sucralfate (6 g twice a day) or placebo treatment for four weeks. APC was repeated every eight weeks, if necessary, after the first session. We considered the risk of bias of this study to be unclear. At all time points (week 8, 16, and 52), no differences between the two groups were found with regard to changes in late radiation proctopathy severity score. Significant differences in changes in endoscopy scores in favour of the placebo group were found at week 8 (score 6 to 9, week 8: risk ratio (RR) 2.26, 95% CI 1.12 to 4.55), but not at week 16 (score 6 to 9, week 16: RR 1.32, 95% CI 0.56 to 3.10) (Analysis 2.1; Analysis 2.2). The number of participants with complications did not significantly differ between groups (RR 1.09, 95% CI 0.82 to 1.45) (Analysis 2.3).

Endoscopic bipolar electrocoagulation versus heater probe

One study randomised 21 participants with late radiation proctopathy that after one year was resistant medical treatment, to either a heater probe or a bipolar electrocoagulation probe (Jensen 1997). We considered the risk of bias of this study to be unclear. Severe bleeding episodes, defined as a bleeding that provoked an unscheduled hospital assessment, occurred in 33% (3/12) of the bipolar probe group and in 11% (1/9) of the heater probe group (RR 2.25, 95% CI 0.28 to 18.22) (Analysis 3.1). There was no difference between the two treatment groups with regard to mean number of severe bleeds (mean difference (MD) ‐0.10, 95% CI ‐0.71 to 0.51) (Analysis 3.2). Mean units of blood transfused after one year was greater for the heater probe group, however the MD was not estimable (Analysis 3.4). No major complications occurred. Participants all expressed an improvement in their general health as a result of their controlled bleeding, which the study authors considered to be an informal quality of life assessment. During follow‐up endoscopy there was resolution of the telangiectasia, scarring, or epithelial replacement in all cases in both groups. Participant interviews, pretreatment and six months after treatment, revealed that rectal bleeds and tenesmus had improved in all participants so that they were encouraged to resume going out with less worry.

Bipolar eletrocoagulation versus argon plasma coagulation

One study randomised 30 participants with recurrent rectal bleeding that had started six months or more after radiotherapy, to either argon plasma coagulation (APC) or bipolar electrocoagulation (BEC) (Lenz 2010). We considered the risk of bias of this study to be unclear. There were no significant differences between the groups with respect to rectal bleeding. Based on an intention‐to‐treat analysis the success rates (defined as eradication of all telangiectasias) were 12/15 (80.0%) for APC and 14/15 (93.3%) for BEC (RR 0.86, 95% CI 0.64 to 1.14) (Analysis 4.1). In a per‐protocol analysis, these results were 92.3% and 93.3% respectively (P = 1.000). There was no difference between the groups with regard to mean number of sessions needed for eradication (APC 3.7 (standard deviation (SD) 1.7), BEC 2.9 (1.9); P = 0.313). Minor complications were recorded in 5 to 15 in the APC group and 10 to 15 in the BEC group (RR 0.50, 95 % CI 0.22 to 1.11) (Analysis 4.2), and major haemorrhagic complications in 1 and 5, respectively (RR 0.20, 95% CI 0.03 to 1.51) (Analysis 4.3). No other major adverse effects, such as fistula, extensive necrosis, perforation, or bowel explosion were observed. Relapse of rectal bleeding occurred in 1 to 12 after APC and in 2 to 14 after BEC (RR 0.58, 95% CI 0.06 to 5.66) (Analysis 4.4).

Hydrocortisone versus betamethasone

One study involved 32 participants with radiation proctopathy who received either a rectally administered hydrocortisone acetate mousse or betamethasone enema (Rougier 1992). We considered the risk of bias of this study to be high. Over the four weeks of treatment, the endoscopic appearance improved more in the hydrocortisone group (12/16) than in the betamethasone group (5/14) (RR 2.10, 95% CI 0.98 to 4.48) (Analysis 5.1). The degree of bleeding was reduced in 6 out of 16 in the hydrocortisone group and in 3 out of 14 of the betamethasone group, but this did not show a significant difference (RR 1.75, 95% CI 0.53 to 5.73) (Analysis 5.2). The duration of this response was only reported for the four‐week follow‐up period and not thereafter. Potential reasons for the difference in effect may be the more aggressive grade of disease in the betamethasone group at baseline, which would have been less likely to respond to any treatment, and also the fact that the betamethasone enema was poorly tolerated in 10/14 participants compared with 2/16 in the hydrocortisone group (RR 0.17, 95% CI 0.05 to 0.67 in favour of the hydrocortisone group) (Analysis 5.3).

Formalin dab versus sucralfate steroid retention enema

One study compared the efficacy of formalin dab versus sucralfate steroid retention enema (Nelamangala 2012). This study randomly allocated 102 participants with late radiation proctopathy, presenting as rectal bleeding after radiotherapy for carcinoma of the cervix, to either formalin dab or sucralfate steroid retention enema. We considered the risk of bias of this study to be high. Ninety per cent of participants treated with formalin dab and 74.5% of participants treated with sucralfate retention enema responded to treatment (P = 0.038). In spite of having a higher median symptom score (graded by the Radiation Proctopathy System Assessments Scale) before treatment, participants treated with formalin dab demonstrated a marked decrease in symptom score after treatment compared with participants treated with sucralfate retention enema, and the difference once again was statistically significant (P = 0.001). Similarly, the median sigmoidoscopic grade was significantly lower for participants in group 1 compared with participants in group 2 after treatment (P = 0.000). There were no specific treatment‐related complications in either group.

Formalin application versus colonic irrigation and oral antibiotics

Another study randomised 50 participants with haemorrhagic radiation proctopathy to either 4% formalin application or colonic irrigation and oral antibiotics (Sahakitrungruang 2012). We considered the risk of bias of this study to be high. The study revealed greater improvement in rectal bleeding, urgency, and diarrhoea in the irrigation group. Twenty out of 24 participants in the irrigation group were satisfied with the treatment compared to ten out of 23 participants in the formalin group (RR 1.92, 95% CI 1.16 to 3.16).

Pentoxifylline in addition to standard therapy

In one study, 40 participants were randomised to either local standard therapies (including blood transfusion, analgesics, anti‐inflammatory agents, dietary modification, local steroids applications, or sucralfate enemas) or identical therapies plus oral pentoxifylline 400 mg three times daily for six months (study group) (Venkitaraman 2008). We considered the risk of bias of this study to be high. Sixteen participants in the pentoxifylline group and 12 in the control group had cessation of rectal bleeding for a week or more (RR 1.33, 95% CI 0.88 to 2.03) (Analysis 6.1). The median time to cessation of bleeding was 22 days (range 1 to 119 days) in the study group and 95 days (range 13 to 172) in the control group (P = 0.12). At least one episode of recurrent bleeding occurred in 14 of the 16 participants in the study group and in all the 12 participants who had cessation of bleeding in the control group. The median duration of freedom from bleeding was 12 days (range 8 to 290) in the study group and 11 days (range 7 to 133) in the control group. There was an overall trend of a reduction of rectal bleeding episodes with time in both groups, as judged by the proportion of days in which one or more rectal bleeding episode was reported. This study could not show a statistically significant advantage with six months of pentoxifylline compared with the used standard measures for late radiation‐induced rectal bleeding.

Oral sulfasalazine plus rectal steroids versus oral placebo plus rectal sucralfate

One study included 32 participants with radiation‐induced proctosigmoidopathy (Kochhar 1991). Participants were randomised to either oral sulfasalazine 500 mg and rectal prednisolone 20 mg or oral placebo and rectal sucralfate suspension. We considered the risk of bias of this study to be unclear. Eight out of 15 participants in the sulfasalazine/steroid group showed a clinical improvement compared to 16/17 in the sucralfate group (RR 0.57, 95% CI 0.35 to 0.92) (Analysis 7.1). Seven out of 15 participants in the sulfasalazine/steroid group showed endoscopic improvement compared to 12/17 in the sucralfate group (RR 0.66, 95% CI 0.35 to 1.23) (Analysis 7.2). Two participants in the sulfasalazine/steroid group did not tolerate the drugs and were excluded due to myalgia, nausea, and headaches.

