Interventions to reduce acute and late adverse gastrointestinal effects of pelvic radiotherapy for primary pelvic cancers

Theresa A Lawrie; John T Green; Mark Beresford; Linda Wedlake; Sorrel Burden; Susan E Davidson; Simon Lal; Caroline C Henson; H Jervoise N Andreyev

doi:10.1002/14651858.CD012529.pub2

. 2018 Jan 23;2018(1):CD012529. doi: 10.1002/14651858.CD012529.pub2

Interventions to reduce acute and late adverse gastrointestinal effects of pelvic radiotherapy for primary pelvic cancers

Theresa A Lawrie ^1,^✉, John T Green ², Mark Beresford ³, Linda Wedlake ⁴, Sorrel Burden ⁵, Susan E Davidson ⁶, Simon Lal ⁷, Caroline C Henson ⁸, H Jervoise N Andreyev ⁹

Editor: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group

PMCID: PMC6491191 PMID: 29360138

Abstract

Background

An increasing number of people survive cancer but a significant proportion have gastrointestinal side effects as a result of radiotherapy (RT), which impairs their quality of life (QoL).

Objectives

To determine which prophylactic interventions reduce the incidence, severity or both of adverse gastrointestinal effects among adults receiving radiotherapy to treat primary pelvic cancers.

Search methods

We conducted searches of CENTRAL, MEDLINE, and Embase in September 2016 and updated them on 2 November 2017. We also searched clinical trial registries.

Selection criteria

We included randomised controlled trials (RCTs) of interventions to prevent adverse gastrointestinal effects of pelvic radiotherapy among adults receiving radiotherapy to treat primary pelvic cancers, including radiotherapy techniques, other aspects of radiotherapy delivery, pharmacological interventions and non‐pharmacological interventions. Studies needed a sample size of 20 or more participants and needed to evaluate gastrointestinal toxicity outcomes. We excluded studies that evaluated dosimetric parameters only. We also excluded trials of interventions to treat acute gastrointestinal symptoms, trials of altered fractionation and dose escalation schedules, and trials of pre‐ versus postoperative radiotherapy regimens, to restrict the vast scope of the review.

Data collection and analysis

We used standard Cochrane methodology. We used the random‐effects statistical model for all meta‐analyses, and the GRADE system to rate the certainty of the evidence.

Main results

We included 92 RCTs involving more than 10,000 men and women undergoing pelvic radiotherapy. Trials involved 44 different interventions, including radiotherapy techniques (11 trials, 4 interventions/comparisons), other aspects of radiotherapy delivery (14 trials, 10 interventions), pharmacological interventions (38 trials, 16 interventions), and non‐pharmacological interventions (29 trials, 13 interventions). Most studies (79/92) had design limitations. Thirteen studies had a low risk of bias, 50 studies had an unclear risk of bias and 29 studies had a high risk of bias. Main findings include the following:

Radiotherapy techniques: Intensity‐modulated radiotherapy (IMRT) versus 3D conformal RT (3DCRT) may reduce acute (risk ratio (RR) 0.48, 95% confidence interval (CI) 0.26 to 0.88; participants = 444; studies = 4; I² = 77%; low‐certainty evidence) and late gastrointestinal (GI) toxicity grade 2+ (RR 0.37, 95% CI 0.21 to 0.65; participants = 332; studies = 2; I² = 0%; low‐certainty evidence). Conformal RT (3DCRT or IMRT) versus conventional RT reduces acute GI toxicity grade 2+ (RR 0.57, 95% CI 0.40 to 0.82; participants = 307; studies = 2; I² = 0%; high‐certainty evidence) and probably leads to less late GI toxicity grade 2+ (RR 0.49, 95% CI 0.22 to 1.09; participants = 517; studies = 3; I² = 44%; moderate‐certainty evidence). When brachytherapy (BT) is used instead of external beam radiotherapy (EBRT) in early endometrial cancer, evidence indicates that it reduces acute GI toxicity (grade 2+) (RR 0.02, 95% CI 0.00 to 0.18; participants = 423; studies = 1; high‐certainty evidence).

Other aspects of radiotherapy delivery: There is probably little or no difference in acute GI toxicity grade 2+ with reduced radiation dose volume (RR 1.21, 95% CI 0.81 to 1.81; participants = 211; studies = 1; moderate‐certainty evidence) and maybe no difference in late GI toxicity grade 2+ (RR 1.02, 95% CI 0.15 to 6.97; participants = 107; studies = 1; low‐certainty evidence). Evening delivery of RT may reduce acute GI toxicity (diarrhoea) grade 2+ during RT compared with morning delivery of RT (RR 0.51, 95% CI 0.34 to 0.76; participants = 294; studies = 2; I² = 0%; low‐certainty evidence). There may be no difference in acute (RR 2.22, 95% CI 0.62 to 7.93, participants = 110; studies = 1) and late GI toxicity grade 2+ (RR 0.44, 95% CI 0.12 to 1.65; participants = 81; studies = 1) between a bladder volume preparation of 1080 mls and that of 540 mls (low‐certainty evidence). Low‐certainty evidence on balloon and hydrogel spacers suggests that these interventions for prostate cancer RT may make little or no difference to GI outcomes.

Pharmacological interventions: Evidence for any beneficial effects of aminosalicylates, sucralfate, amifostine, corticosteroid enemas, bile acid sequestrants, famotidine and selenium is of a low or very low certainty. However, evidence on certain aminosalicylates (mesalazine, olsalazine), misoprostol suppositories, oral magnesium oxide and octreotide injections suggests that these agents may worsen GI symptoms, such as diarrhoea or rectal bleeding.

Non‐pharmacological interventions: Low‐certainty evidence suggests that protein supplements (RR 0.23, 95% CI 0.07 to 0.74; participants = 74; studies = 1), dietary counselling (RR 0.04, 95% CI 0.00 to 0.60; participants = 74; studies = 1) and probiotics (RR 0.43, 95% CI 0.22 to 0.82; participants = 923; studies = 5; I² = 91%) may reduce acute RT‐related diarrhoea (grade 2+). Dietary counselling may also reduce diarrhoeal symptoms in the long term (at five years, RR 0.05, 95% CI 0.00 to 0.78; participants = 61; studies = 1). Low‐certainty evidence from one study (108 participants) suggests that a high‐fibre diet may have a beneficial effect on GI symptoms (mean difference (MD) 6.10, 95% CI 1.71 to 10.49) and quality of life (MD 20.50, 95% CI 9.97 to 31.03) at one year. High‐certainty evidence indicates that glutamine supplements do not prevent RT‐induced diarrhoea. Evidence on various other non‐pharmacological interventions, such as green tea tablets, is lacking.

Quality of life was rarely and inconsistently reported across included studies, and the available data were seldom adequate for meta‐analysis.

Authors' conclusions

Conformal radiotherapy techniques are an improvement on older radiotherapy techniques. IMRT may be better than 3DCRT in terms of GI toxicity, but the evidence to support this is uncertain. There is no high‐quality evidence to support the use of any other prophylactic intervention evaluated. However, evidence on some potential interventions shows that they probably have no role to play in reducing RT‐related GI toxicity. More RCTs are needed for interventions with limited evidence suggesting potential benefits.

Plain language summary

Interventions to reduce digestive side effects of pelvic x‐ray treatment

Background Radiotherapy (RT: x‐ray treatment) is a common anti‐cancer treatment that often cures people of their cancer, but can damage the gastrointestinal (digestive) tract and lead to distressing short‐term (acute) and long‐term (late) gastrointestinal side effects, which can start many months or years after the radiotherapy has finished. These side effects, such as diarrhoea, faecal urgency (a sudden need to pass stool), and faecal incontinence (leakage of stool from the rectum) can damage a person's quality of life (QoL). We conducted this review to establish whether there are any treatments that can be given to people undergoing pelvic radiotherapy (RT) to reduce gastrointestinal side effects.

Methods We searched the medical literature up to 2 November 2017 and selected randomised controlled trials (RCTs) of any preventive treatment (intervention) given to people undergoing RT for pelvic cancer (such as bladder, endometrial, cervix, rectum and prostate cancers). We combined data from similar RCTs to provide a summary estimate of the effect of an intervention and made a judgement about how confident (certain) we are of the findings, using established methods (GRADE).

Results We identified 92 RCTs involving 44 different interventions to reduce RT‐related gastrointestinal side effects. These included new methods (RT techniques) and other aspects of delivering RT (lower RT dosages, different bladder volumes, morning or evening RT delivery, injected gels or rectally‐inserted balloons (spacers] to protect the rectum, and other options), drugs (aminosalicylates, amifostine, corticosteroids, famotidine, octreotide, magnesium oxide, misoprostol, selenium, sodium butyrate, smectite, sucralfate, superoxide dismutase), and non‐drug treatments (different types of diets, glutamine, counselling, green tea, and other options). We found some evidence to show that certain interventions have no role to play in reducing gastrointestinal side effects (particularly glutamine supplements, misoprostol suppositories, oral magnesium oxide and octreotide injections). However, we found little good evidence (moderate or high certainty) to show that any of the options is helpful. The exceptions to this are the evidence on RT techniques, which shows that conformal (modern) RT techniques are better than older RT techniques, and evidence that vaginal brachytherapy (small radioactive balls placed in the vagina) for early endometrial cancer reduces acute gastrointestinal side effects compared with external‐beam radiotherapy.

Conclusions Modern (conformal) RT methods are helpful in reducing RT‐related side effects. There is insufficient evidence to robustly support the use of any single drug or non‐drug option or other RT delivery device/option to reduce RT‐related gastrointestinal effects. More high‐quality research is needed.

Summary of findings

Background

Description of the condition

In 2012, 14.1 million people worldwide were diagnosed with cancer and 32.6 million people were living with cancer (within five years of diagnosis) (GLOBOCAN 2012). The number of people surviving cancer has increased significantly over the past few decades, due to earlier diagnosis and advances in multimodal treatment (Andreyev 2012; Cancer Res 2016). Radiotherapy (RT) is a key component of anti‐cancer treatment and approximately four out of every 10 people with cancer have radiotherapy as part of their treatment (Cancer Res 2016). Whilst anti‐cancer treatment is not always curative, it enables many people with a diagnosis of cancer to live for significantly extended periods.

Pelvic radiotherapy is used to treat various urological, gynaecological and gastrointestinal cancers, where it might be given alone as primary treatment, combined with chemotherapy, or given before or after surgery. During treatment, pelvic radiotherapy inevitably exposes the surrounding normal gastrointestinal tract (small and large bowel) to some degree of radiation. Depending on various factors, such as the type of radiotherapy, the size and site of the treatment field, and the dose delivered, irradiation of normal tissue can lead to bowel injury (Andreyev 2007). In addition, other factors may influence the risk of bowel injury, including chemotherapy, previous abdominal surgery, smoking, co‐existing medical conditions or their treatments (such as diabetes, hypertension and HIV), concurrent medication, genetic factors, and psychological issues (Andreyev 2007; Theis 2010).

