Elemental formulae

Rationale. Elemental nutritional formulae provide essential macronutrients in readily digestible (liquid) form with protein supplied as amino acids or peptides, fats primarily as medium chain TAG (MCT) and carbohydrates largely as maltodextrins. In appropriate quantities, these formulae contain all essential macro and micronutrients and can be used as a sole source of nutrition for prolonged periods. The rationale for their use during radiotherapy is 2-fold: first, the provision of nutrients that can be readily absorbed by the gastrointestinal mucosa and secondly their potential to reduce pancreatic and biliary secretions which may aggravate pre-existing mucosal inflammation. Delivery of elemental formula to the mid-distal and distal jejunum can suppress pancreatic secretions⁽Reference Kaushik, Pietraszewski and Holst^35, Reference Vu, Van der Veek and Frolich³⁶⁾ whilst delivery of elemental formula to the proximal duodenum suppresses maximal mean post-prandial pancreatic secretions by up to 50 %, compared to polymeric formula, in healthy human volunteers⁽Reference O'Keefe, Lee and Anderson³⁷⁾.

Evidence. Six studies, four RCT⁽Reference Brown, Buchanan and Karran^38–Reference Foster, Brown and Alberti⁴¹⁾ and two comparator trials⁽Reference Craighead and Young^42, Reference McArdle, Reid and Laplante⁴³⁾ have recruited 836 patients. One study⁽Reference Foster, Brown and Alberti⁴¹⁾ is an analysis of a sub-group of patients recruited to a larger RCT⁽Reference Brown, Buchanan and Karran³⁸⁾. All studies were preventative in aim with elemental formula providing between 33 and 100 % of daily energy needs. Two studies used elemental formula as the sole nutritional intervention⁽Reference McGough, Wedlake and Baldwin^40, Reference McArdle, Reid and Laplante⁴³⁾ the remaining studies advised patients to additionally follow a low-fibre diet⁽Reference Brown, Buchanan and Karran^38, Reference Foster, Brown and Alberti⁴¹⁾ a low-fibre, lactose-restricted, low-fat diet⁽Reference Craighead and Young⁴²⁾ or a natural diet (not defined)⁽Reference Capirci, Polico and Amichetti³⁹⁾. All studies (except one⁽Reference McArdle, Reid and Laplante⁴³⁾) used an interventional period of between 3 and 6 weeks coincident with radiotherapy treatment. The largest study (n 677) reported a significant reduction in the proportion of patients experiencing radiotherapy oncology group toxicity grades 1 and 2 in those patients in the elemental group v. those consuming a standard diet but did not report a significance value⁽Reference Capirci, Polico and Amichetti³⁹⁾. However, a significant decrease (P < 0·05) was reported in the number of patients whose treatment was interrupted due to toxicity in the elemental group v. the standard diet group. In three further studies⁽Reference Brown, Buchanan and Karran^38, Reference McGough, Wedlake and Baldwin^40, Reference Foster, Brown and Alberti⁴¹⁾, no significant differences between elemental and non-interventional groups were reported in mean stool frequency⁽Reference Brown, Buchanan and Karran³⁸⁾, time to onset of diarrhoea⁽Reference Brown, Buchanan and Karran³⁸⁾, change in Inflammatory Bowel Disease Questionnaire-bowel score (IBDQ-B)⁽Reference McGough, Wedlake and Baldwin⁴⁰⁾, change in inflammatory marker fecal calprotectin⁽Reference McGough, Wedlake and Baldwin⁴⁰⁾ or change in markers of nutritional status⁽Reference Foster, Brown and Alberti⁴¹⁾. Compliance with elemental prescription was a concern. In one study⁽Reference Brown, Buchanan and Karran³⁸⁾, 41 % of patients were unable to tolerate the elemental formula for the prescribed period and in another study, mean dose of formula taken was just 21 % of daily energy requirement compared with the prescribed 33 %⁽Reference McGough, Wedlake and Baldwin⁴⁰⁾.

Two further non-randomised studies have been reported: a phase II investigation of seventeen patients with gynaecological cancer receiving a 4/5-week course of treatment⁽Reference Craighead and Young⁴²⁾ and a study which commenced as an RCT in patients receiving pre-surgical, short-course radiotherapy for invasive bladder cancer⁽Reference McArdle, Reid and Laplante⁴³⁾. In the latter study, the interventional period was for just 5 d with elemental formula providing 100 % of energy intake⁽Reference McArdle, Reid and Laplante⁴³⁾. The phase II study (which additionally asked patients to reduce fibre, lactose and fat) reported a significant reduction (P < 0·001) in the proportion of compliant patients experiencing radiotherapy oncology group grade 2/3 diarrhoea together with a reduced need for anti-diarrhoeal medication⁽Reference Craighead and Young⁴²⁾. Compliance was reportedly high in the elemental group with 76·5 % of patients taking the prescribed formula for >80 % of the time. In the short-course study, randomisation to the conventional feeding group (normal hospital diet or parenteral nutrition) was halted after a benefit was identified in just four patients receiving elemental feeding⁽Reference McArdle, Reid and Laplante⁴³⁾. The authors reported a significant reduction (P < 0·001) in the incidence of severe post-operative diarrhoea in elementally fed patients when compared with a retrospective group receiving conventional feeding.