2. Treatments targeted at a combination of anorectal symptoms

(see Table 2)

Open in table viewer

Table 2. Treatment targeted at something very localised but not a single pathology

Study ID	Participant characteristics	Intervention(s)	Results	Level of evidence (GRADE)
Cavcic 2000	Chronic radiation proctopathy producing diarrhoea and rectal bleeding	Metronidazole (3 x 400 mg orally per day), mesalazine (3 x 1 g orally per day), and betamethasone enema (once a day) (n = 30) versus Same doses of mesalazine and betamethasone enema, but without metronidazole (n = 30)	Rectal bleeding score < 2, 1 year after treatment (an in‐house scoring system was used) 22/24 versus 5/12 (RR 1.57, 95% CI 0.96 to 2.57)	Very low due to high RoB and very serious imprecision (single study/OIS not reached)
			Diarrhoea score < 2, 1 year after treatment (an in‐house scoring system was used) 23/24 versus 8/12 (RR 1.44, 95% CI 0.96 to 2.16)	Very low due to high RoB and very serious imprecision (single study/CI includes both benefits and harms)
			No rectal ulceration, 1 year after treatment (an in‐house scoring system was used) 22/24 versus 7/12 (RR 1.57, 95% CI 0.96 to 2.57)	Very low due to high RoB and very serious imprecision (single study/CI includes both benefits and harms)
Talley 1997	Symptoms consistent with chronic radiation proctopathy (≥ 2 months)	Butyric acid (SCFA) enema (60 ml containing 40 mmol butyric acid), twice a day, used for 2 weeks versus Normal saline placebo enema NB: this was a cross‐over study with a 1‐week wash‐out period before giving the alternate enema (n = 15 participants were randomised and 12 completed both arms of the study, number of participants per group not specified)	Symptom scores (in‐house scoring system: total symptom score was calculated combining 6 items: rectal pain, rectal bleeding episodes per week, quantity of blood passed, number of days of diarrhoea per week, number of stools per week, and urgency) Mean score 3.5 (range 3 to 5) versus 4.5 (range 3 to 6) (P = 0.3)	Very low due to unclear RoB and very serious imprecision (precision not quantified/small sample size)
			Bleeding 38% versus 38%	Very low due to unclear RoB and very serious imprecision (precision not quantified and OIS not reached)
			Urgency (time in min able to defer defecation) 5 (1 to 42.5) in the placebo group versus 10 (5 to 20) in the treatment group	Very low due to unclear RoB and very serious imprecision (precision not quantified and OIS not reached)
			Days with diarrhoea 1 (1 to 5.5) in the placebo group versus 1 (1 to 2) in the treatment group	Very low due to unclear RoB and very serious imprecision (precision not quantified and OIS not reached)
			Number of stools 1.5 (1 to 3) in the placebo group versus 1.5 (1 to 2.5) in the treatment group	Very low due to unclear RoB and very serious imprecision (precision not quantified and OIS not reached)
			Pain (rectal) 33% in the placebo group versus 8% in the treatment group	Very low due to unclear RoB and very serious imprecision (precision not quantified and OIS not reached)
			“Neither changes in the symptom score nor changes in the individual symptoms were statistically significant”	‐
			“No side effects were reported and there was no QOL assessment” (2 participants experienced problems inserting the enema)	‐
Yeoh 2013	People who had (1) completed external beam radiation therapy for prostate carcinoma ≥ 6 months previously; (2) intractable rectal bleeding, defined as a frequency of ≥ 1x per week and/or requiring blood tranfusions, attributed to chronic radiation proctopathy at colonoscopy; (3) no constant requirement for medications likely to influence anorectal motility, such as opioid analgesic and antidiarrhoeal agents; and (4) provided written informed consent	APC (outpatient procedure) (n = 17) versus Topical formalin (n = 13) NB: cross‐over to the other therapy was allowed if the treatment endpoint was not reached after 4 treatment sessions. 2 microlax enemas were administered before each session of either APC or topical formalin therapy	Anorectal symptom parameters (after treatment), median (range) (measured by SOMA‐LENT and VAS) No. of bowel actions per week: 16 (7 to 46) versus 14 (4 to 42) Faecal incontinence scores: 0 (0 to 4) versus 0 (0 to 2) Urgency of defaecation scores: 4 (0 to 6) versus 4 (0 to 6) Rectal bleeding scores: 1 (0 to 2) versus 1 (0 to 2) VAS for rectal bleeding (mm): 14 (0 to 34) versus 13 (0 to 25) No between‐group comparisons were made	Low due to high risk of bias and imprecision (precision not quantified)
Yeoh 2013			Comparisons of participant outcomes after APC and topical formalin treatment, median (range) (measured by SOMA‐LENT and VAS) Rectal bleeding scores: 1 (0 to 2) versus 1 (0 to 2), NS VAS for rectal bleeding (mm): 14 (0 to 34) versus 13 (0 to 25), NS	Low due to high risk of bias and imprecision (precision not quantified)

APC: argon plasma coagulation
CI: confidence interval
RR: risk ratio
SCFA: short chain fatty acid
VAS: visual analogue scale
NB: nota bene
NS: not significant
OIS: Optimal Information Size

Short‐chain fatty acid (SCFA) versus placebo

The first study was a prospective randomised, double‐blind, cross‐over pilot study that randomised 15 participants with late radiation proctopathy, to either a normal saline placebo enema or a SCFA enema, which was 60 ml in volume and administered twice a day (Talley 1997). It contained 40 mM of butyrate in the Harig preparation, used for two weeks with a one‐week wash‐out period before giving the alternate enema. We considered the risk of bias of this study to be unclear. The total symptom score at baseline ranged from 2 to 11 (median 5.5). Symptom scores improved slightly on the active treatment (median score 3.5 (range 3 to 5) compared with 4.5 median score (range 3 to 6) for those receiving placebo. Neither changes in the symptom score nor changes in the individual symptoms were statistically significant.

Topical formalin versus argon plasma coagulation

The second study compared the effect of topical formalin and argon plasma coagulation (APC) for intractable rectal bleeding and anorectal dysfunction associated with late radiation proctopathy (Yeoh 2013). Thirty men with intractable rectal bleeding (defined as one per week or more or requiring blood transfusions, or both) after radiotherapy for prostate carcinoma were randomised to treatment with APC or topical formalin. We considered this study to be at high risk of bias. Control of rectal bleeding was achieved in 100% of the topical formalin group and 94% of the APC group after a median of two sessions of the respective treatment. No significant differences in efficacy and durability of rectal bleeding between the two groups (rectal bleeding scores, median (range): 1 (0 to 2) versus 1 (0 to 2); visual analogue scale for rectal bleeding (mm), median (range): 13 (0 to 25) versus 14 (0 to 34)) were found. There were no differences between topical formalin and APC for anorectal symptoms and function, nor for anal sphincteric morphology. The treatments were well tolerated. No skin toxicity was noted in participants who needed more than one formalin treatment session.

Metronidazole in addition to mesalazine and betamethasone

In the third study participants with rectal bleeding and diarrhoea were randomly allocated to either metronidazole (3 x 400 mg orally per day), mesalazine (3 x 1 g orally per day), and betamethasone enema (once a day) or to the same doses of mesalazine and betamethasone enema, but without metronidazole (Cavcic 2000). We considered the risk of bias of this study to be high. The incidence of rectal bleeding and mucosal ulcers was significantly lower in the metronidazole group at 4 weeks (P = 0.009), 3 months (P = 0.031), and 12 months (P = 0.029). There was also a significant decrease in diarrhoea and oedema in the metronidazole group at 4 weeks (P = 0.044), 3 months (P = 0.045), and 12 months (P = 0.034) after treatment. One year after treatment, 22/24 participants in the metronidazole group had demonstrated a reduction in the grade of their rectal bleeding compared to 5/12 in the group treated with mesalazine and betamethasone (RR 1.57, 95% CI 0.96 to 2.57) (Analysis 8.1). Similarly, 23 out of 24 participants in the metronidazole group compared to 8/12 in the control group had experienced reduction in their diarrhoea and rectal erythema (RR 1.44, 95% CI 0.96 to 2.16) (Analysis 8.2; Analysis 8.3). The degree of rectal ulceration at 1 year had decreased in 22/24 participants in the metronidazole group compared with 7/12 of the group treated with anti‐inflammatories alone (RR 1.57, 95% CI 0.96 to 2.57) (Analysis 8.4).

3. Treatments targeted at pelvic radiation disease

(see Table 3)

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Table 3. Treatments targeted at the more global collection of symptoms