Pelvic radiation disease (PRD), the term used for non‐cancerous tissue injury secondary to radiotherapy, is increasingly being recognised as an unacceptable consequence of radiotherapy treatment (Morris 2015). Radiation‐induced gastrointestinal tissue injury is brought about initially by an acute inflammatory process that leads to blood vessel damage, ischaemia (inadequate blood supply to the tissue), fibrosis (thickening and scarring), and loss of stem cells (Denham 2002). With repeated exposures over the course of radiotherapy treatment, the cycle of tissue injury and disrupted healing leads to progressive alteration in the affected tissue architecture and function. Gastrointestinal symptoms can be acute (occurring during radiotherapy or within three months), or chronic (persisting or appearing after three months) (Frazzoni 2015). Acute symptoms, including diarrhoea, abdominal pain, nausea, bloating, rectal bleeding, and urgency, typically begin during the second week of treatment and peak at four to five weeks (Khalid 2006). Acute symptoms usually resolve upon cessation of radiotherapy; however, they can necessitate dose reductions and treatment interruption, which can have a negative impact on the curative effect of treatment (Morris 2015; Stacey 2014). In addition, their occurrence may increase the risk of late gastrointestinal effects (Barnett 2011; O'Brien 2002). Chronic symptoms, including faecal incontinence, urgency, rectal bleeding, flatulence, and abdominal pain, can follow acute symptoms or arise on their own some time later (Andreyev 2012). Incontinence can be particularly distressing and may be caused by injury to the anal sphincter and rectal tissue, leading to decreased rectal distensibility and storage capacity (Krol 2014). However, as widely‐separate parts of the gastrointestinal tract that lie in the path of the radiotherapy beam can be affected, symptoms associated with injury can have more than one physiological cause (Andreyev 2007). In addition, bile acid malabsorption, carbohydrate intolerances, and small bowel bacterial overgrowth occurring as a result of radiation‐induced impaired bowel motility may exacerbate bowel symptoms (Andreyev 2007; Muls 2014). Chronic symptoms are very common, with up to 90% of patients reporting a permanent change in their bowel habits (Olopade 2005), and up to 30%, 40% and 66% respectively of urological, gynaecological and colorectal cancer survivors experiencing chronic gastrointestinal symptoms that negatively affect their quality of life (Andreyev 2012). Rarely, severe intestinal failure can occur as a result of RT damage; furthermore, RT‐exposed intestine has an increased risk of needing surgery (Gavazzi 2006; Kalaiselvan 2014).

Description of the intervention

Radiotherapy is a cancer treatment involving the use of high‐energy radiation, usually x‐rays or similar beams (such as electrons or protons), to destroy cancer cells. The aim of modern radiotherapy is to ensure a high level of accuracy in tumour targeting, to reduce normal tissue exposure, and to minimise side effects (NCAT 2012). A variety of different strategies have been proposed to reduce its impact on normal tissues and prevent adverse gastrointestinal effects. These include improved radiotherapy delivery techniques, other aspects of radiotherapy delivery (e.g. timing of delivery, patient positioning or positioning devices), pharmacological interventions, and non‐pharmacological interventions:

Radiotherapy delivery techniques

Conventional radiotherapy is delivered as external beam radiotherapy (EBRT). Conformal radiotherapy is the type of EBRT that is commonly used in high‐income countries (Cancer Res 2016; CCS 2016). There are two types:

3D conformal radiotherapy (3DCRT) is intended to improve tumour targeting and reduce the amount of radiation to the surrounding tissues by aiming shaped radiotherapy beams from several different directions at the tumour (CCS 2016). It uses pretreatment imaging with computerised tomography (CT) or other types of scans to plan the radiotherapy treatment area in three dimensions (width, height and depth), matching the radiation beams to the 3D shape of the tumour. With 3DCRT, the radiation beams are all the same intensity;
Intensity‐modulated radiotherapy (IMRT) uses computerised methods to orientate multiple small beams of different intensities to the volume of tumour tissue that needs to be treated (Cancer Res 2016; NCAT 2012). IMRT may potentially conform more precisely to the tumour than 3DCRT, as it allows the dose of radiation to be adjusted for different parts of the treatment area and can create concave edges to reduce exposure to adjacent normal tissues. Volumetric modulated arc therapy (VMAT) is a type of IMRT in which the machine rotates around the patient during treatment, continuously adapting the radiation beam to the tumour volume as it moves.

All radiation doses quoted in this review assume a fraction size of 1.8 to 2.0 Gy, unless otherwise stated. It is currently unclear whether the occurrence or severity of adverse gastrointestinal effects in patients undergoing radiotherapy differ between these techniques.

Image‐guided radiotherapy (IGRT)

IGRT includes any imaging performed at pretreatment and treatment delivery that improves or verifies the accuracy of radiotherapy (NCAT 2012). It encompasses a wide variety of techniques ranging from simple visual field alignment checks through to CT imaging that enables direct visualisation of the radiotherapy target volume and surrounding anatomy (NCAT 2012). If sufficiently accurate, IGRT has the potential to allow a reduction in the setup margin for a particular cancer site, reducing the radiation exposure to normal tissue. Four‐dimensional adaptive radiotherapy (4D‐ART) combines IMRT and IGRT to take into account the 3D tumour shape over time (the fourth dimension) by tracking tumour motion during treatment (NCAT 2012).

Stereotactic body radiotherapy (SBRT)

SBRT involves the use of a high and precise radiation dose in a small number of fractions (NCAT 2012). Radiotherapy beams are orientated from many different positions around the body to minimise the radiation dose to the surrounding tissues (Cancer Res 2016). SBRT is currently mainly used for small tumours of the brain, liver, lung and spinal cord; however, its use could potentially be extended to prostate cancer (Lischalk 2016; Moon 2017).

Brachytherapy (BT)

BT involves the placement of radioactive seeds within the tumour (interstitial brachytherapy), or within a cavity adjacent to the tumour (intracavitary brachytherapy) (Shadad 2013). Irradiation may be over a prolonged period of time (low dose) or temporary and short‐term (high dose). BT is often used in combination with EBRT. Where evaluated as an alternative to EBRT‐based treatments, it has been associated with lower gastrointestinal toxicity (Nout 2010; Sorbe 2012).

Gastrointestinal injury is more likely with higher prescribed radiation doses (Barnett 2011; Michalski 2010). Therefore, limiting the volume of normal tissue exposed to intermediate (45 to 60 Gy) and high doses (60 or more Gy) by using dose‐volume constraints is an important part of treatment planning (Michalski 2010). Such parameters need adaptation and validation for different EBRT techniques (Michalski 2010). Irrespective of the radiotherapy technique used, effective immobilisation both in the patient's bony anatomy and of internal organ motion during treatment is critical to avoid ‘geographical miss’, which will underdose the tumour and overdose the surrounding normal tissues (NCAT 2012).

Other aspects of radiotherapy delivery

Patient positioning or positioning devices

The position of a patient during radiotherapy delivery might influence the dose of radiation delivered to normal pelvic structures and subsequent gastrointestinal injury. A systematic review of prospective and retrospective studies of patient positioning and the use of belly boards suggests that delivering radiotherapy to patients positioned in the prone position (lying on their front) rather that the supine position (lying on their back), and using positioning devices such as belly boards, might facilitate displacement of the small bowel away from the treatment field and reduce the volume of small bowel irradiated (Weisendanger‐Wittmer 2012).

Timing of delivery

Physiological 'clocks' that regulate the timing of physiological processes through gene expression exist in every organ and cell of the human body (Fuhr 2015). The circadian clock or day‐night cycle is the core clock that might influence response to anti‐cancer treatments and the development of treatment side effects (Fuhr 2015). It has been suggested that radiotherapy delivered in the morning may be more likely to cause damage to gastrointestinal mucosal cells than radiotherapy delivered in the evening, due to limited evidence that gastrointestinal cellular proliferation follows a circadian rhythm, with bowel mucosal proliferation (DNA synthesis) being greatest in the morning and lowest in the evening (Buchi 1991; Ijiri 1990).

Fractionation

Curative pelvic radiotherapy treatment comprises a number of doses or fractions (usually 2 Gy or less per fraction), usually given over a period of about four to eight weeks to make up the total prescribed radiotherapy dose. Certain cancers such as prostate cancer have been shown to be more sensitive to fraction size than other tumours, behaving more like normal tissues; therefore, increasing the fraction size (hypofractionation) for each treatment, which allows the total dose to be delivered in fewer treatments, might improve the treatment outcome or therapeutic ratio (Bossi 2016; Soh 2015). Several randomised trials of hypofractionation in prostate cancer have been conducted (Aluwini 2015; Arcangeli 2010; CHHiP 2016; Hoffman 2014; Norkus 2013; Pollack 2013). A 2015 systematic review concludes that moderate fractionation (2.5 to 4 Gy per fraction) is associated with late gastrointestinal toxicity similar to conventional fractionation; however, extreme fractionation (5 to 10 Gy per fraction) may have greater toxicity than conventional fractionation (Koontz 2015). Whilst potential benefits of hypofractionation include patient convenience, reduced treatment time and cost reduction (Moon 2017; Soh 2015), hypofractionation is not expected to reduce toxicity and might increase it; most trials of hypofractionation therefore hope to show that it is safe and non‐inferior to conventional fractionation in terms of toxicity. We therefore consider interventions dealing with altered fractionation schedules to be outside the scope of this review. A separate Cochrane Review to evaluate the efficacy and toxicity of altered fractionation schedules for prostate cancer is currently underway (Soh 2015).

Other interventions

Various surgical techniques have been proposed, such as the surgical placement of absorbable mesh slings to exclude the small bowel from the field of radiation, to reduce the gastrointestinal effects of pelvic radiotherapy (Devereux 1988; Rodier 1991); however, the clinical effectiveness of such techniques remains uncertain (Stacey 2014). Using daily endorectal balloons filled with air or water, which aim to reduce the volume of normal tissues being irradiated, might be beneficial for men undergoing prostate radiotherapy; findings from a non‐Cochrane review suggest that such devices might reduce prostate motion, improve dosimetry and reduce early gastrointestinal toxicity (Both 2012). Similarly, gel or balloon spacers inserted into the prerectal space before RT might protect the rectum from adverse effects of this treatment.

Pharmacological interventions

Mucosal protectants

Drugs that might protect the mucosa of the gastrointestinal tract from damage due to pelvic radiotherapy include sucralfate (a sucrose sulfate‐aluminium complex) and various agents with antioxidant properties:

Sucralfate binds to tissue proteins, creating a physical barrier over damaged mucosal surfaces and facilitating epithelial healing (Van de Wetering 2016). Low‐ to moderate‐certainty Cochrane evidence suggests that it may be useful in the treatment of acute radiation‐induced rectal bleeding, but it remains unclear whether it can prevent rectal bleeding or other gastrointestinal symptoms of PRD when administered prophylactically (Van de Wetering 2016).
Amifostine is thought to mediate a protective effect within normal cells by free‐radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia (Kouvaris 2007). It is used to protect renal cells from the effects of platinum chemotherapy in ovarian cancer, and in people undergoing radiotherapy for head and neck cancers to reduce xerostomia (dryness of the mouth) (Kouvaris 2007).
Antioxidants, such as vitamins C, D, and E, might reduce radiotherapy‐induced injury by reducing antioxidant stress within gastrointestinal cells and facilitating tissue repair. Glutamine, a non‐essential amino acid, selenium, and other agents with antioxidant properties could also potentially be protective (Hall 2016).

Anti‐inflammatory agents

5‐aminosalicylates (e.g. sulfasalazine, balsalazide) are used in the treatment of certain inflammatory bowel conditions, e.g. ulcerative colitis, and therefore might have a role in preventing acute inflammatory gastrointestinal effects of radiation, as suggested by the findings of some small trials (Jahraus 2005; Kilic 2001). Other anti‐inflammatory agents that could potentially reduce gastrointestinal damage include other nonsteroidal anti‐inflammatories and corticosteroids.