Conclusion. Evidence for the efficacy of elemental formula from RCT is weak. Whilst the sole study⁽Reference Capirci, Polico and Amichetti³⁹⁾ which did report improved outcomes was by far the largest, it is published in abstract only. Three further studies failed to provide evidence of efficacy although these suffered from poor compliance and thus it is unclear whether the intervention itself was ineffective or the lack of endpoints in non-compliant patients resulted in underpowering⁽Reference Brown, Buchanan and Karran^38, Reference McGough, Wedlake and Baldwin^40, Reference Foster, Brown and Alberti⁴¹⁾. One non-RCT in which diet was completely replaced with the elemental formula provided evidence of efficacy in pre-surgical patients in a short-term setting albeit using retrospective controls⁽Reference McArdle, Reid and Laplante⁴³⁾. Whether 100 % replacement of normal diet with elemental formula could be achieved in patients during long-course radiotherapy is debatable.

Low or modified fat diets

Rationale. Fat intake in health comprises approximately one-third of total energy requirements (approximately 95 g fat/d (males), 70 g fat/d (women)⁽⁴⁴⁾. Dietary fats comprise long-chain TAG (LCT) with (three) fatty acids, mostly twelve to eighteen carbon atoms in length. In contrast, MCT comprise fatty acids of eight to fourteen carbon atoms in length which are absorbed directly into the portal blood. They occur in only a few foods (e.g. coconut) but may be prescribed in supplement form under medical or dietetic supervision. The rationale for the use of low or modified fat (MCT-predominant) diets during radiotherapy is 4-fold. Damage to the gastrointestinal brush border⁽Reference Hauer-Jensen, Wang and Denham⁴⁵⁾ may reduce its ability to absorb LCT, high-fat (LCT-based) diets may be pro-inflammatory⁽Reference Middleton, Rucker and Kirby⁴⁶⁾, reduced production of bile acids may occur ⁽Reference Chary and Thompson^25, Reference Boseaus, Andersson and Nystro⁴⁷⁾ and MCT do not stimulate exocrine pancreatic secretions (specifically amylase and lipase)⁽Reference Symersky, Vu and Frolich⁴⁸⁾ sparing gastrointestinal mucosa from the proteolytic effects of these enzymes.

Evidence. Four RCT recruiting 316 patients⁽Reference Bye, Kaasa and Ose^21, Reference Chary and Thompson^25, Reference Karlson, Kahn and Portman^49, Reference Wedlake, McGough and Shaw⁵⁰⁾ have examined the efficacy of low or modified fat diets. All studies were preventative in aim. Dietary interventions were used in all four studies with a low LCT fat arm consuming 20 g/d⁽Reference Foster, Brown and Alberti⁴¹⁾ and 40 g/d⁽Reference Bye, Kaasa and Ose^21, Reference Chary and Thompson^25, Reference Wedlake, McGough and Shaw⁵⁰⁾. Interventional strategies differed, two studies⁽Reference Karlson, Kahn and Portman^49, Reference Wedlake, McGough and Shaw⁵⁰⁾ used MCT-based supplements to compensate for reduced total energy intake, lactose was additionally restricted in one study⁽Reference Bye, Kaasa and Ose²¹⁾ and in another⁽Reference Chary and Thompson²⁵⁾ all patients were instructed to follow a low-fat diet but were randomised at 2 weeks to receive the bile acid binder cholestyramine (4 g twice daily) or placebo. Two studies⁽Reference Bye, Kaasa and Ose^21, Reference Chary and Thompson²⁵⁾ reported benefits associated with a low-fat intervention. In one, significant differences between patients consuming a low-fat, low-lactose diet v. patients on a regular (hospital) diet were reported including a halving of the incidence of new-onset diarrhoea, a 50 % reduction (P < 0·01) in the mean number of anti-diarrhoeal tablets used and a significant reduction (P < 0·01) in the number of loose, watery stools per week⁽Reference Bye, Kaasa and Ose²¹⁾. In the other, diarrhoea control was significantly better (P < 0·05) in the cholestyramine arm although >50 % patients in this group reported side effects, including nausea and abdominal cramps⁽Reference Chary and Thompson²⁵⁾.

In the remaining two studies, one reported reduced bowel frequency in the low-fat MCT-supplemented group v. the low-fat group although results were NS and the difference in frequency modest (mean 1·6 (sd 0·9) v. 2·0 (sd 1·0) movements daily)⁽Reference Karlson, Kahn and Portman⁴⁹⁾. The other study used a three-arm design to compare a normal fat diet v. low fat v. low fat + MCT supplement (50:50 ratio of LCT:MCT) and reported no significant difference in the fall in IBDQ-B scores or change in secondary nutritional endpoints between groups. Poor compliance in the normal fat group⁽Reference Wedlake, McGough and Shaw⁵⁰⁾ resulted in the majority of patients consuming a diet with low LCT content. The authors commented that the fall in IBDQ-B score for the cohort (n 107) compared favourably with a mean pooled fall in score of −9 points from previous studies in similar cohorts (n 409) suggesting a positive impact of dietary intervention (irrespective of study arm) and/or a benefit of reduced fat intake across all groups⁽Reference Khalid, McGough and Hackett^4, Reference Wedlake, Thomas and McGough^23, Reference Wedlake, Thomas and Lalji^30, Reference McGough, Wedlake and Baldwin⁴⁰⁾.