Study ID	Participant characteristics	Intervention(s)	Results	Level of evidence (GRADE)
Andreyev 2013 (ORBIT)	Adults (aged ≥ 18 years) who had troublesome, persisting gastrointestinal symptoms, started during or after radiotherapy given with curative intent for histologically proven prostatic, bladder, vulval, vaginal, cervical, endometrial, anal, or rectal malignant neoplasia or para‐aortic irradiation for metastatic disease from any of those primary sites or the testis. Radiotherapy should have been completed at least 6 months before enrolment	Gastroenterologist group (management according to an algorithm by a consultant gastroenterologist) (n = 70) versus Nurse group (management according to an algorithm by a specially trained research nurse) (n = 80) versus Booklet group (detailed advice booklet on self management of bowel symptoms) (n = 68) N.B.: the algorithm provides a step‐by‐step approach along a care pathway from initial identification of symptoms to long‐term management. Participants in the booklet group whose symptoms continued 6 months after recruitment were offered consultation with the gastroenterologist and, if appropriate, investigation and treatment. Participants in the nurse‐led care group were crossed over to the gastroenterologist‐led care group if they had gastrointestinal issues that were beyond the scope of the algorithm	Pair‐wise mean difference in change in IBDQ‐B score between groups: Gastroenterologist versus booklet: 5.47 (95% CI 1.14 to 9.81; P = 0.01) Nurse versus booklet: 4.12 (95% CI 0.04 to 8.19; P = 0.04) “Outcomes in the nurse group were not inferior to outcomes in the gastroenterologist group (mean difference 1.36; one sided 95% CI –1.48).” “No statistical analysis between the three groups was planned for the second time point at 12 months as a result of the crossover from booklet to gastroenterologist group.”	Low due to high risk of bias and imprecision (lower boundary of CI seems to be lower than the minimal important difference)
			Mean IBDQ‐B (SD) (10 = worst possible outcome, 70 = best possible outcome) At 6 months: Gastroenterologist group versus booklet group: 62.3 (8.4) versus 57.5 (12.9) (MD 4.80, 95% CI ‐0.52 to 10.12)	Low due to high risk of bias and imprecision (CI includes both benefits and harms)
			Mean IBDQ‐B (SD) (10 = worst possible outcome, 70 = best possible outcome) At 6 months: Nurse group versus booklet group: 62.0 (10.2) versus 57.5 (12.9) (MD 4.50, 95% CI ‐0.99 to 9.99) Gastroenterologist group versus nurse group: 62.3 (8.4) versus 62.0 (10.2) (MD 0.30, 95% CI ‐2.99 to 3.59)	Moderate due to high risk of bias
			St Mark’s incontinence score, median (range) (0 = perfect continence, 24 = total incontinence) At 6 months: Booklet group: 6.5 (0 to 22) Gastroenterologist group: 5 (0 to 20) Nurse group: 4.5 (0 to 18)	Moderate due to high risk of bias
			Change in rectal SOMA‐LENT, mean (SD) (best possible score = 0, worst = 56) At 6 months: Gastroenterologist group versus booklet group: ‐0.10 (0.17) versus ‐0.04 (0.2) (MD ‐0.06, 95% CI ‐0.15 to 0.03) Nurse group versus booklet group: ‐0.12 (0.17) versus ‐0.04 (0.2) (MD ‐0.08, 95% CI ‐0.17 to 0.01) Gastroenterologist group versus nurse group: ‐0.10 (0.17) versus ‐0.12 (0.17) (MD 0.02, 95% CI ‐0.04 to 0.08)	Low due to high risk of bias and imprecision (CI includes both benefits and harms)
			Change in small intestine SOMA‐LENT, mean (SD) (best possible score = 0, worst = 52) At 6 months: Gastroenterologist group versus booklet group: ‐0.10 (0.12) versus –0.04 (0.15) (MD ‐0.06, 95% CI ‐0.12 to 0.00) Nurse group versus booklet group: ‐0.09 (0.12) versus –0.04 (0.15) (MD ‐0.05, 95% CI ‐0.11 to 0.01) Gastroenterologist group versus nurse group: ‐0.10 (0.12) versus ‐0.09 (0.12) (MD ‐0.01, 95% CI ‐0.05 to 0.03)	Low due to high risk of bias and imprecision (CI includes both benefits and harms)
			12‐Item Short Form Health Survey quality of life Physical component summary scales, mean change in score (SD) At 6 months: Gastroenterologist group versus booklet group: 3.30 (10.18) versus ‐0.26 (6.79) (MD 3.56, 95% CI ‐0.09 to 7.21) Nurse group versus booklet group: ‐0.57 (6.63) versus ‐0.26 (6.79) (MD ‐0.31, 95% CI ‐3.36 to 2.74) Gastroenterologist group versus nurse group: 3.30 (10.18) versus ‐0.57 (6.63) (MD 3.87, 95% CI 0.79 to 9.95)	Low due to high risk of bias and imprecision (lower boundary of CI seems to be lower than the minimal important difference)
			Mental component summary scales, mean change in score (SD) At 6 months: Gastroenterologist group versus booklet group: ‐1.42 (9.44) versus 0.32 (8.01) (MD ‐1.74, 95% CI ‐5.60 to 2.12) Nurse group versus booklet group: 0.53 (8.06) versus 0.32 (8.01) (MD 0.21, 95% CI ‐3.42 to 3.84) Gastroenterologist group versus nurse group: ‐1.42 (9.44) versus 0.53 (8.06) (MD ‐1.95, 95% CI ‐5.08 to 1.18) “HAD anxiety seemed to improve at 6 months, but HAD depression seemed to worsen, which is possibly related to very large changes in scores from baseline in a small number of individuals at 6 months”	Low due to high risk of bias and imprecision (CI includes both benefits and harms)
Clarke 2008	Late rectal radiation tissue injury present for >= 3 months that has not responded sufficiently to other therapies	100% oxygen at 2.0 ATA for 90 min, once daily, 5 times weekly (n = 75) (30 sessions) versus 21% oxygen (normal air) at 1.1 ATA for 90 min (sham treatment), once daily, 5 times weekly (n = 75) (30 sessions)	SOMA‐LENT score (improvement) 5.00 versus 2.61 (MD (based on repeated measurements model) 1.93, 95% CI 0.38 to 3.48) The decrease was greater in the hyperbaric oxygen group (P = 0.0019)	Moderate due to imprecision (OIS not reached)
			Clinical evaluation Proportion healed or improved: 56/63 (88.9%) versus 35/65 (62.5%) (RR 1.42, 95% CI 1.14 to 1.77) (OR for improvement (based on repeated measurements model) 5.93, 95% CI 2.04 to 17.24)	Moderate due to imprecision (OIS not reached)
			QoL Improvement on Expanded Prostate Cancer Index Composite QoL: Bowel bother: 14% versus 5% Bowel function: 9% versus 6%	Low due to imprecision (results not quantified and OIS not reached)
			Harms 19 (15.8%) participants complained of ear pain or discomfort, of which 7 had tympanic membrane changes consistent with with barotrauma, and 1 had both tympanic membrane injury and middle ear effusion	Low due to imprecision (results not presented per group and OIS not reached)
Ehrenpreis 2005	Eligible people were more than 6 months post‐pelvic radiotherapy and had significant symptoms as measured with the RPSAS	Retinol palmitate 10,000 IU by mouth for 90 days (n = 10) versus Identical placebo capsules (n = 9)	Response to treatment 7/9 versus 2/8 (RR 3.11, 95% CI 0.89 to 10.86)	Low due to very serious imprecision (CI includes both benefits and harms; very small sample size)
Ehrenpreis 2005			Mean pre‐post‐treatment change in RPSAS 11 +/‐ 5 versus 2.5 +/‐ 3.6 (P = 0.013, Mann‐Whitney U test) "One patient from each group enrolled in the study but did not take a single dose of medication and was therefore excluded from analysis"	Low due to very serious imprecision (OIS not reached and very small sample size)
Tian 2008	People diagnosed with chronic rectal radiation damage	Intergrated Chinese traditional plus Western medicine (smectite powder 6 g, dexamethasone 5 mg, levofloxacin hydrochloride 0.2 g, anisodamine 10 mg, and physiological saline 100 ml) (n = 32) versus Western medicine (smectite powder 6 g, dexamethasone 5 mg, levofloxacin hydrochloride 0.2 g, anisodamine 10 mg, and physiological saline 100 ml) (n = 26)	Grade of radioproctitis after treatment (defined according to colonoscopy test results) Grade 0 to 1: 22/32 versus 7/26 (RR 2.55, 95% CI 1.30 to 5.02)	Low due to high RoB and imprecision (OIS not reached)
Tian 2008	People diagnosed with chronic rectal radiation damage		Treatment effect after 37 days Cured‐better: 30 to 32 versus 14 to 26 (RR 1.74, 95% CI 1.21 to 2.51)	Low due to high RoB and imprecision (OIS not reached)

ATA: atmosphere absolute
CI: confidence interval
IBDQ‐B: Inflammatory Bowel Disease Questionnaire–Bowel
MD: mean difference
OR: odds ratio
QoL: quality of life
RPSAS: Radiation Proctopathy System Assessments Scale
RR: risk ratio
SD: standard deviation
SOMA‐LENT: Subjective, Objective, Management, Analytic ‐ Late Effects of Normal Tissue
HAD: Hospital Anxiety Depression
OIS: Optimal Information Size

Hyperbaric oxygen therapy versus placebo

One study included 150 participants with refractory radiation proctopathy who were randomised to hyperbaric oxygen at 2.0 atmospheres absolute or air at 1.1 atmospheres absolute (sham treatment) (Clarke 2008). The sham participants were subsequently crossed to group 1 (however, only the results before the cross‐over are reported here). We considered this study to be at unclear risk of bias. A decrease (improvement) of the Subjective, Objective, Management, Analytic ‐ Late Effects of Normal Tissue (SOMA‐LENT) score of 5.00 points occurred in the intervention group, and a decrease of 2.61 points in the sham group. The decrease was significantly larger in the intervention group than in the sham group (P = 0.0019). The proportion of responders (healed, significant improvement, or modest improvement versus no improvement) in the intervention group was higher than in the sham group (88.9% versus 62.5%, respectively; RR 1.42, 95% CI 1.14 to 1.77) (Analysis 9.1). Based on a repeated measures logistic model, the odds ratio for improvement was 5.93 (95% CI 2.04 to 17.24), of which a risk difference was derived of 0.32 (32%) resulting in a number needed to treat for an additional beneficial outcome of 3. With respect to bowel‐specific QoL marked improvement was noted for the intervention group after treatment but not for the sham group (14% for bowel bother and 9% for bowel function versus 5% and 6%, respectively).

Retinol palmitate (Vitamin A) versus placebo

One study randomised 19 participants with radiation proctopathy to either retinol palmitate (10,000 IU by mouth for 90 days) or placebo (Ehrenpreis 2005). We considered this study to be at unclear risk of bias. Response was defined as a reduction in two or more symptoms by at least two Radiation Proctopathy System Assessments Scale (RPSAS) points. Seven out of nine retinol palmitate participants responded, whereas 2/8 placebo participants responded (RR 3.11, 95% CI 0.89 to 10.86) (Analysis 10.1). Mean pre‐post‐treatment change in RPSAS score in the retinol palmitate group was 6 to 16 and ‐1.1 to 6.1 in the placebo group (P = 0.013).