Statins (3‐hydroxy‐methylglutaryl coenzyme‐a reductase inhibitors) and angiotensin‐converting enzyme (ACE) inhibitors

A retrospective study of the effects of statins and ACE inhibitors on gastrointestinal effects in a cohort of people undergoing radiotherapy for pelvic malignancies reported better acute and long‐term gastrointestinal symptom scores among those receiving statins (with or without ACE inhibitors) (Wedlake 2012); however, retrospective studies have a high risk of bias. Theoretically, statins might counteract some effects of radiation on normal tissues, due to their vasculoprotective properties (Wang 2007).

Other agents

Octreotide is an analogue of the hypothalamic release‐inhibiting hormone somatostatin (BNF 2016). It is mainly used to relieve diarrhoeal symptoms associated with neuroendocrine tumours, but it may have a role to play in reducing chemoradiotherapy‐related diarrhoea, through inhibitory effects on gastrointestinal secretions and hormones, and on gastrointestinal motility (Sun 2014; Yavuz 2002). However, weak evidence from a 2014 review of octreotide (given subcutaneously or intramuscularly) compared with placebo among people undergoing chemotherapy or radiotherapy suggests that octreotide might reduce diarrhoea when used therapeutically but not preventively in this context (Sun 2014). Various other pharmacological agents, such as bile acid sequestrants (e.g. cholestyramine), sodium butyrate, and smectite, have also been investigated. Bile acid sequestrants act by binding bile acids, which are normally reabsorbed in the terminal ileum and might cause diarrhoea if reabsorption is disrupted, for example, by radiotherapy‐induced dysfunction (Stryker 1983). Sodium butyrate is a short chain fatty acid that has been shown to have anti‐inflammatory properties and trophic effects on colonic mucosa (Maggio 2014); and smectite is a natural aluminomagnesium clay that has anti‐diarrhoeal properties (Dupont 2009).

Non‐pharmacological interventions

Probiotics

Probiotic preparations contain live and defined micro‐organisms (usually lactobacilli and bifidobacteria) which, when administered in sufficiently large amounts, alter the host's microflora and potentially confer a health benefit (Kligler 2008). The potential mechanism/s of action of probiotics include epithelial cell proliferation, enhancing secretion of protective mucins, inhibiting bacterial translocation and stimulating the immune response (Van de Wetering 2013). Several clinical studies have investigated the role of probiotics for radiation‐induced gastrointestinal injury, but the role of probiotics in preventing or reducing PRD remains uncertain (Stacey 2014; Wedlake 2013).

Nutritional interventions

Malnutrition can occur as a consequence of radiotherapy‐induced impaired gastrointestinal absorption and digestive functioning, and can also influence the development of gastrointestinal toxicity (Henson 2013). A 2013 Cochrane Review evaluated the evidence for various nutritional interventions in improving the nutritional status of people undergoing radiotherapy, and found that dietary modification of fat, lactose, or non‐starch polysaccharides (fibre) intake, or combinations of these dietary modifications, probably reduces diarrhoea at the end of radiotherapy (Henson 2013). However, another review concluded that there was insufficient evidence on nutritional interventions to guide clinical practice (Wedlake 2013).

Why it is important to do this review

The focus of cancer and anti‐cancer treatment is usually on survival. However, an increasing number of people survive cancer and can develop distressing side effects as a result of treatment. The impact of treatment on the cancer survivor's quality of life has been a much‐neglected area of research in cancer treatment. In addition, clinicians tend to focus on ruling out cancer recurrence and progression at follow‐up appointments, rather than asking about and addressing quality‐of‐life‐related symptoms. These factors together suggest to cancer survivors that the side effects of radiotherapy treatment are a necessary trade‐off against survival. Those affected may therefore be embarrassed to discuss their gastrointestinal symptoms with healthcare professionals, may delay seeking help for them, and may try to manage these problems themselves (Muls 2014).

To our knowledge, there is no comprehensive systematic review of prophylactic interventions to reduce the gastrointestinal toxicity of radiotherapy. Systematic reviews of endorectal balloons (Both 2012), patient positioning (Weisendanger‐Wittmer 2012) and IMRT (Yu 2016) have included prospective and retrospective studies and have not graded the quality or certainty of evidence; two systematic reviews on nutritional interventions have reached slightly different conclusions (Henson 2013; Wedlake 2013); a systematic review of octreotide pooled data from prevention and treatment studies (Sun 2014), and a Cochrane Review of selenium supplements is out of date (Dennert 2006). These factors make interpretation of existing evidence difficult. The aim of this review is therefore to systematically and critically appraise the evidence from randomised controlled trials on prophylactic interventions that might reduce the incidence or severity of gastrointestinal symptoms caused by pelvic radiotherapy, and to bring them all together in one comprehensive review, in order to highlight those interventions that will lead to improvements in the quality of life of cancer survivors, and to direct the much‐needed research in this field.

Objectives

To determine which prophylactic interventions reduce the incidence, severity, or both of adverse gastrointestinal effects among adults receiving radiotherapy to treat primary pelvic cancers.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs). We excluded quasi‐RCTs and cross‐over designs.

Types of participants

Adults aged 18 years and older undergoing primary, adjuvant or neoadjuvant radiotherapy as part of anti‐cancer treatment for primary pelvic cancers, including urological, gynaecological and gastrointestinal (GI) cancers. We excluded studies of participants receiving palliative radiotherapy or radiotherapy for recurrent cancer, and studies of participants with stomas. Where we found studies that include mixed groups that include some ineligible participants, we attempted to extract data for the relevant participant subgroups only. If this was not possible, we included the study if at least 80% of the participants were eligible, and indicated our concerns related to the types of participants in the 'Risk of bias' assessment of the study. We excluded studies in which fewer than 80% of participants were eligible. Included studies needed to include at least 20 participants.

Types of interventions

Interventions to prevent adverse gastrointestinal effects of pelvic radiotherapy, including:

Radiotherapy techniques (e.g. 3DCRT, IMRT, BT);
Interventions related to radiotherapy delivery, including radiotherapy timing (e.g. evening radiotherapy schedules), patient positioning and positioning devices (e.g. belly boards), and other interventions (e.g. endorectal balloons);
Pharmacological interventions (e.g. sucralfate, 5‐aminosalicylates, antioxidants, statins, ACE inhibitors);
Non‐pharmacological interventions, including dietary modification of macronutrients (carbohydrate, fats, protein, with or without micronutrients) and/or non‐starch polysaccharides (dietary fibre), probiotics, and other interventions.

Comparators for radiotherapy techniques or timing are other radiotherapy techniques or timing, whereas comparators for other types of interventions are placebos, no intervention, or alternative interventions. We excluded trials of interventions to treat patients with acute symptoms, as these are not preventive interventions in the first instance. We also excluded trials of altered fractionation and dose escalation schedules, and trials of pre‐ versus postoperative radiotherapy regimens.

Types of outcome measures

Included studies needed to evaluate gastrointestinal toxicity.

Primary outcomes

Gastrointestinal symptom score, according to the Inflammatory Bowel Disease Questionnaire‐bowel function dimension (IBDQ‐BD), Gastrointestinal Symptom Rating Scale (GSRS), or another scale.
Moderate or severe GI symptoms (toxicity), according to the Common Terminology Criteria for Adverse Events (CTCAE 2010), European Organisation for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG) scoring system, IBDQ, GSRS, or another scale, including:
- Overall GI symptoms (grade 2+ toxicity);
- Diarrhoea (the passing of frequent, loose stool);
- Faecal incontinence (leakage of stool from the rectum);
- Faecal urgency (a sudden, almost uncontrollable, need to pass stool);
- Rectal bleeding;
- Tenesmus (a feeling of incomplete evacuation and a constant urge to pass stool);
- Abdominal pain/cramps;
- Nausea;
- Vomiting;
- Flatulence;
- Weight loss.
Quality of life (QoL) score, according to EORTC QLQ‐C30, QLQ‐PR25, Prostate Cancer Quality of Life Scale (PC‐QOL), IBDQ or another scale.

We assessed these outcomes at specific time points to reflect acute (during and up to three months after radiotherapy) and late (six months post‐radiotherapy and longer) effects.

Secondary outcomes

GI toxicity grade 1+;
Toxicity‐related discontinuation;
Medication use for GI symptom control;
Patient satisfaction (as measured by investigators);
Total mean bowel dose (Gy) (for studies evaluating radiotherapy techniques, patient positioning or positioning devices).

We excluded studies that evaluated dosimetric parameters only.

Search methods for identification of studies

Electronic searches

We searched the following databases up to September 2016:

Cochrane Central Register of Controlled Trials (CENTRAL): Issue 9, 2016
MEDLINE: 1946 to September Week 3 2016
Embase: 1980 to 2016 week 39

In November 2017, we updated the search as follows:

CENTRAL: Issue 11, 2017
MEDLINE: September 2016 to October Week 4, 2017
Embase: September 2016 to 2017 week 44

We present the CENTRAL, MEDLINE and Embase search strategies in Appendix 1, Appendix 2. Appendix 3 respectively.

We did not apply language restrictions to any of the searches.

Searching other resources

We searched the following databases for ongoing trials:

ClinicalTrials.gov (clinicaltrials.gov/)
International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/)

If we found ongoing trials that had not been published through these searches, we approached the principal investigators for an update on the trial status. We tabulated details of the ongoing trials, including any information acquired from investigators on the trial status, in the Characteristics of ongoing studies section of the review.

We used the 'Related articles' feature of PubMed and the reference lists of included studies to identify newly‐published articles and relevant additional studies. We did not handsearch conference proceedings for conference abstracts due to resource limitations and because we considered that we would find most relevant records by the electronic searches, so that any additional yield would be negligible. See Potential biases in the review process for comment on handsearching.

Data collection and analysis

Selection of studies

The Information Specialist at the Cochrane Gynaecological, Neuro‐oncology and Orphan Cancer Group downloaded all titles and abstracts retrieved by electronic searching to Endnote® and removed duplicates and those studies that clearly did not meet the inclusion criteria. Two review authors (Theresa Lawrie (TL) and John Green (JG)) independently screened the remaining records by title and abstract using Covidence (www.covidence.org/). We obtained the full texts of the short list of potentially eligible references. TL and JG independently assessed the eligibility of the full‐text records, with the help of a third review author (Mark Beresford (MB)), who assisted when necessary to resolve disagreements and uncertainties. We documented the reasons for exclusion of all excluded studies.