Conclusion. Evidence for the efficacy of low LCT fat interventions is limited. Whilst two high-quality RCT provided evidence of efficacy, neither manipulated fat as the sole intervention making it difficult to determine which intervention was responsible for efficacy⁽Reference Bye, Kaasa and Ose^21, Reference Chary and Thompson²⁵⁾. Although a third RCT⁽Reference Karlson, Kahn and Portman⁴⁹⁾ reported a modest benefit of low fat it is published in abstract only. The final adequately powered high-quality study found no significant difference in outcomes between groups although inadequate differential in fat intake between groups precluded robust conclusions⁽Reference Wedlake, McGough and Shaw⁵⁰⁾.

Lactose restriction

Rationale. Lactose is a disaccharide of glucose and galactose found in milk and milk products. Typical quantities are 13·5 g/one-half pint (284 ml) milk (full cream or skimmed) with similar amounts in other dairy products such as yoghurt and ice cream. Lactose must be cleaved to its monomeric units before absorption by enzyme lactase present in the brush border. Unabsorbed lactose contributes to an osmotic load in the large intestine causing watery diarrhoea. In many races, a genetically programmed fall in lactase occurs after weaning resulting in intolerance to milk products. In white Caucasian populations (despite a mistaken tendency to attribute various abdominal symptoms to lactose intolerance⁽Reference Suarez, Savaiano and Levitt⁵¹⁾) endogenous lactase does not diminish with adulthood and genetically based lactase deficiency occurs in about 5–19 % of adults. Lactase deficiency may arise secondary to radiation-induced damage of the intestinal mucosa and depletion of brush border enzymes. Although the incidence of new-onset lactose intolerance during radiotherapy has not been definitively quantified, one small study⁽Reference Wedlake, Thomas and McGough²³⁾ in a cohort of twenty-six patients has suggested that it may be about 15 %.

Evidence. Three studies recruiting 118 patients have examined the incidence of lactose malabsorption⁽Reference Stryker, Mortel and Hepner^22, Reference Weiss and Stryker⁵²⁾ and the efficacy of a lactose-restricted (or modified) diet during treatment⁽Reference Stryker and Bartholomew⁵³⁾. Two prospective case series⁽Reference Stryker, Mortel and Hepner^22, Reference Weiss and Stryker⁵²⁾ in white Caucasian cohorts have demonstrated new-onset lactose intolerance during pelvic radiotherapy. In the first of these studies, 50 % of (n 24) patients exhibited significantly reduced lactose absorption as assessed by ¹⁴C lactose breath test⁽Reference Stryker, Mortel and Hepner²²⁾ and a significant correlation (P < 0·05) was reported between the breath test results at 5 weeks and increased stool frequency suggesting that patients with the most marked lactose malabsorption also had the most severe diarrhoea. A later study by the same group investigated the impact of volume of small bowel irradiated on lactose malabsorption⁽Reference Weiss and Stryker⁵²⁾ and found a clear separation in absorption rates in patients with large bowel volumes within the radiotherapy field compared with those with smaller volumes but no correlation between the change in breath test and stool frequency in either group.

Only one RCT has examined the efficacy of lactose restricted diets during pelvic radiotherapy⁽Reference Stryker and Bartholomew⁵³⁾. In a three-arm study in which sixty-four mixed pelvic site patients were randomised to follow diets (supplemented with 480 ml milk) v. (lactose restriction (amounts not reported)) v. (supplemented with 480 ml milk + lactase enzyme) no benefit was found in any arm on multivariate analysis in reduced stool frequency or number of diarrhoea tablets used. The authors suggested that delayed gastric emptying following 5 weeks of radiotherapy may have confounded breath test results in the earlier studies⁽Reference Stryker, Mortel and Hepner^22, Reference Weiss and Stryker⁵²⁾ and/or that sites of maximal lactose absorption (mid-jejunum and upper ileum) escaped irradiation and/or that other factors (e.g. bile acid malabsorption) overwhelmed any benefit of the lactose restriction.

Conclusions. Whilst it is acknowledged that true lactose malabsorption is less prevalent than commonly supposed⁽Reference Suarez, Savaiano and Levitt⁵¹⁾, limited evidence suggests that patients can become lactose intolerant during pelvic radiotherapy, but there is no evidence that restricting its consumption (or providing it in pre-hydrolysed form) is helpful. The sole RCT found no difference between groups in relevant gastrointestinal endpoints⁽Reference Stryker and Bartholomew⁵³⁾. Whilst this study used an elegant design the published paper lacked data on study powering and given the 17 % drop out, the possibility of a type II error cannot be ruled out.

Dietary fibre

Rationale. The definition of fibre has been debated for years and measurement techniques vary. In 2008, a Codex (Codex Alimentarius Commission) Committee on Nutrition and Foods for Special Dietary Uses agreed on a definition of dietary fibre as carbohydrate polymers with ten or more monomeric units which are not hydrolysed by endogenous enzymes in the small intestine of human beings⁽Reference Cummings, Mann and Hishida⁵⁴⁾. This definition encompasses naturally occurring, edible, plant-based polymers found in fruit, vegetables, seeds, nuts and cereals (i.e. those items promoted in the UK as components of ‘healthy eating’) and also extracted or synthetic carbohydrate polymers with proven physiological effects. Naturally occurring dietary fibre comprises both soluble and insoluble fractions with distinct properties. Both fractions occur naturally in most foods but one or the other normally predominates in extracted or synthetic supplements. Insoluble fibre is less easily fermentable than soluble fibre and provides stool bulk promoting healthy bowel physiology and motility. Soluble fibre (e.g. psyllium also called ispaghula or plantago ovate) provides a fermentable substrate for bowel microbiota, producing SCFA of which butyrate has received much attention due to its trophic, immune-modulatory and anti-inflammatory actions⁽Reference Cook and Selin^55, Reference Hamer, Jonkers and Venema⁵⁶⁾.