Gastroenterologist‐led algorithm‐based treatment versus nurse‐led algorithm‐based treatment versus usual care

One study compared the efficacy of a gastroenterologist‐led algorithm‐based treatment with a nurse‐led algorithm‐based treatment or with usual care (a detailed self help booklet) (Andreyev 2013). The algorithm provided a step‐by‐step approach along a care pathway from initial identification of symptoms to long‐term management. The study randomised 218 participants (18 years of age and older) with new‐onset gastrointestinal symptoms persisting 6 months after pelvic radiotherapy were randomised to one of the three arms. We considered the risk of bias of this study to be high. The primary endpoint was change in Inflammatory Bowel Disease Questionnaire–Bowel subset score (IBDQ‐B) at six months, on which the following pair‐wise mean differences in change in IBDQ‐B score between groups were recorded: nurse versus booklet 4.12 (95% CI 0.04 to 8.19), gastroenterologist versus booklet 5.47 (1.14 to 9.81). Outcomes in the nurse group were not inferior to outcomes in the gastroenterologist group (MD 1.36, one‐sided 95% CI –1.48). When considering IBDQ‐B at six months, a MD of 4.80 (95% CI ‐0.52 to 10.12) was found for the gastroenterologist versus booklet group; a MD of 4.50 (95% CI ‐0.99 to 9.99) for the nurse versus booklet group; and a MD of 0.30 (95% CI ‐2.99 to 3.59) for the gastroenterologist versus nurse group (Analysis 11.1). No significant differences were found on change in rectal and small intestine SOMA‐LENT at six months (Analysis 11.2; Analysis 11.3). A significant difference on the SF12 QoL physical component summary scales was found for the gastroenterologist group versus nurse group (MD 3.87, 95% CI 0.79 to 9.95) (Analysis 11.4). No other significant differences were found for QoL outcomes (Analysis 11.4; Analysis 11.5).

Chinese traditional medicine plus Western medicine versus Western medicine alone

One study published in Chinese randomised 58 participants with rectal radiation proctopathy to either integrated Chinese traditional medicine plus Western medicine or Western medicine alone (Tian 2008). We considered this study to be at high risk of bias. Significant differences in grade of proctopathy after treatment (defined according to colonoscopy test results) in favour of the treatment group (Chinese traditional medicine) were found (Grade 0 to 1: RR 2.55, 95% CI 1.30 to 5.02) (Analysis 12.1). Also, the treatment effect after 37 days showed a significant difference in favour of the treatment group (Cured‐better: RR 1.74, 95% CI 1.21 to 2.51) (Analysis 12.2).

Discussion

This review included 13 studies that assessed non‐surgical interventions for the management of late radiation proctopathy, 2 that assessed non‐surgical interventions for a broader spectrum of symptoms, and 1 that evaluated a gastroenterologist‐led algorithm for the broader pelvic radiation disease.

Summary of main results

Nine studies assessed treatments for bleeding only, of which five were at unclear risk of bias (Chruscielewska 2012; Jensen 1997; Kochhar 1991; Lenz 2010; Pinto 1999), and four were at high risk of bias (Nelamangala 2012; Rougier 1992; Sahakitrungruang 2012; Venkitaraman 2008). Of these, five studies compared different active interventions with each other, three studies assessed the effect of the addition of one intervention to another intervention, and one study was placebo controlled. We only found significant differences in our primary outcomes for the studies that assessed argon plasma coagulation (APC) followed by oral sucralfate versus APC with placebo (significant difference in endoscopic score 6 to 9 at week 8 in favour of APC with placebo) (Chruscielewska 2012); formalin dab treatment (4%) versus sucralfate steroid retention enema (significant difference in favour of formalin on symptom score after treatment (graded by the Radiation Proctopathy System Assessments Scale and sigmoidoscopic score)) (Nelamangala 2012); colonic irrigation plus ciprofloxacin and metronidazole versus formalin application (4%) (significant difference in favour of colonic irrigation on the outcomes bleeding, urgency, and diarrhoea) (Sahakitrungruang 2012).

Three studies assessed treatments targeted at more than one symptom, yet confined to the anorectal region, of which one was at unclear risk of bias (Talley 1997), and two were at high risk of bias (Cavcic 2000; Yeoh 2013). Of these, one study assessed the effect of interventions in addition to other interventions (Cavcic 2000), one study compared two active interventions with each other (Yeoh 2013), and another was placebo controlled (Talley 1997). We identified no significant differences in our primary outcomes.

Four studies assessed treatments targeted at the collection of symptoms referred to as pelvic radiation disease, of which two studies were at unclear risk of bias (Clarke 2008; Ehrenpreis 2005), and two were at high risk of bias (Andreyev 2013; Tian 2008). Two studies compared various interventions with each other (Andreyev 2013; Tian 2008), and two studies were placebo controlled (Clarke 2008; Ehrenpreis 2005). Significant differences were found for the studies that assessed gastroenterologist‐led algorithm‐based treatment versus usual care (a detailed self help booklet) (significant difference in favour of gastroenterologist‐led algorithm‐based treatment on the outcome change in Inflammatory Bowel Disease Questionnaire–Bowel subset score (IBDQ‐B) score at six months) and nurse‐led algorithm‐based treatment versus usual care (significant difference in favour of the nurse‐led algorithm‐based treatment on the outcome change in IBDQ‐B score at six months), hyperbaric oxygen therapy (at 2.0 atmospheres absolute) versus sham treatment (SOMA‐LENT score (improvement) in favour of hyperbaric oxygen therapy), retinol palmitate versus placebo (significant difference in favour of retinol palmitate on the outcome improvement in RPSAS) and integrated Chinese traditional plus Western medicine versus Western medicine (significant difference in favour of integrated Chinese traditional medicine with respect to grade 0 to 1 radioproctitis after treatment (defined according to colonoscopy test results)).

Pooling outcomes for a meta‐analysis was impossible due to the lack of a common standard therapy and variation in study characteristics and endpoints across the included studies.

Overall completeness and applicability of evidence

Well‐conducted randomised trials investigating non‐surgical interventions for late radiation proctopathy are scarce. All included RCTs reported our primary outcome 'response of the presenting symptoms as recorded with diaries and scoring systems'. Interpretation and applicability of the evidence was limited, since many of the reported trials tended to focus mainly on rectal bleeding, whereas radiation‐associated proctopathy is more complex, and in itself only one aspect of what may be labelled pelvic radiation disease (Andreyev 2010). A number of studies have explicitly examined rectal bleeding, which may be a very dominant and well‐measurable symptom of radiation proctopathy. Though the results from these studies only relate to the reduction of rectal bleeding, they are still relevant. One of the treatments often used in clinical practice to reduce rectal bleeding is argon plasma coagulation. We found no placebo‐controlled trials investigating the effect of this treatment. However, it is remarkable that the studies comparing this treatment to other forms of coagulation or formalin showed no significant differences, but very high effect rates on rectal bleeding in both treatment arms (Jensen 1997; Lenz 2010; Yeoh 2013). Other studies also investigated the improvement of other clinical symptoms, but used different scales to score this, so comparison is difficult.

Some interventions showed a significant improvement of symptoms, such as hyperbaric oxygen therapy, retinol palmitate, and adding metronidazole to the anti‐inflammatory regimen. Chinese traditional medicine improved colonoscopic results. Some treatments were significantly better than others, suggesting at least some efficacy (such as rectal sucralfate suspension, colonic irrigation, and formalin dab). Since there is no common standard for the treatment of late radiation proctopathy, these results are even more difficult to interpret or compare. We could not compare the largest study in this review, Andreyev 2013, with 218 participants, to any of the other studies because the study investigates the logistic application of an algorithm (by medical specialist, nurse, or a self help booklet), in which a number of the aforementioned treatments are represented as 'standard', dependent of the symptoms of the participants.

Quality of the evidence

Using GRADE we downgraded the level of evidence for the majority of outcomes to low or very low, mainly due to imprecision and study limitations. Most included studies had small sample sizes. Only 4 out of 16 studies included more than 100 participants, and 9 of 16 fewer than 40 participants. Eight studies compared two active interventions against each other without a placebo‐controlled group, making it difficult to draw conclusions about the results of these studies. The best evidence for the effectiveness were the placebo‐controlled studies. Of the two placebo‐controlled studies with a positive result, the study investigating hyperbaric oxygen therapy has the highest level of evidence given the sample size (150 participants), but had an uncertain risk of bias (Clarke 2008). The other positive placebo‐controlled study (retinol palmitate) had a low risk of bias, but included only 19 participants.

Potential biases in the review process

We performed a comprehensive search in several electronic databases, however we did not search for conference abstracts. To overcome this, we did search a prospective trial register. In addition, the previous version of this review included both randomised and non‐randomised studies. In this update, we included only RCTs, as we felt that the benefit of including non‐randomised studies did not outweigh the risk of including them, as non‐randomised studies suffer from very high risk of bias.

Agreements and disagreements with other studies or reviews

Although we did not systematically search for reviews assessing non‐surgical interventions for late radiation proctopathy, we did identify the reviews of Do 2011, Hanson 2012, and Wilson 2006, which concluded that studies assessing treatments for late radiation proctopathy are few and suffer from small sample sizes and short follow‐up times, and that more and larger randomised placebo‐controlled studies are needed to prospectively look at both the prevention and treatment of late radiation proctopathy. The study of Wilson 2006 also concluded that a standardised system of classification of late radiation proctopathy would assist with interpretation of study results. These findings are in line with the results and conclusions of the present review.

The previous version of this review also included a phase II study, which we moved to the ongoing studies section. The conclusions of the previous versions of this review are in line with the conclusions of the present review.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Analysis 1.1

Comparison 1 Short chain fatty acid (SCFA) enemas versus placebo, Outcome 1 Mean reduction of endoscopic score after treatment.

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Analysis 1.2

Comparison 1 Short chain fatty acid (SCFA) enemas versus placebo, Outcome 2 Mean number of days of rectal bleeding after treatment.

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Analysis 1.3

Comparison 1 Short chain fatty acid (SCFA) enemas versus placebo, Outcome 3 Mean haemoglobin levels at the end of treatment period (5 weeks).