Data extraction and management

Two review authors (from TL, JG, MB, Susan Davidson (SD), Linda Wedlake (LW) and Sorrel Burden (SB)) independently extracted data from included studies to a predesigned Excel® data extraction form, to include the following:

Author contact details;
Country;
Setting;
Funding source;
Inclusion and exclusion criteria;
Study design, methodology;
Study population and baseline characteristics:
- Number of participants enrolled;
- Number of participants analysed;
- Mean (SD) or median (range) age of participants;
- Numbers of male and female participants;
- Number of participants with urological, gynaecological, colorectal, and other cancer;
- Number of participants who received primary, adjuvant, or neoadjuvant radiotherapy;
- Other anti‐cancer treatment;
- Radiotherapy type, total dose and dose‐volume;
- Baseline gastrointestinal symptoms.
Intervention details:
- Type of intervention, i.e. radiotherapy techniques, pharmacological interventions, treatment schedules, patient positioning and positioning devices, nutritional and other interventions, including dose, frequency, and timing;
- Type of comparator, e.g. other intervention, no active intervention (observation or placebo).
Risk of bias in study (see below);
Duration of follow‐up;
Study outcomes;
Review outcomes:
- time point/s for collection;
- type of scale used, scale thresholds used for determining severity of symptoms;
- For dichotomous outcomes (e.g. number of participants with moderate or severe gastrointestinal symptoms), the number of participants in each treatment arm who experienced the outcome of interest and the number of participants assessed at the time point;
- For continuous outcomes (e.g. QoL scores), the value and standard deviation of the outcome of interest and the number of participants assessed at the relevant time point in each treatment arm. We also extracted change‐from‐baseline score data where reported;
- Where possible, all data extracted were those relevant to an intention‐to‐treat analysis, in which participants were analysed in the groups to which they were assigned. We resolved differences between review authors by discussion or by appeal to a third review author when necessary;
- We anticipated inter‐study heterogeneity in the measurement and reporting of gastrointestinal symptoms. We therefore prespecified that we would consider acute and late GI effects to be ‘severe’ if they were classified as grade 3 or higher according to CTCAE or EORTC RTOG criteria, or determined to be ‘severe’ by investigators according to investigator‐interview or self‐report questionnaires, such as the Gastrointestinal Symptom Rating Scale (GSRS). Similarly, we considered ‘moderate’ GI effects to be the equivalent of CTCAE or RTOG grade 2 assessments or as determined by investigators according to the measurement scale used, and 'mild' effects to be the equivalent of grade 1 (Table 26). In the event that symptom events were reported but not graded, we extracted the available symptom data from the report and noted the potential risk of bias for these data.

1. Toxicity scoring systems.

Common gastrointestinal toxicity scoring systems
	Grade 1	Grade 2	Grade 3	Grade 4
EORTC/RTOG small/large intestine: acute morbidity	Increased frequency or change in quality of bowel habits not requiring medication / rectal discomfort not requiring analgesics	Diarrhoea requiring medication / mucous discharge not necessitating sanitary pads / rectal or abdominal pain requiring analgesics	Diarrhoea requiring parenteral support / severe mucous or blood discharge necessitating sanitary pads / abdominal distention (flat plate radiograph demonstrates distended bowel loops)	Acute or subacute obstruction, fistula or perforation; GI bleeding requiring transfusion; abdominal pain or tenesmus requiring tube decompression or bowel diversion
EORTC/RTOG small/large intestine: late morbidity	‐ Mild diarrhoea ‐ Mild cramping ‐ Bowel movement 5 times daily ‐ Slight rectal discharge or bleeding	‐ Moderate diarrhoea and colic ‐ Bowel movement > 5 times daily ‐ Excessive rectal mucus or intermittent bleeding	Obstruction or bleeding requiring surgery	Necrosis / Perforation Fistula
CTCAE version 4.0 (diarrhoea)	Increase of < 4 stools a day over baseline	Increase of 4 ‐ 6 stools per day over baseline	Increase of ≥ 7 stools a day over baseline; incontinence; hospitalisation indicated	Life‐threatening consequences; urgent intervention indicated
CTCAE version 4.0 (rectal bleeding)	Mild; intervention not indicated	Moderate symptoms; medical intervention or minor cauterisation indicated	Transfusion, radiologic, endoscopic, or elective operative intervention indicated	Life‐threatening consequences; urgent intervention indicated

Study ID	Intervention (I)	Comparator (C)	Participants	Cancer type	Primary or adjuvant radiotherapy	Findings		Risk of bias judgement (study limitations)	Study conclusions	Reviewer comments
Study ID	Intervention (I)	Comparator (C)	Participants	Cancer type	Primary or adjuvant radiotherapy	Acute gastrointestinal toxicity	Late gastrointestinal toxicity	Risk of bias judgement (study limitations)	Study conclusions	Reviewer comments
Pharmacological interventions
Hombrink 2000	smectite	placebo	176 men and women	mainly pelvic, plus some abdominal cancers	primary and adjuvant	NR Reported time to development of diarrhoea	NR	Unclear risk	"Prophylactic smectite can delay the development of RT‐induced diarrhoea. A statistical significance could not be verified..."	No usable data for review purposes
Kardamakis 1995	tropisetron (oral)	placebo	33 men and women	various pelvic	primary	5/? vs 4/? No difference in number of bowel actions	NR	High risk	Tropisetron showed no anti‐diarrhoeal effect	Poorly‐reported study that suggests no benefit
McGuffin 2016	simethicone (oral)	placebo	78 men	prostate	primary	NR	NR	Unclear risk	"standardized bowel preparation education alone may be sufficient to limit the variation in rectal size over a course of radiation treatment."	GI toxicity was not reported by study arm in this conference abstract, but authors noted no benefits with this anti‐flatulence treatment
Razzaghdoust 2014	famotidine (oral)	placebo	36 men	prostate	primary	G2+ GI toxicity 2/16 (I) and 10/18 (C)	NR	Unclear risk	"We demonstrated that famotidine significantly reduces radiation‐induced injury on rectal mucosa..." Famotidine inhibits gastric acid secretion and is a powerful free radical scavenger.	Pilot study ‐ more research needed
Stryker 1979	ibuprofen (oral)	no intervention	31 women/1 man	gynaecological/prostate	primary	NR Reported no. of participants reporting 4 or more stools a day at least once: 10/17 (I) vs 8/15 (C) Vomiting: 0/17 (I) vs 4/15 (C)	NR	High risk	"The incidence and severity of diarrhoea was the same." "Prophylactic ibuprofen may be beneficial in reducing the severity of nausea and preventing radiation‐induced vomiting..."	Older study with very uncertain evidence and applicability
Non‐pharmacological interventions
Ahmad 2010	soy diet	regular diet	42 men (26 analysed)	prostate	primary	cramping or diarrhoea: 2/13 (I) vs 1/13 (C) pain with bowel movements: 1/13 (I) vs 0/13 (C)	cramping or diarrhoea: 1/13 (I) vs 3/13 (C) pain with bowel movements: 1/13 (I) vs 2/13 (C)	High risk	Soy isoflavones might reduce GI and other radiation‐induced toxicity	High attrition was a problem in this underpowered study, so findings are inconclusive/very uncertain
Arregui Lopez 2012	steady diet	control (exclusion diet)	29	rectal	primary	NR	NR	High risk	"control group showed a significant increase in incidence and grade of acute diarrhoea > G2 at end of treatment"	Available as abstract only with scant details of the intervention and data
Emami 2014	green tea (oral tablet)	placebo	23 men and 19 women	various pelvic	primary and adjuvant	G1+ diarrhoea: 7/21 (I) vs 12/21 (C)	NR	High risk	"Green tea...could be effective in decreasing the frequency and severity of radiotherapy induced diarrhoea"	Underpowered study, so findings are inconclusive/very uncertain ‐ more research needed
Hejazi 2013	curcumin (oral tablet)	placebo	40 men	prostate	primary	Mean GI symptom score: 25 (12.4) (I) vs 20.0 (18.0) (C)	NR	High risk	Curcumin "could not reduce the severity of bowel symptoms" but "could confer radioprotective effect...through reducing severity of radiotherapy related urinary symptoms"	Underpowered study, so findings are inconclusive/very uncertain ‐ more research needed
Other aspects of radiotherapy delivery
Gaya 2013	belly board	standard practice	30	rectal	NR	Poorly‐reported toxicity data could not be extracted according to treatment arms	NR	High risk	"Set‐up reproducibility, small bowel V15, patient comfort and satisfaction were all significantly improved by the use of the Belly Board"	Interim analysis with serious design limitations
Habl 2016	proton technique	carbon ion technique	92 men	prostate	primary	G2+ diarrhoea occurred in 4/46 (I) vs 0/45 (C) participants, respectively. 2 participants in the proton arm developed G3 rectal fistulas	NR	Unclear risk	Authors attributed the fistulas to the use of spacer gel, which they have stopped using. Diarrhoea scores and bowel symptoms tended to be worse in the proton arm than the carbon ion arm at end of treatment, 6 weeks and 6‐month assessments. Authors concluded that hypofractionation with "either carbon ions or protons results in comparable acute toxicities and QoL parameters."	More evidence is needed
Ljubenkovic 2002	patient table	standard practice	183 women	cervix	NR	G2+ "stool frequency" during RT occurred in 7/90 (I) and 34/93 (C) participants; 8/90 (I) vs 39/93 (C) required anti‐diarrhoeal medication; G2+ cramping occurred in 4/90 (I) vs 32/93 (C)	NR	High risk	"Use of the unique patient‐table led to protection of the small bowel during radiotherapy for uterine malignancies..."	Serious study design limitations undermine the usefulness of these findings
Sidik 2007	HBOT**	no HBOT	65 women	cervix	NR	Change from baseline in LENT‐SOMA scores were reported but data were not usable (reported as percentages)	Change from baseline in LENT‐SOMA scores were reported but data were not usable (reported as percentages)	High risk	"The HBOT procedure yield hyperoxia, hypervascular and hypercellular that improved the tissue damage after pelvic radiation. This condition will decrease acute and late side effect showed by LENT SOMA scale and improved QoL shown by Karnofsky score."	Serious study design limitations undermine the usefulness of these findings

Conformal RT compared with conventional RT to reduce adverse GI effects of radiotherapy
Patient or population: People with urological (prostate) gynaecological (cervical) cancer Settings: Tertiary care setting Intervention: Conformal RT (3DCRT and IMRT) Comparison: Conventional RT
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Conventional RT	Conformal RT (3DCRT and IMRT)
Mean GI symptom scores	‐	‐	Not estimable	0	‐	No data
Acute and late GI toxicity grade 2+	Acute toxicity (up to 3 months post‐RT): 365 per 1000	Acute toxicity (up to 3 months post‐RT): 208 per 1000 (146 to 299)	RR 0.57 (0.40 to 0.82)	307 (2)	⊕⊕⊕⊕ high	The effects in 3DCRT and IMRT subgroups were consistent with the overall effect estimate
Acute and late GI toxicity grade 2+	Late toxicity (from 6 months post‐RT): 155 per 1000	Late toxicity (from 6 months post‐RT): 76 per 1000 (34 to 171)	RR0.49 (0.22 to 1.09)	517 (3)	⊕⊕⊕⊝ moderate¹	The effects in 3DCRT and IMRT subgroups were consistent with the overall effect estimate but there was substantial heterogeneity within the 3DCRT subgroup (I² = 60%)
Diarrhoea (grade 2+)	‐	‐	Not estimable	0	‐	No data
QoL scores	‐	‐	Not estimable	0	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