Evidence. Eight studies⁽Reference Lodge, Evans and Wilkins^57–Reference Wedlake, Shaw and McNair⁶⁵⁾ recruiting 639 patients, comprising six RCT⁽Reference Lodge, Evans and Wilkins^57, Reference Murphy, Stacey and Crook^59, Reference Pettersson, Johansson and Persson^61–Reference Wedlake, Shaw and McNair⁶⁵⁾ (including one cross-over trial⁽Reference Lodge, Evans and Wilkins⁵⁷⁾) and two cohort studies⁽Reference Liu, Glicksman and Coachman^58, Reference McNair, Wedlake and McVey⁶⁰⁾ have explored the benefit of manipulating dietary and/or supplemental fibre during pelvic irradiation. Of the interventional RCT, two manipulated dietary fibre alone⁽Reference McNair, Wedlake and McVey^60, Reference Wedlake, Shaw and McNair⁶⁵⁾, three used a fibre supplement⁽Reference Murphy, Stacey and Crook^59, Reference Itoh, Mizuno and Ikeda^63, Reference Garcia-Peres, Velasco and Hernandez⁶⁴⁾ (two of which included additional dietary restrictions⁽Reference Murphy, Stacey and Crook^59, Reference Garcia-Peres, Velasco and Hernandez⁶⁴⁾) and a further study with long-term follow-up manipulated dietary fibre in combination with a low-lactose restriction⁽Reference Pettersson, Johansson and Persson^61, Reference Pettersson, Nygren and Persson⁶²⁾. Seven studies⁽Reference Liu, Glicksman and Coachman^58–Reference Wedlake, Shaw and McNair⁶⁵⁾ explored the role of fibre in preventing gastrointestinal toxicity (i.e. as a prophylactic agent) whilst one⁽Reference Lodge, Evans and Wilkins⁵⁷⁾ explored the therapeutic efficacy of the psyllium v. codeine phosphate for the control of radiation-induced diarrhoea.

In the sole therapeutic RCT⁽Reference Lodge, Evans and Wilkins⁵⁷⁾, patients receiving pelvic radiotherapy for gynaecological cancer were instructed to follow a low-fibre diet. A cross-over design was used to compare the efficacy of psyllium with codeine phosphate on presentation of treatment-induced diarrhoea⁽Reference Lodge, Evans and Wilkins⁵⁷⁾. The study was prematurely terminated after recruitment of ten patients due to lack of efficacy of psyllium, with all patients crossed-over to codeine phosphate. In the two-cohort studies⁽Reference Liu, Glicksman and Coachman^58, Reference McNair, Wedlake and McVey⁶⁰⁾, one reported favourable effects of a low residue diet⁽Reference Liu, Glicksman and Coachman⁵⁸⁾ whilst the other, benefits or increased fibre consumption⁽Reference McNair, Wedlake and McVey⁶⁰⁾. In the early large cohort study (n 156) in prostate cancer patients who were instructed to follow dietary restrictions (low residue, restricted caffeine, alcohol and spicy foods) throughout radiotherapy, improved genitourinary and gastrointestinal symptoms were reported in compliant v. non-compliant patients⁽Reference Liu, Glicksman and Coachman⁵⁸⁾. All non-compliant patients experienced side effects but grade 1 toxicity, which occurred in 41 % of these patients, was easily managed by reinforcement of dietary advice. In the smaller prospective cohort study⁽Reference McNair, Wedlake and McVey⁶⁰⁾ (n 22), prostate cancer patients were given individual advice to increase dietary fibre (and fluid) with the aim of stabilising rectal dimensions to prevent prostate deformation during treatment. Improved IBDQ-B scores were reported in those who met their fibre prescription v. those who did not although the study was not powered for this endpoint.