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Analysis 2.1

Comparison 2 Endoscopic argon plasma coagulation (APC) plus oral sucralfate versus APC plus placebo, Outcome 1 Endoscopy scores Gilinsky scale grade 6‐9 at 8 weeks.

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Analysis 2.2

Comparison 2 Endoscopic argon plasma coagulation (APC) plus oral sucralfate versus APC plus placebo, Outcome 2 Endoscopy scores Gilinsky scale grade 6‐9 at 16 weeks.

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Analysis 2.3

Comparison 2 Endoscopic argon plasma coagulation (APC) plus oral sucralfate versus APC plus placebo, Outcome 3 Number of participants with complications.

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Analysis 3.1

Comparison 3 Endoscopic bipolar electrocoagulation versus heater probe, Outcome 1 Severe bleeding episodes.

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Analysis 3.2

Comparison 3 Endoscopic bipolar electrocoagulation versus heater probe, Outcome 2 Mean number of severe bleeds after first year.

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Analysis 3.3

Comparison 3 Endoscopic bipolar electrocoagulation versus heater probe, Outcome 3 Mean haematocrit after first year.

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Analysis 3.4

Comparison 3 Endoscopic bipolar electrocoagulation versus heater probe, Outcome 4 Mean units of blood transfused after first year.

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Analysis 4.1

Comparison 4 APC versus bipolar electrocoagulation, Outcome 1 Eradication of all telangiectasias.

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Analysis 4.2

Comparison 4 APC versus bipolar electrocoagulation, Outcome 2 Complications ‐ Minor.

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Analysis 4.3

Comparison 4 APC versus bipolar electrocoagulation, Outcome 3 Complications ‐ Major.

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Analysis 4.4

Comparison 4 APC versus bipolar electrocoagulation, Outcome 4 Relapse.

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Analysis 5.1

Comparison 5 Hydrocortisone versus betamethasone, Outcome 1 Improvement of endoscopic appearance.

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Analysis 5.2

Comparison 5 Hydrocortisone versus betamethasone, Outcome 2 Reduction of rectal bleeding.

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Analysis 5.3

Comparison 5 Hydrocortisone versus betamethasone, Outcome 3 Poor tolerance of enema.

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Analysis 6.1

Comparison 6 Standard treatment plus oral pentoxifylline versus standard treatment, Outcome 1 Cessation of rectal bleeding.

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Analysis 7.1

Comparison 7 Oral sulfasalazine plus rectal steroids versus oral placebo plus rectal sucralfate, Outcome 1 Clinical improvement.

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Analysis 7.2

Comparison 7 Oral sulfasalazine plus rectal steroids versus oral placebo plus rectal sucralfate, Outcome 2 Endoscopic improvement.

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Analysis 8.1

Comparison 8 Metronidazole in addition to mesalazine and betamethasone versus no metronidazole, Outcome 1 Rectal bleeding score < 2 after 1 year.

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Analysis 8.2

Comparison 8 Metronidazole in addition to mesalazine and betamethasone versus no metronidazole, Outcome 2 Diarrhoea score < 2 after 1 year.

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Analysis 8.3

Comparison 8 Metronidazole in addition to mesalazine and betamethasone versus no metronidazole, Outcome 3 No rectal erythema after 1 year.

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Analysis 8.4

Comparison 8 Metronidazole in addition to mesalazine and betamethasone versus no metronidazole, Outcome 4 No rectal ulceration after 1 year.

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Analysis 9.1

Comparison 9 Hyperbaric oxygen therapy versus placebo, Outcome 1 Clinical evaluation ‐ healed or improved.

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Analysis 10.1

Comparison 10 Retinol palmitate versus placebo, Outcome 1 Response to treatment.

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Analysis 11.1

Comparison 11 Algorithm‐based management, Outcome 1 Bowel subset score (IBDQ‐B) at 6 months (higher score indicates better).

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Analysis 11.2

Comparison 11 Algorithm‐based management, Outcome 2 Change in rectal SOMA‐LENT at 6 months.

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Analysis 11.3

Comparison 11 Algorithm‐based management, Outcome 3 Change in small intestine SOMA‐LENT at 6 months.

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Analysis 11.4

Comparison 11 Algorithm‐based management, Outcome 4 SF12: change in physical component score at 6 months.

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Analysis 11.5

Comparison 11 Algorithm‐based management, Outcome 5 SF12: change in mental component score at 6 months.

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Analysis 12.1

Comparison 12 Integrated Chinese traditional medicine plus Western medicine versus Western medicine, Outcome 1 Grade of radioproctitis after treatment Grade I.

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Analysis 12.2

Comparison 12 Integrated Chinese traditional medicine plus Western medicine versus Western medicine, Outcome 2 Cured ‐ better after 37 days.

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Table 1. Treatment for bleeding only