IMRT compared with 3DCRT to reduce adverse GI effects of radiotherapy
Patient or population: People with urological (prostate) and gynaecological (cervical) cancer Settings: Tertiary care setting Intervention: IMRT Comparison: 3DCRT
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	3DCRT	IMRT
Mean GI symptom scores (EORTC‐QLQPR25 scale; lower scores better)	At 6 months post‐RT, the mean GI symptom score in the control group was 9	At 6 months post‐RT, the mean GI symptom score in the intervention group was 4 (1 to 9 points lower)	MD ‐5.00 (‐9.06 to ‐0.94)	181 (1)	⊕⊕⊝⊝ low^{1, 2}	‐
Acute and late GI toxicity Grade 2+	Acute toxicity (up to 3 months post‐RT): 445 per 1000	Acute toxicity (up to 3 months post‐RT): 214 per 1000 (116 to 392)	RR 0.48 (0.26 to 0.88)	444 (4)	⊕⊕⊝⊝ low^{1, 3}	Inconsistency was present between studies in the gynaecological cancer subgroup but not between gynaecological and urological subgroups
Acute and late GI toxicity Grade 2+	Late toxicity (from 6 months post‐RT): 228 per 1000	Late toxicity (from 6 months post‐RT): 84 per 1000 (48 to 148)	RR0.37 (0.21 to 0.65)	332 (2)	⊕⊕⊝⊝ low⁴	Findings were consistent across gynaecological and urological subgroups.
Diarrhoea (grade 2+)	Acute toxicity (up to 3 months post‐RT): 720 per 1000	Acute toxicity (up to 3 months after RT): 273 per 1000 (158 to 490)	RR 0.38 (0.22 to 0.68)	72 (1)	⊕⊕⊝⊝ low^{1, 5}	‐
QoL scores	‐	‐	Not estimable	0	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; MD: mean difference; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

BT compared with EBRT to reduce adverse GI effects of radiotherapy
Patient or population: People with urological (prostate) and gynaecological (endometrial) cancer Settings: Tertiary care settings Intervention: BT Comparison: EBRT
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	EBRT	BT
Mean GI symptom scores	‐	‐	Not estimable	348 (1)	‐	1 high‐quality study reported data on GI symptom scores at various time points after radiotherapy up to 5 years. Due to the numberous time points and domains, we could not use these data in the review meta‐analysis in a meaningful way. However, the findings favoured BT for 'limitation in daily activities due to bowel symptoms' (P < 0.001), faecal leakage (P < 0.001) and rectal blood loss (P = 0.04) at most time points up to 5 years post‐radiotherapy
Acute and late GI toxicity (grade 2+)	Acute GI toxicity (Up to 3 months after RT): ‐	Acute GI toxicity (Up to 3 months after RT): ‐	not pooled	not pooled	‐	Due to clinical and statistical heterogeneity, data from the two relevant studies were not pooled for this outcome and subgroup evidence was graded separately. Evidence from the urological (prostate) cancer was graded as very low certainty. However, the evidence in favour of BT from the one study in the 'gynaecological cancer' subgroup was graded as high‐certainty (RR 0.02, 95% CI 0.00 to 0.18; participants = 423; studies = 1).
Acute and late GI toxicity (grade 2+)	Late GI toxicity (from 6 months post‐RT): 26 per 1000	Late GI toxicity (from 6 months post‐RT): 4 per 1000 (0 to 35)	RR 0.16 (0.02 to 1.33)	423 (1)	⊕⊕⊝⊝ low³	‐
Diarrhoea (grade 2+)	Acute diarrhoea (Up to 3 months after RT)	‐	Not estimable	0	‐	No data
QoL scores (EORTC Q30)	Measured in one study at various time points up to 5 years and beyond	‐	Not estimable	348 (1)	‐	1 high‐quality study reported data on QoL scores at various time points after radiotherapy to 5 years and found no clear difference in global health status between BT and EBRT groups
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Reduced radiation dose volume compared with standard dose volume to reduce adverse GI effects of radiotherapy
Patients/population: People undergoing RT for pelvic cancer¹ Settings: Tertiary care Intervention: Reduced radiation dose‐volume Comparison: Standard radiation dose‐volume
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	standard radiation dose volume	reduced radiation dose volume
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute (up to 3 months post‐RT) : 282 per 1000	Acute (up to 3 months post‐RT): 341 per 1000 (228 to 510)	RR 1.21 (0.81 to 1.81)	211 (1)	⊕⊕⊕⊝ moderate²	‐
	Late (1 year post‐RT): 37 per 1000	Late (1 year post RT): 38 per 1000 (6 to 258)	RR 1.02 (0.15 to 6.97)	107 (1)	⊕⊕⊝⊝ low³	‐
	Late (2 years post‐RT): 71 per 1000	Late (2 years post RT): 27 per 1000 (3 to 247)	RR 0.38 (0.04 to 3.48)	79 (1)	⊕⊕⊝⊝ low³	‐
Diarrhoea (grade 2+)	‐	‐	not estimable	‐	‐	No data
QOL scores	‐	‐	not estimable	‐	‐	no data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Higher bladder volume (BV) compared with lower BV preparation to reduce adverse GI effects of radiotherapy
Patients/population: Men undergoing RT for prostate cancer Settings: Tertiary care Intervention: BV prep of 1080 mls Comparison: BV prep of 540 mls
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	540 mls BV prep	1080 mls BV prep
Mean GI symptom scores (during RT)	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute (up to 3 months post RT): 60 per 1000	Acute (up to 3 months post‐RT): 133 per 1000 (37 to 476)	RR 2.22 (0.62 to 7.93)	110 (1)	⊕⊕⊝⊝ low^1,2	‐
Acute and late GI toxicity (grade 2+)	Late (up to 1 year post‐RT): 158 per 1000	Late (up to 1 year post‐RT): 70 per 1000 (19 to 261)	RR 0.44 (0.12 to 1.65)	81 (1)	⊕⊕⊝⊝ low^1,2	‐
Diarrhoea (grade 2+)	‐	‐	not estimable	‐	‐	No data
QOL scores	‐	‐	not estimable	‐	‐	Insufficient data for meta‐analysis; however, authors stated that "There were no statistically significant associations between bladder filling preparations...and median QOL scores."
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Evening RT compared with morning RT to reduce adverse GI effects of radiotherapy
Patients/population: Women undergoing RT for cervical cancer Settings: Tertiary care Intervention: Evening RT Comparison: Morning RT
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	morning RT	evening RT
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute (during RT): 349 per 1000	Acute (during RT): 178 per 1000 (119 to 265)	RR 0.51 (0.34 to 0.76)	294 (2)	⊕⊕⊝⊝ low¹	Measured as diarrhoea grade 2+
Acute and late GI toxicity (grade 2+)	Late: ‐	Late: ‐	not estimable	‐	‐	No data
Diarrhoea (grade 2+) (during RT)	See evidence on acute toxicity (grade 2+)					‐
QOL scores	‐	‐	not estimable	‐	‐	no data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Transperineal hydrogel spacer/injection compared with no intervention to reduce adverse GI effects of radiotherapy
Patients/population: Men undergoing RT for prostate cancer Settings: Tertiary care Intervention: Transperineal hydrogel spacer/injection Comparison: No intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	no intervention	hydrogel spacer
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data available
Acute and late GI toxicity (grade 2+)	Acute (up to 3 months post‐RT): 65 per 1000	Acute (up to 3 months post‐RT): 33 per 1000 (5 to 220)	RR 0.51 (0.08 to 3.38)	289 (2)	⊕⊕⊝⊝ low^{1, 2}	Events in these contributing studies were few
	Late (up to 15 months post‐RT): 14 per 1000	Late (up to 15 months post‐RT): 2 per 1000 (0 to 55)	RR 0.16 (0.01 to 3.96)	220 (1)	⊕⊕⊝⊝ low^{1, 2}	Events in this contributing study were few
	Late (median of 3 years): 67 per 1000	Late (median of 3 years): 15 per 1000 (0 to 88)	RR 0.07 (0.00 to 1.31)	139 (1)	⊕⊕⊝⊝ low^{1, 2}	Events in this contributing study were few
Diarrhoea (grade 2+)	‐	‐	not estimable	‐	‐	No data available
QOL scores	‐	‐	not estimable	‐	‐	Data could not be meta‐analysed, but findings from 2 studies suggested beneficial effects on bowel‐related QOL with the hydrogel spacer (see Effects of interventions section).
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Endorectal balloon compared with no intervention to reduce adverse GI effects of radiotherapy
Patients/population: Men undergoing RT for prostate cancer Settings: Tertiary care Intervention: Endorectal balloon Comparison: No intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	no intervention	endorectal balloon
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute (during RT): 292 per 1000	Acute (during RT): 292 per 1000 (120 to 707)	RR 1.00 (0.41 to 2.42)	48 (1)	⊕⊝⊝⊝ very low^{1, 2}	Evidence on acute grade 1+ GI toxicity was of low certainty and suggested little or no difference in acute toxicity with ERB (see Effects of interventions section)
Acute and late GI toxicity (grade 2+)	Late (up to 1 year): 83 per 1000	Late (up to 1 year): 17 per 1000 (1 to 329)	RR 0.20 (0.01 to 3.96)	48 (1)	⊕⊝⊝⊝ very low^{1, 2}	Evidence on late grade 1+ toxicity was of low certainty and suggested a reduction in late toxicity with ERB (see Effects of interventions section)
Diarrhoea (grade 2+)	Late (2 to 4 years): 565 per 1000	Late (2 to 4 years): 401 per 1000 (209 to 723)	RR 0.71 (0.37 to 1.35)	43 (1)	⊕⊝⊝⊝ very low^{1, 2}	‐
QOL scores	‐	‐	not estimable	‐	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QOL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Aminosalicylates compared with placebo administered prophylactically to reduce adverse GI effects of radiotherapy
Patient or population: People undergoing pelvic radiotherapy for urological, gynaecological or colorectal cancer Settings: Tertiary care Intervention: Aminosalicylates Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	aminosalicylates
Mean GI symptom scores (IBDQ‐B)	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute (during treatment) (mesalazine): 380 per 1000	Acute (during treatment) (mesalazine): 388 (464 to 551)	RR 1.02 (1.22 to 1.45)	143 (2)	⊕⊕⊕⊝ moderate¹	Formulations appear to differ in effects on this outcome; therefore subgroup data were not pooled. The sulfasalazine findings were very inconsistent (I² = 73%) across the 2 contributing studies, with the better‐quality study showing no reduction in acute toxicity
	Acute (during treatment) (sulphasalazine): 447 per 1000	Acute (during treatment) (sulphasalazine): 130 (49 to 335)	RR 0.29 (0.11 to 0.75)	182 (2)	⊕⊕⊝⊝ low^1,2
	Late: ‐	Late: ‐	not estimable	‐	‐	No data
Diarrhoea (grade 2+)	‐	‐	not pooled	‐	‐	As above, subgroup data were not pooled and findings were as follows: mesalazine: RR 1.55, 95% CI 1.14 to 2.10; participants = 191; studies = 2; I² = 0% olsalazine: RR 1.70, 95% CI 1.00 to 2.87; participants = 58; studies = 1 sulfasalazine: RR 0.80, 95% CI 0.41 to 1.58; participants = 171; studies = 2; I² = 69%. Downgrading of these findings by 1 level was due to study design limitations (unclear risk of bias) in all subgroups, and also due to inconsistency for the sulfasalazine subgroup
QOL scores	‐	‐	not estimable	‐	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Acute GI toxicity: grade 2+	2	307	Risk Ratio (IV, Random, 95% CI)	0.57 [0.40, 0.82]
1.1.1 3DCRT vs conRT	1	263	Risk Ratio (IV, Random, 95% CI)	0.60 [0.39, 0.93]
1.1.2 IMRT vs conRT	1	44	Risk Ratio (IV, Random, 95% CI)	0.50 [0.25, 1.00]
1.2 Late GI toxicity: grade 2+	3	517	Risk Ratio (IV, Random, 95% CI)	0.49 [0.22, 1.09]
1.2.1 3DCRT vs conRT	2	473	Risk Ratio (IV, Random, 95% CI)	0.56 [0.23, 1.35]
1.2.2 IMRT vs conRT	1	44	Risk Ratio (IV, Random, 95% CI)	0.20 [0.03, 1.58]
1.3 Acute GI toxicity: grade 1+	2	307	Risk Ratio (IV, Random, 95% CI)	0.75 [0.42, 1.36]
1.3.1 3DCRT vs conRT	1	263	Risk Ratio (IV, Random, 95% CI)	0.94 [0.85, 1.04]
1.3.2 IMRT vs conRT	1	44	Risk Ratio (IV, Random, 95% CI)	0.50 [0.25, 1.00]
1.4 Late GI toxicity: grade 1+	2	292	Risk Ratio (IV, Random, 95% CI)	0.55 [0.19, 1.59]
1.4.1 3DCRT vs conRT	1	248	Risk Ratio (IV, Random, 95% CI)	0.84 [0.68, 1.04]
1.4.2 IMRT vs conRT	1	44	Risk Ratio (IV, Random, 95% CI)	0.27 [0.09, 0.85]
1.5 Vomiting: grade 2+	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
1.5.1 IMRT vs conRT	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
1.6 Medication for GI symptom control	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
1.6.1 3DCRT vs conRT	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 GI symptom score (6 months)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2.1.1 Urological cancer	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2.2 GI symptom score (2 years)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2.2.1 Urological cancer	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2.3 Acute GI toxicity: grade 2+	4	444	Risk Ratio (IV, Random, 95% CI)	0.48 [0.26, 0.88]
2.3.1 Gynaecological cancer	3	229	Risk Ratio (IV, Random, 95% CI)	0.54 [0.28, 1.07]
2.3.2 Urological cancer	1	215	Risk Ratio (IV, Random, 95% CI)	0.31 [0.15, 0.66]
2.4 Late GI toxicity: grade 2+	2	332	Risk Ratio (IV, Random, 95% CI)	0.37 [0.21, 0.65]
2.4.1 Gynaecological cancer	1	117	Risk Ratio (IV, Random, 95% CI)	0.46 [0.20, 1.05]
2.4.2 Urological cancer	1	215	Risk Ratio (IV, Random, 95% CI)	0.30 [0.13, 0.66]
2.5 Acute GI toxicity: grade 1+	4	444	Risk Ratio (IV, Random, 95% CI)	0.59 [0.41, 0.86]
2.5.1 Gynaecological cancer	3	229	Risk Ratio (IV, Random, 95% CI)	0.67 [0.48, 0.95]
2.5.2 Urological cancer	1	215	Risk Ratio (IV, Random, 95% CI)	0.31 [0.15, 0.66]
2.6 Late GI toxicity: grade 1+	2	332	Risk Ratio (IV, Random, 95% CI)	0.65 [0.46, 0.93]
2.6.1 Urological cancer	1	215	Risk Ratio (IV, Random, 95% CI)	0.71 [0.47, 1.05]
2.6.2 Gynaecological cancer	1	117	Risk Ratio (IV, Random, 95% CI)	0.46 [0.20, 1.05]
2.7 Diarrhoea: grade 2+	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
2.7.1 Gynaecological cancer	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
2.8 Vomiting: grade 2+	2	112	Risk Ratio (IV, Random, 95% CI)	0.60 [0.29, 1.24]
2.8.1 Gynaecological cancer	2	112	Risk Ratio (IV, Random, 95% CI)	0.60 [0.29, 1.24]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Acute GI toxicity: grade 2+	2		Risk Ratio (IV, Random, 95% CI)	Subtotals only
3.1.1 Gynaecological cancer	1	423	Risk Ratio (IV, Random, 95% CI)	0.02 [0.00, 0.18]
3.1.2 Urological cancer	1	20	Risk Ratio (IV, Random, 95% CI)	0.33 [0.04, 2.69]
3.2 Late GI toxicity: grade 2+	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
3.2.1 Gynaecological cancer	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
3.3 Acute GI toxicity: grade 1	2		Risk Ratio (IV, Random, 95% CI)	Subtotals only
3.3.1 Gynaecological cancer	1	423	Risk Ratio (IV, Random, 95% CI)	0.33 [0.22, 0.50]
3.3.2 Urological cancer	1	20	Risk Ratio (IV, Random, 95% CI)	0.75 [0.22, 2.52]
3.4 Late GI toxicity: grade 1	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
3.4.1 Gynaecological cancer	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
3.5 Treatment discontinuation	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
3.5.1 Gynaecological cancer	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Acute GI toxicity: grade 2+	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
4.2 Acute GI toxicity: grade 1+	3	354	Risk Ratio (IV, Random, 95% CI)	0.61 [0.34, 1.10]
4.3 Late GI toxicity: grade 2+ (1 year post‐RT)	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
4.4 Late GI toxicity: grade 2+ (2 years post‐RT)	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
4.5 Late GI toxicity: grade 1+	2	154	Risk Ratio (IV, Random, 95% CI)	1.15 [0.49, 2.68]