Of the three RCT which explored the efficacy of a fibre supplement⁽Reference Murphy, Stacey and Crook^59, Reference Itoh, Mizuno and Ikeda^63, Reference Garcia-Peres, Velasco and Hernandez⁶⁴⁾, one reported reduced incidence (P = 0·049) and severity (P = 0·030) of diarrhoea (using a non-validated scale) in patients following a low-fibre, low-stimulant (caffeine and alcohol), low-fat diet plus a psyllium supplement v. those following the diet alone⁽Reference Murphy, Stacey and Crook⁵⁹⁾. This study also reported a reduced need for anti-diarrhoeal medication in the diet plus psyllium group although the difference between groups was NS. A small placebo-controlled, double-blind, exploratory RCT⁽Reference Itoh, Mizuno and Ikeda⁶³⁾ examined the efficacy of 3 g hydrolysed rice bran to prevent gastrointestinal toxicity in twenty patients receiving radiotherapy for cervical cancer. Frequency and severity of diarrhoea and use of anti-diarrhoeal medication was not significantly different between groups although the authors reported a reduced mean diarrhoeal assessment score in the hydrolysed rice bran group at 3 weeks compared with the control group. The study was not statistically powered and six patients were excluded from the final analysis due to failure to comply with an interventional prescription. Finally, the efficacy of an inulin + fructo-oligosaccharide prebiotic (6 g twice daily) to prevent acute radiation enteritis was examined in forty-six post-surgical gynaecology patients⁽Reference Garcia-Peres, Velasco and Hernandez⁶⁴⁾. Patients in both the prebiotic group and placebo groups were additionally instructed to follow a low-fat, low-fibre and low-lactose diet for 1 week prior to radiotherapy, during treatment and for 3 weeks following treatment. A sample size of n 54 (twenty-seven per group) was required to detect a 10 % difference in the incidence of grade 2 diarrhoea (Common Technology Criteria for Adverse Events (CTCAE)). Of the thirty-eight patients with evaluable data, no difference between groups was observed in stool frequency although the number of days with loose stool (Bristol Stool Chart Type 7) was less in the prebiotic group (P = 0·008). No differences were observed in time to onset of diarrhoea or use of anti-diarrhoeal medication.

The two most recent and larger RCT both used non-blinded dietary interventions. The first of these studies explored the efficacy of a low insoluble fibre + low lactose diet v. standard of care diet in 130 prostate cancer patients⁽Reference Pettersson, Johansson and Persson^61, Reference Pettersson, Nygren and Persson⁶²⁾. The intervention commenced 1 week prior to the start of radiotherapy and continued during radiotherapy with post-treatment follow-ups at 7, 12, 18 and 24 months⁽Reference Pettersson, Johansson and Persson^61, Reference Pettersson, Nygren and Persson⁶²⁾. A FFQ was designed to guide patients’ food choices and monitor adherence to dietary instructions. A significant interaction effect (P < 0·001) was noted between randomisation and time in FFQ scores, indicating compliance with intervention in both groups. Radiotherapy-induced toxicity was assessed using the prostate-specific QLQ-PR25 and European Organisation for Research and treatment of Cancer QLQ-C30 together with a non-validated study-specific Gastrointestinal Side Effects Questionnaire which assessed ‘bother’ associated with diarrhoea, blood in stool, mucous discharge, intestinal cramps, intestinal pain, intestinal gas and flatulence. Despite a trend towards reduced incidence of symptoms (using selected variables taken from the QLQ-PR25) no significant differences between groups in any gastrointestinal toxicity or quality of life measures were found in the short-term results at 2 months⁽Reference Pettersson, Johansson and Persson⁶¹⁾. Incidence of self-reported diarrhoea at 8 weeks (end of radiotherapy) was slightly less in the interventional group 30 % (fourteen of fifty-one patients) v. the standard care arm 33 % (nineteen of sixty patients) but NS. At 24 months, evaluable data were obtained for 102 patients (attrition rate of 22 %). The authors again reported no obvious effect of the interventional diet on gastrointestinal symptoms or health-related quality of life at any time-points post-treatment⁽Reference Pettersson, Nygren and Persson⁶²⁾. The authors noted that the study may have been underpowered due to the lack of observable events (33–50 % of patients reported no symptoms during radiotherapy)⁽Reference Pettersson, Johansson and Persson⁶¹⁾ and an assumption at study powering with respect to bowel symptom scores that turned out to be incorrect.

The second, most recent RCT randomised 166 patients with mixed pelvic malignancies to low-fibre (≤10 g/d NSP), habitual (control) or high-fibre (≥18 g/d) diets during radiotherapy⁽Reference Wedlake, Shaw and McNair⁶⁵⁾. Patients received individualised counselling at the start of radiotherapy to achieve their dietary targets with study-specific instructional booklets for guidance. The primary endpoint was the difference between groups in the change in the IBDQ-B score between start and nadir (worst) score during treatment. Other measures included macronutrient intake, stool diaries and fecal SCFA. Fibre intakes were significantly different between groups (P < 0·001) both at the start and end of radiotherapy indicating adherence to interventional prescription. The difference between groups in the change in IBDQ-B score between start and end of radiotherapy was smaller in the high-fibre group compared with the habitual fibre group (P = 0·011) thus indicating a benefit of high-fibre consumption. This difference between groups was maintained at 1-year post-radiotherapy (P = 0·004) prompting the authors to conclude that restrictive, non-evidence based advice to reduce fibre intake during radiotherapy should be abandoned. However, despite this important observation, it was noted that a dose–response relationship was not observed with the low-fibre group (who consumed the least amount of fibre) faring better than the habitual fibre group. No significant differences were observed in stool frequency, form or SCFA concentrations although the study was not powered for these endpoints. Significant reductions in energy, protein and fat intake occurred in the low and habitual fibre groups only. In addition, it was noted that high-fibre intake had no adverse effect on satiety, total energy intake or stool form.