Study ID	Participant characteristics	Intervention(s)	Results	Level of evidence (GRADE)
Chruscielewska 2012	Adults with chronic radiation proctopathy or proctosigmoiditis were included if all of the following criteria were met: radiotherapy for a pelvic tumour completed at least 3 months before enrolment, the presence of rectal bleeding, radiation‐induced telangiectasia in the rectum and/or sigmoid colon on endoscopy, informed written consent by the person to participate in the study	Endoscopic APC followed by oral sucralfate (6 g twice daily) for 4 weeks (n = 60) versus APC with placebo administration for 4 weeks (n = 62)	Changes in chronic radiation proctopathy severity score (based on scales previously proposed by Chutkan et al. and Kochhar et al., median (interquartile range)) Overall severity score Week 8: 2 (1.3) versus 2 (1.3) Week 16: 2 (1.3) versus 2 (1.3) Week 52: 1 (1.2) versus (1.2) P > 0.05 for all between‐group comparisons	Moderate due to imprecision (precision not quantified)
			Diarrhoea score Week 8: 1 (1.1) versus 1 (1.1) Week 16: 1 (1.1) versus 1 (1.1) Week 52: 1 (1.1) versus 1 (1.1) P > 0.05 for all between‐group comparisons	Moderate due to imprecision (precision not quantified)
			Bleeding score Week 8: 1 (0.1) versus 0 (0.1) Week 16: 0 (0.1) versus 0 (0.1) Week 52: 0 (0.1) versus 0 (0.0) P > 0.05 for all between‐group comparisons	Moderate due to imprecision (precision not quantified)
			Tenesmus ⁄ rectal pain score Week 8: 0 (0.1) versus 0 (0.1) Week 16: 0 (0.0) versus 0 (0.1) Week 52: 0 (0.0) versus 0 (0.0) P > 0.05 for all between‐group comparisons	Moderate due to imprecision (precision not quantified)
			Endoscopy scores (graded according to the Gilinsky scale as endoscopic severity score) Score 6 to 9: Week 8: 20 to 59 versus 9 to 60 (RR 2.26, 95% CI 1.12 to 4.55) Week 16: 10 to 57 versus 8 to 60 (RR 1.32, 95% CI 0.56 to 3.10)	‐
			Complications Number (%) of people with complications: 38/60 (63%) versus 36/62 (58%) (RR 1.09, 95% CI 0.82 to 1.45)	Moderate due to imprecision (CI includes both benefits and harms)
			APC‐related complications Asymptomatic rectal ulcer: 30 versus 30 Symptomatic rectal ulcers: 7 versus 5 Rectovaginal fistula: 2 versus 0 Adynamic ileus: 0 versus 1	Low due to very serious limitations for imprecision (CI includes both benefits and harms)
			Other complications Severe constipation: 4 versus 0 Urticaria: 1 versus 0	‐
			Complication severity (APC‐related) Severe + fatal: 2/60 versus 0/62 (RR 5.17, 95% CI 0.25 to 105.4) P > 0.05 for all between‐group comparisons regarding complications	Low due to very serious imprecision (CI includes both benefits and harms)
Jensen 1997	People being considered for surgery, having failed 1 year of medical therapy, pelvic radiotherapy for a cancer at least 2 years earlier, rectal bleeds at least 3 times per week, anaemia, and a life expectancy of at least 2 years	Bipolar electrocoagulation (n = 12) versus Heater probe (n = 9)	Severe bleeding episodes after 1 year (measured by participant interview) 3/12 (33%) versus 1/9 (11%) (RR 2.25, 95% CI 0.28 to 18.22)	Low due to very serious imprecision (CI includes both benefits and harms)
			Mean number of severe bleeds after 1 year, mean (SD) (measured by participant interview) 0.3 (0.3) versus 0.4 (0.9) (MD ‐0.10, 95% CI ‐0.71 to 0.51)	Low due to very serious imprecision (CI includes both benefits and harms)
			Mean haematocrits after 1 year, mean (SD) 38.2 (4.8) versus 37.6 (3.0) (MD 0.60, 95% ‐2.75 to 3.95)	Low due to very serious imprecision (CI includes both benefits and harms)
			Mean units of red blood cells transfused after 1 year, mean (SD) 0.0 (0.0) versus 0.2 (0.6) (MD not estimable)	Low due to very serious imprecision (OIS not reached)
			Complications No major complications occurred
			QoL QoL informally assessed with participant responses, which improved with treatment
Kochhar 1991	Symptomatic radiation‐induced proctosigmoiditis	Oral sulfasalazine (500 mg tds) + rectal prednisolone (20 mg bd) for 4 weeks (n = 8) versus Oral placebo + rectal sucralfate suspension (2 g bd) for 4 weeks (n = 19)	Clinical improvement at 4 weeks (an in‐house scoring system was used measuring diarrhoea, bleeding per rectum, bleeding requiring blood transfusion, and tenesmus) 8 to 15 versus 16 to 17 (RR 0.57, 95% CI 0.35 to 0.92)	Low due to unclear RoB and imprecision (OIS not reached)
			Endoscopic improvement at 4 weeks (injury was graded according to the criteria of Gilinsky et al.) 7 to 15 versus 12 to 17 (RR 0.66, 95% CI 0.35 to 1.23)	Very low due to unclear RoB and very serious imprecision (CI includes both benefits and harms)
			Side effects at 4 weeks (participants were questioned and examined for any side effects of the medication) 2 participants in the sulfasalazine group did not tolerate the drugs due to myalgia, nausea, and headaches	Very low due to unclear RoB and very serious imprecision (very small sample size)
Lenz 2010	Recurrent rectal bleeding, started 6 months after radiotherapy with at least 1 bleeding episode in the week before and endoscopically confirmed radiation telangiectasias	APC (n = 15) versus Bipolar electrocoagulation (n = 15)	Eradication of all telangiectasias at 1 year 12/15 versus 14/15 (RR 0.86, 95% CI 0.64 to 1.14)	Low due to indirectness and imprecision (CI includes both benefits and harms)
			Complications Minor: 5/15 versus 10/15 (RR 0.50, 95% CI 0.22 to 1.11) Major: 1/15 versus 5/15 (RR 0.20, 95% CI 0.03 to 1.51)	Low due to very serious imprecision (CI includes both benefits)
			Relapse 1/12 versus 2/14 (RR 0.58, 95% CI 0.06 to 5.66)	Low due to very serious imprecision (CI includes both benefits and harms)
Nelamangala 2012	Rectal bleeding as a result of chronic haemorrhagic radiation proctopathy, following radiotherapy for carcinoma of the cervix	Formalin dab treatment (4%) as an outpatient procedure (formalin applied directly to each lesion via a rigid sigmoidoscope or a proctoscope under local anaesthesia. Under direct vision, a small piece of gauze soaked in 4% formalin was applied to the haemorrhagic areas for 2 min until the mucosa turned pale) (n = 51) versus Sucralfate steroid retention enema (100 mg of prednisolone and 1 g of sucralfate in 100 ml of normal saline), twice daily for 7 to 10 days (n = 51)	Symptom score after treatment (graded by the RPSAS), median (range) 9 (6 to 24) versus 13 (8 to 27) (P < 0.001)	Low due to high risk of bias and imprecision (OIS not reached)
			Sigmoidoscopic score (median (range) after treatment) 1 (0 to 3) versus 2 (0 to 3) (P < 0.001)	Very low due to high risk of bias, imprecision and indirectness (OIS not reached)
			Adverse events “Mild pain occurred in 33.3% patients in Group 1 during the application of formalin but this subsided within 1 day. There were no complications in Group 2.”	Low due to high risk of bias and imprecision (OIS not reached)
Pinto 1999	Clinical and histological diagnosis of chronic radioproctitis: Grade III Pourquier classification with rectal bleeding at least once a week, persistent symptoms for a minimum of 12 months (except 1 participant)	SCFA enema (as per Harig preparation 60 ml bd 5 weeks) (n = 10) versus Placebo: identically appearing enemas containing saline isotonic solution, bd 5 weeks (n = 9)	Mean endoscopic score after 5 weeks, mean (SD) 2.6 (1.8) versus 1.6 (4.2) (MD 1.00, 95% CI ‐2.33 to 4.33)	Low due to indirectness and imprecision (CI includes both benefits and harms)
			Number of days of rectal bleeding at the end of treatment (after 5 weeks), mean (SD) (participant diary) 1.4 (2.2) versus 3.4 (2.6) (MD ‐2.00, 95% CI ‐4.40 to 0.40)	Low due to very serious imprecision (CI includes both benefits and harms)
			Haemoglobin levels after 5 weeks, mean (SD) 13.1 ± 0.9 g/dl versus 10.7 ± 2.1 g/dl (MD 2.40, 95% CI 0.74 to 4.06)	Low due to imprecision (very small sample size)
Rougier 1992	Chronic radiation proctopathy confirmed and graded on sigmoidoscopy	Hydrocortisone acetate mousse 90 mg bd for 4 weeks (n = 16) versus Betamethasone lavage 5 mg od for 4 weeks (n = 16)	Improvement of endoscopic appearance 12/16 versus 5/14 (RR 2.10, 95% CI 0.98 to 4.48)	Very low due to high RoB, indirectness, and imprecision (CI includes both benefits and harms)
			Reduction of degree of bleeding (an in‐house scoring system was used) 6/16 versus 3/14 (RR 1.75, 95% CI 0.53 to 5.73)	Very low due to high RoB and very serious imprecision (CI includes both benefits and harms)
			Poor tolerance of enema 2/16 versus 10/14 (RR 0.17, 95% CI 0.05 to 0.67)	Low due to high RoB and imprecision (OIS not reached)
Sahakitrungruang 2012	Symptomatic haemorrhagic radiation proctopathy for more than 6 months without complications of rectal stricture, deep ulceration, fistula formation, or sepsis	Colonic irrigation (with 1000 ml of tap water via a 20F Foley catheter) plus ciprofloxacin (500 mg twice daily) and metronidazole (500 mg 3 times daily) by mouth for 1 week (n = 25) versus Formalin application in an office setting (4% formalin‐soaked gauze applied for 3 minutes under direct vision by using proctoscopy followed by immediate cleansing with water irrigation) (n = 25)	Comparison between the 2 treatment groups after 8 wks of treatment (measured by participant survey) Bleeding (days/week) median (min,max) ‐5 (‐7,0) versus ‐2 (‐7,4) (P = 0.007)	Low due to high RoB and imprecision (OIS not reached)
			Frequency (times/day) ‐2 (‐8,2) versus ‐2 (‐4,2) (P = 0.09)	Low due to high RoB and imprecision (OIS not reached)
			Urgency (days/week) ‐2 (‐7,3) versus 0 (‐2,7) (P = 0.0004)	Low due to high RoB and imprecision (OIS not reached)
			Diarrhoea (days/week) ‐2 (‐6,0) versus 0 (‐7,2) (P = 0.007)	Low due to high RoB and imprecision (OIS not reached)
			Tenesmus (days/week) ‐2 (‐7,0) versus 0 (‐4,4) (P = 0.07)	Low due to high RoB and imprecision (OIS not reached)
			Haematocrit (mg/dL) 0 (‐9,10) versus 0 (‐7,18) (P = 0.86)	Low due to high RoB and imprecision (OIS not reached)
			Vienna rectoscopy score after 8 wks of treatment No significant differences between groups (P = 0.78)	Low due to high RoB and imprecision (OIS not reached)
			Adverse events after 8 wks of treatment "There were no serious adverse drug reactions." "Four patients in the irrigation group and 8 patients in the formalin group required blood transfusion during the study, but this finding did not reach the statistic difference."	Low due to high RoB and imprecision (OIS not reached)
			Patient satisfaction 20/24 versus 10/23 (RR 1.92, 95% CI 1.16 to 3.16)	Low due to high RoB and imprecision (OIS not reached)
Venkitaraman 2008	Symptomatic late morbidity with at least 1 episode of rectal bleeding more than 6 months since pelvic radiotherapy	Standard therapies for late radiation‐induced bleeding plus oral pentoxifylline (400 mg) 3 times daily for 6 months (n = 20) versus Standard treatment for late radiation‐induced bleeding (n = 20)	Cessation of rectal bleeding (measured using a daily participant symptom diary) 16/20 versus 12/20 (RR 1.33, 95% CI 0.88 to 2.03)	Very low due to high RoB and very serious imprecision (CI includes both benefits and harms)
			Median time to cessation of bleeding (measured using a daily participant symptom diary) 22 days (range 1 to 119 days) versus 95 days (range 13 to 172) (P = 0.12) “However, at least one episode of recurrent bleeding occurred in 14 of the 16 patients in the study group and in all the 12 patients who had cessation of bleeding in the control group.”	Low due to high RoB and imprecision (OIS not reached)
			The median duration of freedom from bleeding (measured using a daily participant symptom diary) 12 days (range 8 to 290) versus 11 days (range 7 to 133)	Very low due to high RoB and very serious imprecision (precision not quantified; very small sample size)
			Adverse events “Pentoxifylline was well tolerated with minor side‐effects and the compliance rate was satisfactory. Seven patients required a dose reduction or temporary discontinuation of pentoxifylline, due to dyspepsia in five patients and rashes and chest pain in one patient each, whereas one patient required permanent discontinuation of pentoxifylline due to dyspepsia. Contrary to expectations, one patient had a transient, but significant, increase in serum fibrinogen levels.”	Very low due to high RoB and very serious imprecision (OIS not reached)
APC: argon plasma coagulation bd: 2 times a day CI: confidence interval MD: mean difference od: once a day QoL: quality of life RoB: risk of bias RPSAS: Radiation Proctopathy System Assessments Scale RR: risk ratio SCFA: short chain fatty acid SD: standard deviation tds: 3 times a day OIS: Optimal Information Size

Table 1. Treatment for bleeding only

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Table 2. Treatment targeted at something very localised but not a single pathology