Superoxide dismutase compared with no intervention to reduce adverse GI effects of radiotherapy
Patient or population: People with rectal cancer Settings: Tertiary care Intervention: Superoxide dismutase (IM) Comparison: No intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	no intervention	superoxide dismutase
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute (3 months): 217 per 1000	Acute (3 months): 43 per 1000 (11 to 187)	RR 0.20 (0.05 to 0.86)	92 (1)	⊕⊕⊝⊝ low^{1, 2}	‐
	Late: (1 year): 135 per 1000	Late (1 year): 12 per 1000 (1 to 209)	RR 0.09 (0.01 to 1.55)	75 (1)	⊕⊝⊝⊝ very low^1,3	‐
	Late (2 to 4 years): 193 per 1000	Late (2 to 4 years): 12 per 1000 (0 to 225)	RR 0.06 (0.00 to 1.11)	68 (1)	⊕⊝⊝⊝ very low^1,3	‐
Diarrhoea (grade 2+)	‐	‐	not estimable	‐	‐	No data
QOL scores	‐	‐	not estimable	‐	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Corticosteroid enema compared with placebo to reduce adverse GI effects of radiotherapy
Patients/population: Men with prostate cancer Settings: Tertiary care Intervention: Corticosteroid enema Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	corticosteroid enema
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute (3 months): 619 per 1000	Acute (3 months): 526 per 1000 (384 to 712)	RR 0.85 (0.62 to 1.15)	126 (1)	⊕⊝⊝⊝ very low^{1, 2, 3}	‐
Acute and late GI toxicity (grade 2+)	Late: (1 year): 136 per 1000	Late (1 year): 91 per 1000 (31 to 262)	RR0.67 (0.23 to 1.93)	114 (1)	⊕⊕⊝⊝ low⁴	‐
Diarrhoea (grade 2+)	Acute: ‐	Acute: ‐	not estimable	‐	‐	No data
Diarrhoea (grade 2+)	Late (1 year): 68 per 1000	Late (1 year): 73 per 1000 (19 to 277)	RR1.07 (0.28 to 4.08)	114 (1)	⊕⊕⊝⊝ low⁴	‐
QOL scores	‐	‐	not estimable	‐	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Sucralfate compared with placebo administered prophylactically to reduce adverse GI effects of radiotherapy
Patient or population: People undergoing pelvic radiotherapy for urological, gynaecological or colorectal cancer Settings: Tertiary care Intervention: Sucralfate Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	sucralfate
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+) [acute = during RT; late = 6 months post‐RT]	Acute (oral route): 398 per 1000	Acute (oral route): 426 per 1000 (330 to 553)	RR 1.07 (0.83 to 1.39)	335 (1)	⊕⊕⊕⊝ moderate¹	‐
	Acute (rectal route): 524 per 1000	Acute (rectal route): 618 per 1000 (456 to 838)	RR 1.18 (0.87 to 1.60)	126 (1)	⊕⊕⊝⊝ low^1,2	‐
	Late (oral route): 284 per 1000	Late (oral route): 216 per 1000 (110 to 324)	RR 0.76 (0.51 to 1.14)	298 (1)	⊕⊕⊕⊝ moderate¹	No data on rectal route
Diarrhoea (grade 2+) [during RT]	Acute (oral route): 490 per 1000	Acute (oral route): 397 per 1000 (201 to 794)	RR 0.81 (0.41 to 1.62	)284 (4)	⊕⊕⊝⊝ low^{1, 3}	‐
Diarrhoea (grade 2+) [during RT]	Acute (rectal route): 357 per 1000	Acute (rectal route): 293 per 1000 (143 to 546)	RR 0.82 (0.44 to 1.53)	83 (1)	⊕⊝⊝⊝ verylow^1,2,4	‐
QOL scores	‐	‐	not estimable	‐	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Amifostine compared with no intervention to reduce adverse GI effects of radiotherapy
Patient or population: People with urological, gynaecological or colorectal cancer Settings: Tertiary care Intervention: Amifostine (subcutaneous or intravenously administered) Comparison: No intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	no intervention	amifostine
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute (during RT): 398 per 1000	Acute (during RT: 100 per 1000 (60 to 167)	RR 0.25 0.15 to 0.42	278 (3)	⊕⊕⊝⊝ low¹	‐
	Acute (up to 3 months): 174 per 1000	Acute (up to 3 months): 21 per 1000 (2 to 369)	RR 0.12 (0.01 to 2.12)	44 (1)	⊕⊝⊝⊝ very low^{2, 3, 4}	‐
	Late (up to 1 year): 59 per 1000	Late (up to 1 year): 87 per 1000 (38 to 204)	RR 1.48 (0.64 to 3.45)	249 (2)	⊕⊕⊝⊝ low^{2, 4}	‐
Diarrhoea (grade 2+) during treatment	Acute (during RT): 500 per 1000	Acute (during RT):125 per 1000 (30 to 490)	RR 0.25 (0.06 to 0.98)	36 (1)	⊕⊝⊝⊝ very low^{2, 3, 4}	‐
QOL scores	‐	‐	not estimable	‐	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Sodium butyrate compared with placebo to reduce adverse GI effects of radiotherapy
Patients/population: Men undergoing RT for prostate cancer Settings: Tertiary care Intervention: Sodium butyrate enema Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	sodium butyrate enema (2 g daily)
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute (during RT): 179 per 1000	Acute (during RT): 163 per 1000 (74 to 354)	RR 0.91 (0.41 to 1.98)	79 (1)	⊕⊕⊕⊝ moderate¹	‐
Acute and late GI toxicity (grade 2+)	‐	‐	not estimable	‐	‐	No data
Diarrhoea (grade 2+)	‐	‐	not estimable	‐	‐	No data
QOL scores	‐	‐	not estimable	‐	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Selenium compared with placebo to reduce adverse GI effects of radiotherapy
Patients/population: Women undergoing RT for gynecological cancer Settings: Tertiary care Intervention: Oral selenium Comparison: No intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	oral selenium
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute: ‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Late: ‐	‐	not estimable	‐	‐	No data
Diarrhoea (grade 2+)	Acute (during RT): 190 per 1000	Acute (during RT): 76 per 1000 ( 23 to 268)	RR 0.40 0.12 to 1.41	81 (1)	⊕⊕⊝⊝ low^{1, 2}	‐
QOL scores	‐	‐	not estimable	‐	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Bile acid sequestrants compared with placebo to reduce adverse GI effects of radiotherapy
Patients/population: People with pelvic cancer Settings: Tertiary care Intervention: Bile acid sequestrants Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	bile acid sequestrants
Mean GI symptom scores (during RT)	The mean (diarrhoea) score in the single study evaluating this outcome was 1.5	Corresponding mean score of 2 (1.5 to 2.5)	MD 0.50 (‐0.00 to 1.00)	33 (1)	⊕⊝⊝⊝ very low^1,2	‐
Acute and late GI toxicity (grade 2+)	Acute (during RT): 125 per 1000	Acute (during RT): 530 per 1000 (134 to 1000)	RR 4.24 (1.07 to 16.70)	33 (1)	⊕⊕⊝⊝ low^{1, 3}	Findings suggest potential for harm
Acute and late GI toxicity (grade 2+)	‐	‐	not estimable	‐	‐	No data
Diarrhoea (grade 2+)	Acute (during RT: 125 per 1000	Acute (during RT): 353 per 1000 (83 to 1000)	RR 2.82 (0.66 to 12.01)	33 (1)	⊕⊝⊝⊝ very low^1,2	‐
QOL scores	‐	‐	not estimable	‐	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Misoprostol compared with placebo to reduce adverse GI effects of radiotherapy
Patients/population: Men with prostate cancer Settings: Tertiary care Intervention: Misoprostol suppository Comparison: Placebo
Outcomes¹	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	misoprostol suppository
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute (during RT): 217 per 1000	Acute (during RT): 340 per 1000 (165 to 545)	RR 1.38 (0.76 to 2.51)	100 (1)	⊕⊕⊝⊝ low^{2, 3}	See footnote 1 below
Acute and late GI toxicity (grade 2+)	Late: ‐	Late: ‐	not estimable	‐	‐	No data
Diarrhoea (grade 2+)	Acute (during RT): 217 per 1000	Acute (during RT): 217 per 1000 (100 to 475)	RR 1.00 (0.46 to 2.19)	100 (1)	⊕⊝⊝⊝ very low^{2, 3, 4}	Late effects on diarrhoea at 1+ years post‐RT were also reported in this single study and the evidence was also of a very low certainty, mainly due to few events
QOL scores	‐	‐	not estimable	‐	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Magnsium oxide compared with placebo to reduce adverse GI effects of radiotherapy
Patients/population: Men with prostate cancer Settings: Tertiary care Intervention: Oral magnesium oxide Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	magnesium oxide
Mean GI symptom scores (during RT)	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute (during RT): 217 per 1000	Acute (during RT): 369 per 1000 (189 to 718)	RR 1.70 (0.87 to 3.31)	92 (1)	⊕⊕⊕⊝ moderate¹	Findings indicate potential for harm
Acute and late GI toxicity (grade 2+)	‐	‐	not estimable	‐	‐	No data
Diarrhoea (grade 2+)	‐	‐	not estimable	‐	‐	No data
QOL scores	‐	‐	not estimable	‐	‐	No data for meta‐analysis. The only included study presents these data graphically and concludes that there was "a trend to worsened quality of life" in the magnesium oxide arm
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Octreotide compared with placebo to reduce adverse GI effects of radiotherapy
Patients/population: People undergoing RT for pelvic cancer Settings: Tertiary care Intervention: Octreotide injection Comparison: Placebo
Outcomes¹	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	octreotide injection
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute: ‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Late: ‐	‐	not estimable	‐	‐	No data
Diarrhoea (grade 2+)	Acute (during RT): 491 per 1000	Acute (during RT): 496 per 1000 (373 to 663)	RR 1.01 (0.76 to 1.35)	340 (2)	⊕⊕⊕⊝ moderate²	‐
QOL scores	‐	‐	not estimable	‐	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