Conclusions. There is moderately convincing evidence that increasing, rather than reducing fibre intake during pelvic radiotherapy has beneficial effects. Two studies using dietary manipulation⁽Reference McNair, Wedlake and McVey^60, Reference Wedlake, Shaw and McNair⁶⁵⁾ and three⁽Reference Murphy, Stacey and Crook^59, Reference Itoh, Mizuno and Ikeda^63, Reference Garcia-Peres, Velasco and Hernandez⁶⁴⁾ using supplements reported improved bowel symptom scores⁽Reference McNair, Wedlake and McVey^60, Reference Wedlake, Shaw and McNair⁶⁵⁾ and improvements in stool consistency and diarrhoea outcomes⁽Reference Murphy, Stacey and Crook^59, Reference Itoh, Mizuno and Ikeda^63, Reference Garcia-Peres, Velasco and Hernandez⁶⁴⁾ compared with low-fibre or non-supplemented groups. In contrast, in two studies using low-fibre dietary interventions, one reported no difference in gastrointestinal symptom scores between intervention and standard care groups either during or in the post-treatment setting⁽Reference Pettersson, Johansson and Persson^61, Reference Pettersson, Nygren and Persson⁶²⁾ whilst a further study⁽Reference Liu, Glicksman and Coachman⁵⁸⁾ reported improved genitourinary and gastrointestinal symptoms in patients compliant with low-fibre dietary advice amongst a number of other dietary restrictions. Overall, these results indicate that advice to restrict or reduce fibre intake during radiotherapy is outmoded and should be discarded. However, the optimum dose, presentation, fibre source (or substrate) and mechanism of action have yet to be fully elucidated.

Probiotics, prebiotics and synbiotics

Rationale. Probiotics are live microorganisms (bacteria) that when administered in adequate amounts confer a health benefit on the host⁽⁶⁶⁾. They include (but are not limited to) lactobacilli and bifidobacteria species and remain viable after passage through the human stomach and small intestine. A prebiotic is a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora that confers benefits on host wellbeing and health⁽Reference Gibson, Probert and Van Loo⁶⁷⁾. Prebiotics include inulin, lactulose and the short-chain carbohydrates fructo-oligosaccharides (oligofructose) and galacto-oligosaccharides. Synbiotics are combinations of probiotics and prebiotics. Prebiotics with ≥3 monomeric units may, according to some European national guidelines, satisfy the definition of fibre⁽Reference Cummings, Mann and Hishida⁵⁴⁾. There are a variety of mechanisms through which probiotics exert their health-giving effects. These include modification of the incumbent microbiota population to favour non-pathogenic species, reduction of luminal pH, competitive inhibition of pathogenic strains and secretion of anti-pathogenic compounds, including bacteriocidins and defensins. Probiotics also exert additional beneficial immunomodulatory effects on local mucosal and systemic immune systems⁽Reference Gerritsen, Smidt and Rijkers⁶⁸⁾. Prebiotics provide a substrate for the preferential growth of non-pathogenic species resulting in the enhanced production of SCFA which promote optimal colonic fluid balance, stimulate water and sodium absorption and preserve mucosal barrier function⁽Reference Cook and Selin⁵⁵⁾. Synbiotics offer a potentially synergistic option but differ in efficacy depending on the specific combination.

Evidence. Nine RCT recruiting 1288 patients⁽Reference Salminen, Elomaa and Minkkinen^69–Reference Mansouri-Tehrani, Rabbani Khorasgani and Roayaei⁷⁹⁾ have examined the efficacy of probiotic or synbiotic preparations. Outcomes for the largest study⁽Reference Delia, Sansotta and Donato⁷¹⁾ are reported in three separate publications⁽Reference Delia, Sansotta and Donato^71, Reference Delia, Sansotta and Donato^74, Reference Delia, Sansotta and Donato⁷⁵⁾. All studies are preventative in aim with the exception of one⁽Reference Urbancsek, Kazar and Mezes⁷⁰⁾. In the earliest open-label study⁽Reference Salminen, Elomaa and Minkkinen⁶⁹⁾, twenty-four patients were randomised to receive either a synbiotic comprising 2 × 10⁹ (radiation-resistant) Lactobacillus acidophilus plus 8 g/d lactulose in addition to a low-fibre, low-lactose, low-fat diet or diet alone. Incidence of diarrhoea was significantly reduced in the synbiotic plus diet group (P < 0·01) v. the diet alone group. The authors postulated that the synbiotic decreased fecal pH and favourably altered fecal microflora, features which had been demonstrated in earlier work that remains unpublished. In a later double-blind (therapeutic) study⁽Reference Urbancsek, Kazar and Mezes⁷⁰⁾ 206 patients were randomised to receive either a probiotic containing 1·5 g L. rhamnosis (equivalent to 1·5 × 10⁹ colony-forming units (CFU)) or placebo to control treatment-induced mild to moderate diarrhoea. No significant difference was found between groups in the time to use of, or frequency of use of rescue medication (Loperamide).