Study ID	Participant characteristics	Intervention(s)	Results	Level of evidence (GRADE)
Cavcic 2000	Chronic radiation proctopathy producing diarrhoea and rectal bleeding	Metronidazole (3 x 400 mg orally per day), mesalazine (3 x 1 g orally per day), and betamethasone enema (once a day) (n = 30) versus Same doses of mesalazine and betamethasone enema, but without metronidazole (n = 30)	Rectal bleeding score < 2, 1 year after treatment (an in‐house scoring system was used) 22/24 versus 5/12 (RR 1.57, 95% CI 0.96 to 2.57)	Very low due to high RoB and very serious imprecision (single study/OIS not reached)
			Diarrhoea score < 2, 1 year after treatment (an in‐house scoring system was used) 23/24 versus 8/12 (RR 1.44, 95% CI 0.96 to 2.16)	Very low due to high RoB and very serious imprecision (single study/CI includes both benefits and harms)
			No rectal ulceration, 1 year after treatment (an in‐house scoring system was used) 22/24 versus 7/12 (RR 1.57, 95% CI 0.96 to 2.57)	Very low due to high RoB and very serious imprecision (single study/CI includes both benefits and harms)
Talley 1997	Symptoms consistent with chronic radiation proctopathy (≥ 2 months)	Butyric acid (SCFA) enema (60 ml containing 40 mmol butyric acid), twice a day, used for 2 weeks versus Normal saline placebo enema NB: this was a cross‐over study with a 1‐week wash‐out period before giving the alternate enema (n = 15 participants were randomised and 12 completed both arms of the study, number of participants per group not specified)	Symptom scores (in‐house scoring system: total symptom score was calculated combining 6 items: rectal pain, rectal bleeding episodes per week, quantity of blood passed, number of days of diarrhoea per week, number of stools per week, and urgency) Mean score 3.5 (range 3 to 5) versus 4.5 (range 3 to 6) (P = 0.3)	Very low due to unclear RoB and very serious imprecision (precision not quantified/small sample size)
			Bleeding 38% versus 38%	Very low due to unclear RoB and very serious imprecision (precision not quantified and OIS not reached)
			Urgency (time in min able to defer defecation) 5 (1 to 42.5) in the placebo group versus 10 (5 to 20) in the treatment group	Very low due to unclear RoB and very serious imprecision (precision not quantified and OIS not reached)
			Days with diarrhoea 1 (1 to 5.5) in the placebo group versus 1 (1 to 2) in the treatment group	Very low due to unclear RoB and very serious imprecision (precision not quantified and OIS not reached)
			Number of stools 1.5 (1 to 3) in the placebo group versus 1.5 (1 to 2.5) in the treatment group	Very low due to unclear RoB and very serious imprecision (precision not quantified and OIS not reached)
			Pain (rectal) 33% in the placebo group versus 8% in the treatment group	Very low due to unclear RoB and very serious imprecision (precision not quantified and OIS not reached)
			“Neither changes in the symptom score nor changes in the individual symptoms were statistically significant”	‐
			“No side effects were reported and there was no QOL assessment” (2 participants experienced problems inserting the enema)	‐
Yeoh 2013	People who had (1) completed external beam radiation therapy for prostate carcinoma ≥ 6 months previously; (2) intractable rectal bleeding, defined as a frequency of ≥ 1x per week and/or requiring blood tranfusions, attributed to chronic radiation proctopathy at colonoscopy; (3) no constant requirement for medications likely to influence anorectal motility, such as opioid analgesic and antidiarrhoeal agents; and (4) provided written informed consent	APC (outpatient procedure) (n = 17) versus Topical formalin (n = 13) NB: cross‐over to the other therapy was allowed if the treatment endpoint was not reached after 4 treatment sessions. 2 microlax enemas were administered before each session of either APC or topical formalin therapy	Anorectal symptom parameters (after treatment), median (range) (measured by SOMA‐LENT and VAS) No. of bowel actions per week: 16 (7 to 46) versus 14 (4 to 42) Faecal incontinence scores: 0 (0 to 4) versus 0 (0 to 2) Urgency of defaecation scores: 4 (0 to 6) versus 4 (0 to 6) Rectal bleeding scores: 1 (0 to 2) versus 1 (0 to 2) VAS for rectal bleeding (mm): 14 (0 to 34) versus 13 (0 to 25) No between‐group comparisons were made	Low due to high risk of bias and imprecision (precision not quantified)
Yeoh 2013			Comparisons of participant outcomes after APC and topical formalin treatment, median (range) (measured by SOMA‐LENT and VAS) Rectal bleeding scores: 1 (0 to 2) versus 1 (0 to 2), NS VAS for rectal bleeding (mm): 14 (0 to 34) versus 13 (0 to 25), NS	Low due to high risk of bias and imprecision (precision not quantified)
APC: argon plasma coagulation CI: confidence interval RR: risk ratio SCFA: short chain fatty acid VAS: visual analogue scale NB: nota bene NS: not significant OIS: Optimal Information Size

Table 2. Treatment targeted at something very localised but not a single pathology

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Table 3. Treatments targeted at the more global collection of symptoms

Study ID	Participant characteristics	Intervention(s)	Results	Level of evidence (GRADE)
Andreyev 2013 (ORBIT)	Adults (aged ≥ 18 years) who had troublesome, persisting gastrointestinal symptoms, started during or after radiotherapy given with curative intent for histologically proven prostatic, bladder, vulval, vaginal, cervical, endometrial, anal, or rectal malignant neoplasia or para‐aortic irradiation for metastatic disease from any of those primary sites or the testis. Radiotherapy should have been completed at least 6 months before enrolment	Gastroenterologist group (management according to an algorithm by a consultant gastroenterologist) (n = 70) versus Nurse group (management according to an algorithm by a specially trained research nurse) (n = 80) versus Booklet group (detailed advice booklet on self management of bowel symptoms) (n = 68) N.B.: the algorithm provides a step‐by‐step approach along a care pathway from initial identification of symptoms to long‐term management. Participants in the booklet group whose symptoms continued 6 months after recruitment were offered consultation with the gastroenterologist and, if appropriate, investigation and treatment. Participants in the nurse‐led care group were crossed over to the gastroenterologist‐led care group if they had gastrointestinal issues that were beyond the scope of the algorithm	Pair‐wise mean difference in change in IBDQ‐B score between groups: Gastroenterologist versus booklet: 5.47 (95% CI 1.14 to 9.81; P = 0.01) Nurse versus booklet: 4.12 (95% CI 0.04 to 8.19; P = 0.04) “Outcomes in the nurse group were not inferior to outcomes in the gastroenterologist group (mean difference 1.36; one sided 95% CI –1.48).” “No statistical analysis between the three groups was planned for the second time point at 12 months as a result of the crossover from booklet to gastroenterologist group.”	Low due to high risk of bias and imprecision (lower boundary of CI seems to be lower than the minimal important difference)
			Mean IBDQ‐B (SD) (10 = worst possible outcome, 70 = best possible outcome) At 6 months: Gastroenterologist group versus booklet group: 62.3 (8.4) versus 57.5 (12.9) (MD 4.80, 95% CI ‐0.52 to 10.12)	Low due to high risk of bias and imprecision (CI includes both benefits and harms)
			Mean IBDQ‐B (SD) (10 = worst possible outcome, 70 = best possible outcome) At 6 months: Nurse group versus booklet group: 62.0 (10.2) versus 57.5 (12.9) (MD 4.50, 95% CI ‐0.99 to 9.99) Gastroenterologist group versus nurse group: 62.3 (8.4) versus 62.0 (10.2) (MD 0.30, 95% CI ‐2.99 to 3.59)	Moderate due to high risk of bias
			St Mark’s incontinence score, median (range) (0 = perfect continence, 24 = total incontinence) At 6 months: Booklet group: 6.5 (0 to 22) Gastroenterologist group: 5 (0 to 20) Nurse group: 4.5 (0 to 18)	Moderate due to high risk of bias
			Change in rectal SOMA‐LENT, mean (SD) (best possible score = 0, worst = 56) At 6 months: Gastroenterologist group versus booklet group: ‐0.10 (0.17) versus ‐0.04 (0.2) (MD ‐0.06, 95% CI ‐0.15 to 0.03) Nurse group versus booklet group: ‐0.12 (0.17) versus ‐0.04 (0.2) (MD ‐0.08, 95% CI ‐0.17 to 0.01) Gastroenterologist group versus nurse group: ‐0.10 (0.17) versus ‐0.12 (0.17) (MD 0.02, 95% CI ‐0.04 to 0.08)	Low due to high risk of bias and imprecision (CI includes both benefits and harms)
			Change in small intestine SOMA‐LENT, mean (SD) (best possible score = 0, worst = 52) At 6 months: Gastroenterologist group versus booklet group: ‐0.10 (0.12) versus –0.04 (0.15) (MD ‐0.06, 95% CI ‐0.12 to 0.00) Nurse group versus booklet group: ‐0.09 (0.12) versus –0.04 (0.15) (MD ‐0.05, 95% CI ‐0.11 to 0.01) Gastroenterologist group versus nurse group: ‐0.10 (0.12) versus ‐0.09 (0.12) (MD ‐0.01, 95% CI ‐0.05 to 0.03)	Low due to high risk of bias and imprecision (CI includes both benefits and harms)
			12‐Item Short Form Health Survey quality of life Physical component summary scales, mean change in score (SD) At 6 months: Gastroenterologist group versus booklet group: 3.30 (10.18) versus ‐0.26 (6.79) (MD 3.56, 95% CI ‐0.09 to 7.21) Nurse group versus booklet group: ‐0.57 (6.63) versus ‐0.26 (6.79) (MD ‐0.31, 95% CI ‐3.36 to 2.74) Gastroenterologist group versus nurse group: 3.30 (10.18) versus ‐0.57 (6.63) (MD 3.87, 95% CI 0.79 to 9.95)	Low due to high risk of bias and imprecision (lower boundary of CI seems to be lower than the minimal important difference)
			Mental component summary scales, mean change in score (SD) At 6 months: Gastroenterologist group versus booklet group: ‐1.42 (9.44) versus 0.32 (8.01) (MD ‐1.74, 95% CI ‐5.60 to 2.12) Nurse group versus booklet group: 0.53 (8.06) versus 0.32 (8.01) (MD 0.21, 95% CI ‐3.42 to 3.84) Gastroenterologist group versus nurse group: ‐1.42 (9.44) versus 0.53 (8.06) (MD ‐1.95, 95% CI ‐5.08 to 1.18) “HAD anxiety seemed to improve at 6 months, but HAD depression seemed to worsen, which is possibly related to very large changes in scores from baseline in a small number of individuals at 6 months”	Low due to high risk of bias and imprecision (CI includes both benefits and harms)
Clarke 2008	Late rectal radiation tissue injury present for >= 3 months that has not responded sufficiently to other therapies	100% oxygen at 2.0 ATA for 90 min, once daily, 5 times weekly (n = 75) (30 sessions) versus 21% oxygen (normal air) at 1.1 ATA for 90 min (sham treatment), once daily, 5 times weekly (n = 75) (30 sessions)	SOMA‐LENT score (improvement) 5.00 versus 2.61 (MD (based on repeated measurements model) 1.93, 95% CI 0.38 to 3.48) The decrease was greater in the hyperbaric oxygen group (P = 0.0019)	Moderate due to imprecision (OIS not reached)
			Clinical evaluation Proportion healed or improved: 56/63 (88.9%) versus 35/65 (62.5%) (RR 1.42, 95% CI 1.14 to 1.77) (OR for improvement (based on repeated measurements model) 5.93, 95% CI 2.04 to 17.24)	Moderate due to imprecision (OIS not reached)
			QoL Improvement on Expanded Prostate Cancer Index Composite QoL: Bowel bother: 14% versus 5% Bowel function: 9% versus 6%	Low due to imprecision (results not quantified and OIS not reached)
			Harms 19 (15.8%) participants complained of ear pain or discomfort, of which 7 had tympanic membrane changes consistent with with barotrauma, and 1 had both tympanic membrane injury and middle ear effusion	Low due to imprecision (results not presented per group and OIS not reached)
Ehrenpreis 2005	Eligible people were more than 6 months post‐pelvic radiotherapy and had significant symptoms as measured with the RPSAS	Retinol palmitate 10,000 IU by mouth for 90 days (n = 10) versus Identical placebo capsules (n = 9)	Response to treatment 7/9 versus 2/8 (RR 3.11, 95% CI 0.89 to 10.86)	Low due to very serious imprecision (CI includes both benefits and harms; very small sample size)
Ehrenpreis 2005			Mean pre‐post‐treatment change in RPSAS 11 +/‐ 5 versus 2.5 +/‐ 3.6 (P = 0.013, Mann‐Whitney U test) "One patient from each group enrolled in the study but did not take a single dose of medication and was therefore excluded from analysis"	Low due to very serious imprecision (OIS not reached and very small sample size)
Tian 2008	People diagnosed with chronic rectal radiation damage	Intergrated Chinese traditional plus Western medicine (smectite powder 6 g, dexamethasone 5 mg, levofloxacin hydrochloride 0.2 g, anisodamine 10 mg, and physiological saline 100 ml) (n = 32) versus Western medicine (smectite powder 6 g, dexamethasone 5 mg, levofloxacin hydrochloride 0.2 g, anisodamine 10 mg, and physiological saline 100 ml) (n = 26)	Grade of radioproctitis after treatment (defined according to colonoscopy test results) Grade 0 to 1: 22/32 versus 7/26 (RR 2.55, 95% CI 1.30 to 5.02)	Low due to high RoB and imprecision (OIS not reached)
Tian 2008	People diagnosed with chronic rectal radiation damage		Treatment effect after 37 days Cured‐better: 30 to 32 versus 14 to 26 (RR 1.74, 95% CI 1.21 to 2.51)	Low due to high RoB and imprecision (OIS not reached)
ATA: atmosphere absolute CI: confidence interval IBDQ‐B: Inflammatory Bowel Disease Questionnaire–Bowel MD: mean difference OR: odds ratio QoL: quality of life RPSAS: Radiation Proctopathy System Assessments Scale RR: risk ratio SD: standard deviation SOMA‐LENT: Subjective, Objective, Management, Analytic ‐ Late Effects of Normal Tissue HAD: Hospital Anxiety Depression OIS: Optimal Information Size