PERMALINK

Interventions to reduce acute and late adverse gastrointestinal effects of pelvic radiotherapy for primary pelvic cancers

Theresa A Lawrie

John T Green

Mark Beresford

Linda Wedlake

Sorrel Burden

Susan E Davidson

Simon Lal

Caroline C Henson

H Jervoise N Andreyev

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

Radiotherapy delivery techniques

Image‐guided radiotherapy (IGRT)

Stereotactic body radiotherapy (SBRT)

Brachytherapy (BT)

Other aspects of radiotherapy delivery

Patient positioning or positioning devices

Timing of delivery

Fractionation

Other interventions

Pharmacological interventions

Mucosal protectants

Anti‐inflammatory agents

Statins (3‐hydroxy‐methylglutaryl coenzyme‐a reductase inhibitors) and angiotensin‐converting enzyme (ACE) inhibitors

Other agents

Non‐pharmacological interventions

Probiotics

Nutritional interventions

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

Selection of studies

Data extraction and management

1. Toxicity scoring systems.

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

'Summary of findings' table and results reporting

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

Radiotherapy techniques

3DCRT versus conventional radiotherapy (conRT)

IMRT versus conRT

IMRT versus 3DCRT

Brachytherapy (BT) versus external beam radiotherapy (EBRT)