The largest study to date used a double-blind placebo-controlled design to test the efficacy of probiotic cocktail VSL#3 comprising eight different bacterial strains in high concentration (450 × 10⁹ CFU) to reduce treatment induced gastrointestinal toxicity assessed using the WHO five-point grading scale. Earlier reports of the same cohort were published (n 190 patients)⁽Reference Delia, Sansotta and Donato^74, Reference Delia, Sansotta and Donato⁷⁵⁾ in which it was stated that patients were additionally instructed to follow a hyperenergetic diet (due to radiotherapy-induced metabolic stress) which entailed restricting fat and fructose but maintaining a normal fibre intake⁽Reference Delia, Sansotta and Donato⁷⁴⁾. However, it is not clear whether these additional dietary instructions applied to all those recruited for this study. A significantly reduced (P < 0·001) number of patients in the probiotic group v. placebo experienced radiation-induced enteritis and colitis (31·6 v. 51·8 %, respectively) with a significantly higher proportion of patients in the placebo group experiencing grade 3 or 4 toxicity (P < 0·001). Mean daily number of bowel movements for patients with radiation-induced diarrhoea was reduced (P < 0·005) in the probiotic group v. placebo (14·7 (sd 6) v. 5·1 (sd 3)) together with significantly reduced (P < 0·001) mean time to use of Loperamide as rescue medication.

Between 2008 and 2010 results of a further three RCT were published⁽Reference Giralt, Regadera and Verges^72, Reference Chitapanarux, Chitapanarux and Traisathit^73, Reference Timko⁷⁶⁾. In a multi-centre, double-blind study⁽Reference Giralt, Regadera and Verges⁷²⁾, 118 patients with gynaecological cancer were randomly assigned to receive a probiotic drink (10⁸ CFU/g L. casei) or placebo. This study was originally powered to recruit 154 patients (seventy per group) but only 118 were randomised. Of these, thirty-three patients were subsequently excluded due to ineligibility resulting in only forty-four and forty-one patients in the intervention and placebo groups respectively amounting to only 55 % of those required. Whilst patients in the probiotic group had a significantly improved mean stool consistency (P = 0·04) including greater median time before experiencing Bristol stool type ≥6 (14 d v. ten in the probiotic v. placebo, respectively) there was no significant difference between groups in the need for anti-diarrhoeal medication or incidence of Common Terminology Criteria (CTCAE) grade 2 toxicity.

Another study using a double-blind design randomised sixty-three patients with cervical cancer to receive a probiotic preparation (10⁹ L. acidophilus and 10⁹ Bifidobacterium bifidum) or placebo starting 7 d prior to radiotherapy and continuing during treatment⁽Reference Chitapanarux, Chitapanarux and Traisathit⁷³⁾. Significantly fewer patients in the probiotic group experienced CTCAE grade ≥2 diarrhoea v. the placebo group (P = 0·002). Use of anti-diarrhoeal medication was also significantly reduced in the probiotic group v. placebo (P = 0·03) together with improved stool consistency (P < 0·001). In the third study completed in this period⁽Reference Timko⁷⁶⁾, forty-two patients with mixed pelvic malignancies were randomised to receive either a probiotic preparation or a preparation containing fermentation products during radiotherapy. The probiotic preparation, ‘5’ Strain Dophilus, contained five probiotic cultures in the proportions: 55 % L. rhamnosus, 20 % B. adolescentis, 5 % L. acidophilus, 5 % B. longum, 15 % Enterococcus faecium, with a total count of six billion active bacteria/capsule at a dose of 2 × 1 capsules daily. The cell-free fermentation product preparation consumed by the comparator group comprised L. helveticus and gut symbionts with 100 ml of the product containing: 24·95 g Escherichia coli metabolita, 12·5 g Streptococci faecalis metabolita, 12·5 g Lactobacilli acidophili metabolita, 49·9 g Lactobacilli helvetici metabolita) in doses of forty drops, three times daily. The study was not powered for a specific endpoint. It was reported that both preparations had beneficial effects on bowel frequency, stool consistency and use of anti-diarrhoeal medication in comparison with previous research and that effects were more marked in the probiotic group⁽Reference Timko⁷⁶⁾. Since 2010, the results of a further three studies have been published⁽Reference Demers, Dagnault and Desjardins^77–Reference Mansouri-Tehrani, Rabbani Khorasgani and Roayaei⁷⁹⁾. It is important to note that during this period radiotherapy techniques have become more sophisticated with more centres now employing image-guided radiotherapy and intensity-modulated radiotherapy. Improved planning and delivery techniques will improve toxicity through the implementation of on-treatment verification protocols (image-guided radiotherapy), the application of smaller margins to allow for uncertainties in radiotherapy delivery and improved dose sculpting to spare normal tissue (intensity-modulated radiotherapy).

In the largest of the trials conducted in this most recent era, 246 patients with mixed pelvic cancers were randomised to receive either placebo or one of two regimens of double-strain Bifilact probiotic (L. acidophilus + B. longum) at a standard dose (1·3 billion CFU) or high dose (ten billion CFU) during radiotherapy treatment⁽Reference Demers, Dagnault and Desjardins⁷⁷⁾. All received individualised nutritional advice aimed at reducing lipid intake, avoiding caffeine and alcohol and advice on the consumption of dietary fibre. The primary endpoint was time to presentation of ≥grade 2, 3 or 4 diarrhoea. Immediately following radiotherapy treatment (60 d) the proportion of patients free from moderate or severe diarrhoea in the standard dose probiotic group (35 %) was 2-fold higher than that of the placebo group (17 %; P = 0·004). Further, in a sub-group analysis of patients who had had previous surgery, the standard dose probiotic group had a higher proportion of patients (97 %) without very severe (grade 4) diarrhoea compared with the placebo group (74 %; P = 0·03). However, the difference between groups in the cumulative proportion of patients without grade 2, 3 or 4 diarrhoea (primary endpoint) was NS (P = 0·13).