Table 3. Treatments targeted at the more global collection of symptoms

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Comparison 1. Short chain fatty acid (SCFA) enemas versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean reduction of endoscopic score after treatment Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

2 Mean number of days of rectal bleeding after treatment Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

3 Mean haemoglobin levels at the end of treatment period (5 weeks) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Comparison 1. Short chain fatty acid (SCFA) enemas versus placebo

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Comparison 2. Endoscopic argon plasma coagulation (APC) plus oral sucralfate versus APC plus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Endoscopy scores Gilinsky scale grade 6‐9 at 8 weeks Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2 Endoscopy scores Gilinsky scale grade 6‐9 at 16 weeks Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3 Number of participants with complications Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 2. Endoscopic argon plasma coagulation (APC) plus oral sucralfate versus APC plus placebo

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Comparison 3. Endoscopic bipolar electrocoagulation versus heater probe

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe bleeding episodes Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2 Mean number of severe bleeds after first year Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

3 Mean haematocrit after first year Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

4 Mean units of blood transfused after first year Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Comparison 3. Endoscopic bipolar electrocoagulation versus heater probe

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Comparison 4. APC versus bipolar electrocoagulation

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Eradication of all telangiectasias Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2 Complications ‐ Minor Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3 Complications ‐ Major Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4 Relapse Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 4. APC versus bipolar electrocoagulation

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Comparison 5. Hydrocortisone versus betamethasone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Improvement of endoscopic appearance Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Reduction of rectal bleeding Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Poor tolerance of enema Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 5. Hydrocortisone versus betamethasone

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Comparison 6. Standard treatment plus oral pentoxifylline versus standard treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cessation of rectal bleeding Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 6. Standard treatment plus oral pentoxifylline versus standard treatment

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Comparison 7. Oral sulfasalazine plus rectal steroids versus oral placebo plus rectal sucralfate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinical improvement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Endoscopic improvement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 7. Oral sulfasalazine plus rectal steroids versus oral placebo plus rectal sucralfate

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Comparison 8. Metronidazole in addition to mesalazine and betamethasone versus no metronidazole

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Rectal bleeding score < 2 after 1 year Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2 Diarrhoea score < 2 after 1 year Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3 No rectal erythema after 1 year Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4 No rectal ulceration after 1 year Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 8. Metronidazole in addition to mesalazine and betamethasone versus no metronidazole

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Comparison 9. Hyperbaric oxygen therapy versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinical evaluation ‐ healed or improved Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 9. Hyperbaric oxygen therapy versus placebo

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Comparison 10. Retinol palmitate versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Response to treatment Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 10. Retinol palmitate versus placebo

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Comparison 11. Algorithm‐based management

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Bowel subset score (IBDQ‐B) at 6 months (higher score indicates better) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

1.1 Gastroenterologist group vs booklet group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Nurse group vs booklet group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 Gastroenterologist group vs nurse group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2 Change in rectal SOMA‐LENT at 6 months Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

2.1 Gastroenterologist group vs booklet group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Nurse group vs booklet group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Gastroenterologist group vs nurse group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 Change in small intestine SOMA‐LENT at 6 months Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

3.1 Gastroenterologist group vs booklet group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Nurse group vs booklet group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 Gastroenterologist group vs nurse group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
4 SF12: change in physical component score at 6 months Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

4.1 Gastroenterologist group vs booklet group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 Nurse group vs booklet group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
4.3 Gastroenterologist group vs nurse group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5 SF12: change in mental component score at 6 months Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

5.1 Gastroenterologist group vs booklet group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Nurse group vs booklet group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5.3 Gastroenterologist group vs nurse group	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 11. Algorithm‐based management

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Comparison 12. Integrated Chinese traditional medicine plus Western medicine versus Western medicine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Grade of radioproctitis after treatment Grade I Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2 Cured ‐ better after 37 days Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 12. Integrated Chinese traditional medicine plus Western medicine versus Western medicine

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Cochrane Review language

Website language

Resumen

Antecedentes

Objetivos

Métodos de búsqueda

Criterios de selección

Obtención y análisis de los datos

Resultados principales

Conclusiones de los autores

PICOs

PICOs

Population

Intervention

Comparison

Outcome

Resumen en términos sencillos

Intervenciones no quirúrgicas para las consecuencias rectales tardías de la radioterapia en pacientes que han recibido radioterapia radical en la pelvis

Visual summary

Authors' conclusions

Implications for practice

Implications for research

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

Included studies

Study design

Types of interventions

Participant characteristics

Excluded studies

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

1. Treatments for rectal bleeding

Short‐chain fatty acid (SCFA) versus placebo

Sucralfate versus placebo following argon plasma coagulation

Endoscopic bipolar electrocoagulation versus heater probe

Bipolar eletrocoagulation versus argon plasma coagulation

Hydrocortisone versus betamethasone

Formalin dab versus sucralfate steroid retention enema

Formalin application versus colonic irrigation and oral antibiotics

Pentoxifylline in addition to standard therapy

Oral sulfasalazine plus rectal steroids versus oral placebo plus rectal sucralfate

2. Treatments targeted at a combination of anorectal symptoms

Short‐chain fatty acid (SCFA) versus placebo

Topical formalin versus argon plasma coagulation

Metronidazole in addition to mesalazine and betamethasone

3. Treatments targeted at pelvic radiation disease

Hyperbaric oxygen therapy versus placebo