Other aspects of radiotherapy delivery

Proton versus carbon ion technique

Diet interventions compared with usual practice to reduce adverse GI effects of radiotherapy
Patient or population: People undergoing pelvic radiotherapy for urological, gynaecological or colorectal cancer Settings: Tertiary care Intervention: Dietary intervention Comparison: Control (usual on‐treatment diet)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	control	diet
Elemental diet
Mean GI symptom scores (IBDQ‐B) (higher scores better)	Acute (during RT): median score 60 (35 ‐ 69) Acute effect (3 months post RT): median score 69 (34 ‐ 70)	Acute (during RT): median score 57 (23‐66) Acute effect (3 months post‐RT): median score 68 (42 ‐ 70)	not estimable	50 (1)	⊕⊕⊝⊝ low¹	There was poor compliance in this study and only a third of daily calories substituted with elemental diet
Acute and late GI toxicity (grade 2+)	Acute: ‐	Acute: ‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Late: ‐	Late: ‐	not estimable	‐	‐	No data
Diarrhoea (grade 2+)	Acute (during RT): 560 per 1000	Acute (during RT): 442 per 1000 (252 to 773)	RR 0.79 (0.45 to 1.38)	50 (1)	⊕⊕⊝⊝ low²	‐
QOL scores (IBDQ) (higher scores better)	During RT the mean QOL score in the control group was 186.4	During RT the mean QOL score in the diet group 4.6 points higher (12.4 points lower to 21.6 points higher)	MD 4.60 (‐12.40 to 21.60)	50 (1)	⊕⊕⊝⊝ low¹	‐
Lactose‐restricted diet
Mean GI symptom scores (IBDQ‐B) (higher scores better)	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute: ‐	Acute: ‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Late: ‐	Late: ‐	not estimable	‐	‐	No data
Diarrhoea (grade 1+)	Acute (during RT): 397 per 1000	Acute (during RT): 294 per 1000 (179 to 488)	RR 0.74 (0.45 to 1.23)	119 (1)	⊕⊕⊝⊝ low³	This study intervention included low insoluble fibre. No grade 2+ events occurred.
QOL scores (QLQ‐PR25)	‐	‐	not estimable	119 (1)	‐	In 1 study, QOL was reported for many time points and domains up to 24 months post‐RT and study authors found little difference between study arms at any time point evaluated; however, these data could not be extracted and analysed for review purposes in a meaningful way
High‐fibre diet
Mean GI symptom scores (IBDQ‐B) (higher scores better)	Acute (at end of RT): The mean IBDQ‐B score in the control group was 48.7	Acute: At the end of RT, the mean IBDQ‐B score in the diet group was 2.80 points higher (from 1.81 points lower to 7.41 points higher)	MD 2.80 (‐1.81 to 7.41)	108 (1)	⊕⊕⊝⊝ low⁴	Mean change in GI symptom scores from baseline to end of RT was also reported in 1 study (Wedlake 2017) and the evidence suggests that the change in IBDQ‐B scores from baseline may be reduced with a high‐fibre diet (see Results section)
	Late (at 1 year post‐RT): At 1 year post‐RT, the mean IBDQ‐B score was 55.7	At 1 year post‐RT, the mean IBDQ‐B score in the diet group was 6.1 points higher (1.71 to 10.49 points higher)	MD 6.10 (1.71 to 10.49)	108 (1)	⊕⊕⊝⊝ low⁴	As above, findings on mean change in GI symptom scores from 1 study suggests that IBDQ‐B scores are less likely to be reduced at 1 year post‐RT from baseline with a high‐fibre diet than with a usual diet (see Results section).
Acute and late GI toxicity (grade 2+)	‐	‐	not estimable	‐	‐	No data
Diarrhoea (grade 2+)	Acute (during RT): 540 per 1000	Acute (during RT): 351 per 1000 (205 to 594 )	RR 0.65 (0.38 to 1.10; participants)	74 (2)	⊕⊕⊝⊝ low⁴	‐
QOL scores (IBDQ) (higher scores better)	During RT the mean QOL score in the control group was 162	During RT, the mean QOL score in the diet group was 6.5 points higher (6 lower to 19 higher)	MD 6.50 (‐5.88 to 18.88)	108 (1)	⊕⊕⊝⊝ low⁴	‐
QOL scores (IBDQ) (higher scores better)	At 1 year post‐RT the mean QOL score was 173	At 1 year post‐RT, the mean QOL score in the diet group was 20.5 points higher (10 to 31 higher)	MD 20.50 (9.97 to 31.03)	108 (1)	⊕⊕⊝⊝ low⁵	‐
Low‐fibre diet
Mean GI symptom scores (IBDQ‐B) (higher scores better)	Acute (at end of RT): The mean IBDQ‐B score in the control group was 48.7	At the end of RT, the mean IBDQ‐B score in the diet group was 3.5 points higher (from 0.93 points lower to 7.93 points higher)	MD 3.50 (‐0.93 to 7.93)	107 (1)	⊕⊕⊝⊝ low⁴	Mean change in GI symptom scores from baseline to end of RT was also reported in 1 study (Wedlake 2017) and findings suggest that there may be little or no difference between diet and control groups (see Results section)
Mean GI symptom scores (IBDQ‐B) (higher scores better)	Late (at 1 year post RT): At 1 year post RT, the mean IBDQ‐B score was 55.7	At 1 year post‐RT, the mean IBDQ‐B score in the diet group was 3.30 points higher (from 0.94 points lower to 7.54 points higher)	MD 3.30 (‐0.94 to 7.54)	107 (1)	⊕⊕⊝⊝ low⁴	As above, mean change in GI symptom scores from baseline to 1 year post‐RT was also reported in one study (Wedlake 2017) and findings suggest that there may be little or no difference between diet and control groups (see Results section)
Acute and late GI toxicity (grade 2+)	‐	‐	not estimable	‐	‐	No data
Diarrhoea (grade 1+)	Acute (during RT): 397 per 1000	Acute (during RT): 294 per 1000 (179 to 488)	RR 0.74 (0.45 to 1.23)	119 (1)	⊕⊕⊝⊝ low²	This study intervention included lactose‐restriction
QOL scores (IBDQ) (higher scores better)	Acute (during RT): During RT the mean QOL score in the control group was 161.5	Acute (during RT): During RT, the mean QOL score in the diet group was 9.80 points higher (1.91 lower to 21.51 points higher)	MD 9.80 (‐1.91 to 21.51)	107 (1)	⊕⊕⊝⊝ low⁴	‐
QOL scores (IBDQ) (higher scores better)	Late (1 year post‐RT): At 6 months post‐RT, the mean QOL score in the control group was 173.6	Late: At 1 year post‐RT, the mean QOL score in the diet group was 9.4 points higher (1.78 lower to 20.58 points higher)	MD 9.40 (‐1.78 to 20.58)	107 (1)	⊕⊕⊝⊝ low⁴	‐
Low‐fat diet
Mean GI symptom scores (Vaizey scale) (higher scores better)	Acute: During RT the mean GI symptom score in the control group was 4.6	Acute: During RT, the mean GI symptom score in the diet group was 4.4 (2.4 to 6.5)	MD ‐0.20 (‐2.29 to 1.89)	70 (1)	⊕⊕⊝⊝ low⁴	‐
Acute and late GI toxicity (grade 2+)	436 per 1000	50 per 1000 (310 to 802)	RR 1.15 (0.71 to 1.84)	79 (1)	⊕⊕⊝⊝ low⁴	‐
Diarrhoea	‐	‐	not estimable	‐	‐	No data
QOL scores (IBDQ)	During RT the mean QOL score in the control group was 187	During RT, the mean QOL score in the diet group was 189 (177 to 201)	MD 2.40 (‐9.52 to 14.32)	76 (1)	⊕⊕⊝⊝ low⁴	‐
Prebiotic diet
Mean GI symptom scores (IBDQ‐B) (higher scores better)	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	‐	‐	not estimable	‐	‐	No data
Diarrhoea	‐	‐	not estimable	‐	‐	No data
QOL scores (IBDQ)	‐	‐	not estimable	‐	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; MD: Mean Difference; QoL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Protein supplements compared with no intervention to reduce adverse GI effects of radiotherapy
Patients/population: Individuals undergoing RT for pelvic cancer Settings: Tertiary care Intervention: Protein supplements Comparison: No intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	no intervention	protein supplements
Mean GI symptom scores (lower is better)	‐	‐	not estimable	‐	‐	Data were insufficient for meta‐analysis. However, diarrhoea scores significantly deteriorated from baseline to end of RT in both the protein supplement and the control groups, and mean diarrhoea scores (without standard deviations) were similar at 3‐month follow‐up
Acute and late GI toxicity (grade 2+)	Acute: ‐	Acute: ‐	not estimable	‐	‐	See evidence on diarrhoea
Acute and late GI toxicity (grade 2+)	Late: ‐	Late: ‐	not estimable	‐	‐	See evidence on diarrhoea
Diarrhoea (grade 2+)	Acute (end of RT): 459 per 1000	Acute (end of RT): 243 per 1000 (124 to 473)	RR 0.53 (0.27 to 1.03)	74 (1)	⊕⊝⊝⊝ verylow^{1, 2, 3}	‐
	Acute (3 months post‐RT): 351 per 1000	Acute (3 months post‐RT): 14 per 1000 (0 to 211)	RR 0.23 (0.07 to 0.74)	74 (1)	⊕⊕⊝⊝ low^{2, 3}	‐
	Late (5 years post‐RT): 296 per 1000	Late (5 years post‐RT):15 per 1000 (0 to 231)	RR 0.60 (0.23 to 1.51)	61 (1)	⊕⊝⊝⊝ verylow^{1, 2, 3}	‐
QOL scores	‐	‐	not estimable	‐	‐	Data were insufficient for meta‐analysis. However, mean global QOL scores (without standard deviations) were reported to be significantly different (better) compared with baseline scores in the protein supplement group at the end or RT and at 3 months post‐RT, but were significantly worse than baseline scores at these time points in the control group
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QOL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Probiotics compared with no probiotics to reduce adverse GI effects of radiotherapy
Patients/population: People undergoing RT for pelvic cancer Settings: Tertiary care Intervention: probiotics Comparison: placebo or no intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo or no intervention	probiotics
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute: ‐	Acute: ‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Late: ‐	Late: ‐	not estimable	‐	‐	No data
Diarrhoea (grade 2+)	Acute (during RT): 440 per 1000	Acute (during RT): 194 per 1000 (92 to 414)	RR 0.43 (0.22 to 0.82)	923 (5)	⊕⊕⊝⊝ low^{1, 2}
QOL scores	‐	‐	not estimable	‐	‐	Very limited narrative data available; see Effects of interventions section.
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio QOL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Proteolytic enzymes compared with control to reduce adverse GI effects of radiotherapy
Patients/population: People undergoing RT for pelvic cancer Settings: Tertiary care Intervention: Proteolytic enzymes Comparison: Placebo or no intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo or no intervention	proteolytic enzymes
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute (3 months post‐RT): 367 per 1000	Acute (3 months post RT): 165 per 1000 (88 to 323)	RR 0.45 (0.24 to 0.88)	120 (1)	⊕⊕⊝⊝ low¹	When grade 1 data were included, the evidence suggested that there may be little or no difference in acute toxicity.
Acute and late GI toxicity (grade 2+)	Late: ‐	Late: ‐	not estimable	‐	‐	No data
Diarrhoea (grade 2+)	Acute (during RT): 357 per 1000	Acute (during RT): 571 per 1000 (317 to 1000)	RR 1.60 (0.89 to 2.89)	56 (1)	⊕⊝⊝⊝ very low^{1, 2}	This study also reported that more participants in the proteolytic enzyme group required medication for diarrhoea symptom control (see Effects of interventions section)
QOL scores	‐	‐	not estimable	‐	‐	No data
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio QOL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Glutamine compared with placebo to reduce adverse GI effects of radiotherapy
Patients/population: People undergoing RT for pelvic cancer Settings: Tertiary care Intervention: Oral glutamine Comparison: Placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	glutamine
Mean GI symptom scores	‐	‐	not estimable	‐	‐	No data
Acute and late GI toxicity (grade 2+)	Acute (during RT): 86 per 1000	Acute (during RT): 206 per 1000 (58 to 734)	RR 2.40 (0.68 to 8.53)	69 (1)	⊕⊕⊝⊝ low¹	‐
Acute and late GI toxicity (grade 2+)	Late (1 year): 74 per 1000	Late (1 year): 334 per 1000 (17 to 1000)	RR 4.52 (0.23 to 90.08)	57 (1)	⊕⊕⊝⊝ low¹	‐
Diarrhoea (grade 2+)	Acute (during RT): 500 per 1000	Acute (during RT): 495 per 1000 (395 to 625)	RR 0.98 (0.78 to 1.24)	289 (4)	⊕⊕⊕⊕ high	We did not downgrade this evidence for design limitations as the findings of the studies with unclear risk of bias were consistent with the low risk of bias study and did not show benefit in favour of the intervention
QOL scores	‐	‐	not estimable	‐	‐	1 study reported that median QOL scores were similar for glutamine and placebo groups at 12 months and 24 months; however these data were not in a usable form for meta‐analysis
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; QOL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Counselling compared with no intervention to reduce adverse GI effects of radiotherapy
Patients/population: Individuals undergoing RT for pelvic cancer Settings: Tertiary care Intervention: Dietary or other counselling Comparison: No intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	no intervention	counselling
Mean GI symptom scores (lower is better)	At 3 months post‐RT, the mean GI symptom score (diarrhoea) in the control group was 1.6	At 3 months post‐RT, the mean GI symptom score (diarrhoea) in the control group was 1.68 (1.22 to 2.14)	MD 0.08 (‐0.38 to 0.54)	152 (1)	⊕⊕⊝⊝ low^{1, 2}	‐
Acute and late GI toxicity (grade 2+)	Acute: ‐	Acute: ‐	not estimable	‐	‐	See evidence on diarrhoea
Acute and late GI toxicity (grade 2+)	Late: ‐	Late: ‐	not estimable	‐	‐	See evidence on diarrhoea
Diarrhoea (grade 2+)	Acute (end of RT): 459 per 1000	55 per 1000 (14 to 165)	RR 0.12 (0.03 to 0.47)	74 (1)	⊕⊕⊝⊝ low^2,3	‐
	Acute (3 months post‐RT): 351 per 1000	14 per 1000 (0 to 211)	RR 0.04 (0.00 to 0.60)	74 (1)	⊕⊕⊝⊝ low^{2, 3}	‐
	Late (5 years post‐RT): 296 per 1000	15 per 1000 (0 to 231)	RR 0.05 (0.00 to 0.78)	61 (1)	⊕⊕⊝⊝ low^{2, 3}	‐
QOL scores (5‐point VAS; lower is better)	At 3 months post‐RT, the mean QOL (fatigue) score in the control group was 2.17	At 3 months post‐RT, the mean QOL (fatigue) score in the control group was 1.76 (1.37 to 2.18)	MD ‐0.41 (‐0.83 to 0.01)	152 (1)	⊕⊝⊝⊝ verylow^{1, 2, 4}	In another included study with no usable data for meta‐analysis, authors reported that, "at 3 months GI [counselling group] patients maintained/improved function, symptoms and single‐item scores (P<0.02)" compared with baseline scores, whereas "QOL remained as poor as after radiotherapy" in the control group
QOL scores (5‐point VAS; lower is better)	At 3 months post RT, the mean QOL (sleeping problem) score in the control group was 1.04	At 3 months post RT, the mean QOL (sleeping problem) score in the control group was 0.58 (0.15 to 1.01)	MD ‐0.46 (‐0.89 to ‐0.03)	152 (1)	⊕⊕⊝⊝ low^{1, 2}
The basis for the assumed risk* is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio; MD: mean difference; QOL: quality of life
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Outcome or subgroup title	No. of studies	Statistical method	Effect size
5.1 Acute GI toxicity: grade 2+	1	Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.2 Acute GI toxicity: grade 1+	1	Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.3 Late GI toxicity: grade 2+	1	Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.4 Late GI toxicity: grade 1+	1	Risk Ratio (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Acute GI toxicity (diarrhoea): grade 2+ (during RT)	2	294	Risk Ratio (IV, Random, 95% CI)	0.51 [0.34, 0.76]
6.2 Acute GI toxicity (diarrhoea): grade 1+ (during RT)	2	294	Risk Ratio (IV, Random, 95% CI)	0.78 [0.68, 0.89]
6.3 Vomiting grade 2+ (during RT)	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Acute GI toxicity: grade 2+	2	289	Risk Ratio (IV, Random, 95% CI)	0.51 [0.08, 3.38]
7.2 Acute GI toxicity: grade 1+	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
7.3 Late GI toxicity: grade 2+	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
7.3.1 15 months	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
7.3.2 3 years	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
7.4 Late GI toxicity: grade 1+	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
7.4.1 15 months	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
7.4.2 3 years	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
7.5 Rectal bleeding (late)	2	289	Risk Ratio (IV, Random, 95% CI)	0.25 [0.03, 1.84]
7.6 Rectal pain (acute)	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Acute GI toxicity: grade 2+	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
8.2 Acute GI toxicity: grade 1+	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
8.3 Late GI toxicity: grade 2+	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
8.4 Late GI toxicity: grade 1+	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
8.5 Diarrhoea (late)	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
8.6 Rectal bleeding (acute)	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
8.7 Rectal bleeding (late)	2	91	Risk Ratio (IV, Random, 95% CI)	0.53 [0.25, 1.09]