In a much smaller pilot double-blind, placebo-controlled RCT, twenty prostate cancer patients were randomised to receive either a synbiotic powder (L. reuteri, 10⁸ CFU + 4·3 of soluble fibre) or placebo for 1 week prior to and during radiotherapy⁽Reference Nascimento, Aguilar-Nascimento and Caporossi⁷⁸⁾. The study was powered to detect a four-point difference between groups in European Organisation for Research and Treatment of Cancer QLQ-PRT23 score. Quality of life + proctitis symptom scores and proctitis symptom scores alone were significantly improved in the probiotic group compared with the placebo group at weeks 2 and 3 of radiotherapy treatment; P < 0·05 and < 0·01 for both comparisons at both time-points.

Finally, in the most recent trial⁽Reference Mansouri-Tehrani, Rabbani Khorasgani and Roayaei⁷⁹⁾, sixty-seven patients with mixed pelvic cancers were randomised to receive either a probiotic preparation; probiotic preparation with honey; or placebo for 1 week prior to and during radiotherapy for 5 weeks. The high strength probiotic, was contained within two capsules daily of LactoCareO and comprised: L. casei (1·5 × 10⁹ CFU); L. acidophilus (1·5 × 10¹⁰ CFU); L. rhamnosus (3·5 × 10⁹ CFU); L. bulgaricus (2·5 × 10⁸ CFU); Bifidobacterium breve (1 × 10¹⁰ CFU); B. longum (5 × 10⁸ CFU); Streptococcus thermophilus (1·5 × 10⁸ CFU) per 500 mg, in 150 g low-fat yoghurt. The results revealed significantly reduced frequency (number of bowel movements/d) throughout treatment, reduced diarrhoea grade, improved stool consistency and less need for anti-diarrhoeal medication in either of the probiotic groups at weeks 4 and 5 of treatment compared with the placebo. However, the study lacked statistical power and bloating was noted in nineteen of twenty-two and sixteen of twenty-one patients in the probiotic and probiotic + honey groups respectively v. ten of twenty-four patients in the placebo group.

Conclusions. There is mounting evidence that probiotics are helpful as prophylactic agents in reducing the gastrointestinal side effects associated with pelvic radiotherapy. Reported benefits include improved gastrointestinal symptoms⁽Reference Delia, Sansotta and Donato^71, Reference Chitapanarux, Chitapanarux and Traisathit^73–Reference Delia, Sansotta and Donato^75, Reference Demers, Dagnault and Desjardins^77, Reference Nascimento, Aguilar-Nascimento and Caporossi⁷⁸⁾ reduced incidence⁽Reference Salminen, Elomaa and Minkkinen^69, Reference Demers, Dagnault and Desjardins⁷⁷⁾ and severity⁽Reference Mansouri-Tehrani, Rabbani Khorasgani and Roayaei⁷⁹⁾ of diarrhoea, reduced need for anti-diarrhoeal medication⁽Reference Delia, Sansotta and Donato^71, Reference Chitapanarux, Chitapanarux and Traisathit^73–Reference Timko^76, Reference Mansouri-Tehrani, Rabbani Khorasgani and Roayaei⁷⁹⁾ and improved stool consistency⁽Reference Giralt, Regadera and Verges^72, Reference Chitapanarux, Chitapanarux and Traisathit^73, Reference Timko^76, Reference Mansouri-Tehrani, Rabbani Khorasgani and Roayaei⁷⁹⁾ and frequency⁽Reference Delia, Sansotta and Donato^71, Reference Giralt, Regadera and Verges^72, Reference Delia, Sansotta and Donato^74–Reference Timko^76, Reference Mansouri-Tehrani, Rabbani Khorasgani and Roayaei⁷⁹⁾. Despite this seemingly convincing evidence, no single probiotic preparation or dose has yet been recommended for routine clinical practice. The most recent definitive clinical guideline for the prevention of gastrointestinal mucositis in this setting⁽Reference Lalla, Bowen and Barasch⁸⁰⁾ includes a suggestion (based on grade III evidence) arrived at by panel consensus, that probiotics containing Lactobacillus species be used to prevent diarrhoea in patients receiving chemotherapy and/or radiation therapy for a pelvic malignancy. Whilst this suggestion reflects the widespread use of this species in research studies and its demonstrated benefits, either alone⁽Reference Salminen, Elomaa and Minkkinen^69, Reference Giralt, Regadera and Verges^72, Reference Nascimento, Aguilar-Nascimento and Caporossi⁷⁸⁾ or in combination with Bifidobacteria ⁽Reference Chitapanarux, Chitapanarux and Traisathit^73, Reference Demers, Dagnault and Desjardins⁷⁷⁾ or with multiple other species⁽Reference Delia, Sansotta and Donato^71, Reference Delia, Sansotta and Donato^74–Reference Timko^76, Reference Mansouri-Tehrani, Rabbani Khorasgani and Roayaei⁷⁹⁾ no recommendation is made regarding dose; which is no doubt a reflection of the wide variety of strengths that have been used, ranging from 1·5 × 10⁹ to 450 × 10⁹ CFU/ml and the lack of a clear dose–response relationship⁽Reference Demers, Dagnault and Desjardins⁷⁷⁾, CFU being the smallest viable unit of the bacteria capable of replication.