Probiotics for the prevention or treatment of chemotherapy‐ or radiotherapy‐related diarrhoea in people with cancer
Treament‐related diarrhoea is one of the most common and troublesome adverse effects related to chemotherapy or radiotherapy in people with cancer. Its reported incidence has been as high as 50% to 80%. Severe treatment‐related diarrhoea can lead to fluid and electrolyte losses and nutritional deficiencies and could adversely affect quality of life (QoL). It is also associated with increased risk of infection in people with neutropenia due to anticancer therapy and often leads to treatment delays, dose reductions, or treatment discontinuation. Probiotics may be effective in preventing or treating chemotherapy‐ or radiotherapy‐induced diarrhoea.
To evaluate the clinical effectiveness and side effects of probiotics used alone or combined with other agents for prevention or treatment of chemotherapy‐ or radiotherapy‐related diarrhoea in people with cancer.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 7), MEDLINE (1946 to July week 2, 2017), and Embase (1980 to 2017, week 30). We also searched prospective clinical trial registers and the reference lists of included studies.
We included randomised controlled trials (RCTs) investigating the effects of probiotics for prevention or treatment of chemotherapy‐ or radiotherapy‐related diarrhoea in people with cancer.
Data collection and analysis
Two review authors independently selected studies, extracted data, and assessed risk of bias. We used random‐effects models for all meta‐analyses. If meta‐analysis was not possible, we summarised the results narratively.
We included 12 studies involving 1554 participants. Eleven studies were prevention studies, of which seven compared probiotics with placebo (887 participants), one compared two doses of probiotics with each other and with placebo (246 participants), and three compared probiotics with another active agent (216 participants).The remaining study assessed the effectiveness of probiotics compared with placebo for treatment of radiotherapy‐related diarrhoea (205 participants).
For prevention of radiotherapy (with or without chemotherapy)‐induced diarrhoea, review authors identified five heterogeneous placebo‐controlled studies (with 926 participants analysed). Owing to heterogeneity, we could not carry out a meta‐analysis, except for two outcomes. For occurrence of any diarrhoea, risk ratios (RRs) ranged from 0.35 (95% confidence interval (CI) 0.26 to 0.47) to 1.0 (95% CI 0.94 to 1.06) (three studies; low‐certainty evidence). A beneficial effect of probiotics on quality of life could neither be demonstrated nor refuted (two studies; low‐certainty evidence). For occurrence of grade 2 or higher diarrhoea, the pooled RR was 0.75 (95% CI 0.55 to 1.03; four studies; 420 participants; low‐certainty evidence), and for grade 3 or higher diarrhoea, RRs ranged from 0.11 (95% CI 0.06 to 0.23) to 1.24 (95% CI 0.74 to 2.08) (three studies; low‐certainty evidence). For probiotic users, time to rescue medication was 36 hours longer in one study (95% CI 34.7 to 37.3), but another study reported no difference (moderate‐certainty evidence). For the need for rescue medication, the pooled RR was 0.50 (95% CI 0.15 to 1.66; three studies; 194 participants; very low‐certainty evidence). No study reported major differences between groups with respect to adverse effects. Although not mentioned explicitly, no studies reported deaths, except one in which one participant in the probiotics group died of myocardial infarction after three sessions of radiotherapy.
Three placebo‐controlled studies, with 128 analysed participants, addressed prevention of chemotherapy‐induced diarrhoea. For occurrence of any diarrhoea, the pooled RR was 0.59 (95% CI 0.36 to 0.96; two studies; 106 participants; low‐certainty evidence). For all other outcomes, a beneficial effect of probiotics could be neither demonstrated nor refuted (one to two studies; 46 to 106 participants; all low‐certainty evidence). Studies did not address quality of life nor time to rescue medication.
Three studies compared probiotics with another intervention in 213 participants treated with radiotherapy (with or without chemotherapy). One very small study (21 participants) reported less diarrhoea six weeks after treatment when dietary counselling was provided (RR 0.30, 95% CI 0.11 to 0.81; very low‐certainty evidence). In another study (148 participants), grade 3 or 4 diarrhoea occurred less often in the probiotics group than in the control group (guar gum containing nutritional supplement) (odds ratio (OR) 0.38, 95% CI 0.16 to 0.89; low‐certainty evidence), and two studies (63 participants) found less need for rescue medication of probiotics versus another active treatment (RR 0.44, 95% CI 0.22 to 0.86; very low‐certainty evidence). Studies did not address quality of life nor time to rescue medication.
One placebo‐controlled study with 205 participants addressed treatment for radiotherapy‐induced diarrhoea and could not demonstrate or refute a beneficial effect of probiotics on average diarrhoea grade, time to rescue medication for diarrhoea (13 hours longer in the probiotics group; 95% CI ‐0.9 to 26.9 hours), or need for rescue medication (RR 0.74, 95% CI 0.53 to 1.03; moderate‐certainty evidence). This study did not address quality of life.
No studies reported serious adverse events or diarrhoea‐related deaths.
This review presents limited low‐ or very low‐certainty evidence supporting the effects of probiotics for prevention and treatment of diarrhoea related to radiotherapy (with or without chemotherapy) or chemotherapy alone, need for rescue medication, or occurrence of adverse events. All studies were underpowered and heterogeneous. Severe side effects were absent from all studies.
Robust evidence on this topic must be provided by future methodologically well‐designed trials.
Dang Wei, Pauline Heus, Fleur T van de Wetering, Geertjan van Tienhoven, Leen Verleye, Rob JPM Scholten
Plain language summary
Live micro‐organisms for prevention or treatment of diarrhoea in people with cancer who are treated with chemotherapy or radiotherapy
Background- Up to 80% of people treated with chemotherapy or radiotherapy for cancer suffer from diarrhoea ‐ one of the most common and troublesome side effects. Severe diarrhoea can lead to dehydration (fluid and salts loss) and malnutrition from changes to digestion and bowel habits and could adversely affect quality of life. It is also associated with increased risk of infection in people with low white cell blood count related to cancer treatment. Diarrhoea often leads to delays in cancer treatment or the need to lower the dose or even discontinue cancer treatment. Foods containing live bacteria or yeast (probiotics) might have a beneficial effect on the occurrence and severity of diarrhoea.
Aim of the review- To evaluate the effects of live micro‐organisms (probiotics) in preventing the occurrence or reducing the severity of diarrhoea in people with cancer who are receiving chemotherapy or radiotherapy.
Main findings- Overall, the studies we found do not give a clear answer on whether probiotics reduce the occurrence or severity of diarrhoea, improve quality of life, or reduce the need for other medication. However, an analysis of only well‐performed studies demonstrated a beneficial effect for some outcomes.
With regard to prevention of diarrhoea compared with placebo in participants treated with radiotherapy with or without chemotherapy, we are not able to conclude whether use of probiotics would be beneficial based on the five relevant studies.
For prevention of diarrhoea due to chemotherapy alone, three studies suggested that use of probiotics may not reduce diarrhoea, and one study reported use of less rescue medication for diarrhoea.
Three studies that compared probiotics with another agent for preventing diarrhoea in patients treated with radiotherapy with or without chemotherapy found beneficial effects of probiotics for the occurrence and severity of diarrhoea and the need for rescue medication.
With respect to treatment of diarrhoea due to radiotherapy, we found only one study that did not demonstrate a clear effect of probiotics compared with placebo.
No study reported serious adverse events nor deaths related to diarrhoea.
Certainty of the evidence- The quality (certainty) of the evidence in prevention studies was low to very low. For the only study that assessed the effects of probiotics on treatment for diarrhoea, the certainty of the evidence was moderate.
What are the conclusions?- Evidence supporting the effects of probiotics in preventing or treating diarrhoea related to cancer treatment is insufficient. However, probiotics appear to be safe, as no studies have found severe side effects.
Dang Wei, Pauline Heus, Fleur T van de Wetering, Geertjan van Tienhoven, Leen Verleye, Rob JPM Scholten
Implications for practice
Prevention of diarrhoea
Overall, available evidence regarding the use of probiotics to prevent radiotherapy‐ or chemotherapy‐induced diarrhoea remains inconclusive. Randomised controlled trials (RCTs) could not deliver proof of clear benefit, as studies were underpowered or were at risk of bias. Moreover, for some outcomes, heterogeneity between studies was considerable and benefits, if any, were small.
However, for prevention of diarrhoea in patients receiving radiotherapy to the pelvis (without chemotherapy), investigators in a well‐powered RCT have compared probiotics versus placebo. This study suggests that use of probiotics may decrease the incidence and severity of diarrhoea, and a recent small study has confirmed these results (TCTR20170314001). As in the other studies, these two studies observed no severe side effects of probiotics. Although the first study had high risk of bias and the second study unclear risk of bias, based on these results, preventative probiotics could be considered for people undergoing radiotherapy, as associated adverse events are limited.
For prevention of chemotherapy‐induced diarrhoea, results suggest that probiotics may prevent diarrhoea. However, no firm conclusions can be drawn because the included studies were very small, and only one was judged to be at low risk of bias.
Treatment of diarrhoea
Available evidence shows that the benefit of probiotics for treatment of radiotherapy‐induced diarrhoea could be neither demonstrated nor refuted. For chemotherapy‐induced diarrhoea, we found no evidence.
Implications for research
For prevention of chemotherapy‐ or radiotherapy‐related diarrhoea, current evidence is of low to very low certainty. Future studies should be designed to minimise potential biases that have been inherent in previous studies and should ensure sufficient power by calculating a sample size in advance that also addresses the rate of loss to follow‐up.
Currently available evidence is insufficient for judgement of the efficacy of probiotics for treatment of radiotherapy‐induced diarrhoea. Future researchers may wish to focus on mild to moderate diarrhoea and probiotics as an add‐on to more active treatment, and new studies should examine treatment for chemotherapy‐induced diarrhoea.
All studies should adhere to CONSORT reporting guidelines to enable assessment of the design and conduct of studies, and consideration should be given to agreement on important core outcome sets, as different studies use different measures, introducing heterogeneity, which prevents meta‐analysis. Agreed important core outcomes should be measured in a standardised way to allow pooling of results.