Description of the condition
Diarrhoea is one of the most common and troublesome adverse effects related to cancer chemo- or radiotherapy (Benson 2004). The incidence of all grades of diarrhoea during chemotherapy and/or radiotherapy has been reported to be as high as 50% to 80% (Sanguineti 2008), with up to one third of patients experiencing severe (grade 3 or 4) diarrhoea (Maroun 2007), especially in those regimens that include bolus 5-fluorouracil (5-FU) or irinotecan. Severe treatment-related diarrhoea can lead to fluid and electrolyte losses, nutritional deficiencies from alterations in gastrointestinal transit and digestion and could adversely affect quality of life (QoL). Diarrhoea is also associated with an increased risk of infection in patients with treatment-related neutropenia. Diarrhoea often leads to delays in treatment, dose reduction or discontinuation of treatment. There is also a small but significant mortality associated with chemotherapy-induced diarrhoea. This level of morbidity has demonstrated the need for a more comprehensive assessment of diarrhoea and a more aggressive and systematic treatment approach. Diarrhoea here defined as having three or more loose or liquid bowel movements per day.
Description of the intervention
According to the currently adopted definition by Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO), probiotics are: "live microorganisms which when administered in adequate amounts confer a health benefit on the host" (FAO and WHO 2001). Lactic acid bacteria and bifidobacteria are the most common types of microbes used as probiotics; but certain yeasts and bacilli may also be helpful. Probiotics are commonly consumed as part of fermented foods with specially added active live cultures; such as in yogurt, soy yogurt or as dietary supplements.
A meta-analysis of randomised controlled trials (RCTs) demonstrated that co-administration of some probiotics such as Lactobacillus rhamnosus GG with standard rehydration therapy reduced the duration of diarrhoea by one day in children less than five years old with acute-onset diarrhoea (Huang 2002). Some RCTs have also shown that probiotics are of benefit in the treatment of antibiotic associated diarrhoea and in the prevention of nosocomial diarrhoea in infants (Cremonini 2002; Szajewska 2001). Furthermore, a recent Cochrane review demonstrated that, based on moderate quality evidence, probiotics were both safe and effective for the prevention of Clostridium difficile-associated diarrhoea in adults and children (Goldenberg 2013).
How the intervention might work
Probiotics such as Lactobacillus rhamnosus GG, which is a strain of Lactobacillus rhamnosus isolated in 1983 from the intestinal tract of a healthy human being, are thought to work by stimulating the cell proliferation rate of bowel epithelial cells, enhancing secretion of protective mucins leading to reduced adherence of enteropathogenic bacteria to the bowel wall, inhibiting bacterial translocation into the tissues and stimulating local and systemic immune response to pathogens (Banasaz 2002; Khaled 2003; Mack 2003; Mattar 2001; Vaarala 2003).
Why it is important to do this review
Recent studies have demonstrated that probiotic supplementation is well tolerated and may reduce the frequency of severe diarrhoea and abdominal discomfort related to chemo- or radiotherapy (Delia 2007; Osterlund 2007; Salminen 1988; Urbancsek 2001). Some trials have also found that probiotic lactic acid-producing bacteria are an easy to use, safe and a feasible approach to protect cancer patients against the risk of chemo- or radiotherapy induced diarrhoea (Osterlund 2007; Delia 2007; Urbancsek 2001).
To date a systematic review has not been conducted to assess and compare the benefits of probiotic therapy on clinically relevant endpoints in cancer patients receiving chemo- and/or radiotherapy.
To evaluate the clinical effectiveness and safety of probiotics either alone or combined with other agents in the prevention or treatment of chemo- or radiotherapy related diarrhoea in cancer patients.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs).
Types of participants
Adults 18 years and over with histologically diagnosed cancer at any stage of disease and receiving chemotherapy, radiotherapy or both.
Types of interventions
- Probiotics versus any other intervention (observation, usual care, placebo or other active agents)
- Probiotics combined with other agents versus the same agents without probiotics
- One regimen of probiotic administration versus a different regimen of probiotic administration (i.e. different kind of medication, intake, dosage and timing)
We will include the following probiotics: lactobacillus (i.e. Lacbobacillus acidophilum, Lacbobacillus casel, Lactobacillus jensenii), bifidobacterium (i.e. Bifidobacterium longum, Bifidobacterium breve,Bifidobacterium oval, Bifidobacterium thermophilum), Saccharomyces buollardii. We will also include studies combining the use of probiotics with prebiotics.
Types of outcome measures
- Proportion of participants with diarrhoea
- Severity of diarrhoea, e.g. according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI 2013)
- Time to rescue medication for diarrhoea
- Proportion of participants requiring rescue medication for diarrhoea
- Mortality caused by diarrhoea
- Quality of life measured using a scale that is validated through reporting of norms in a peer-reviewed publication
- Adverse effects such as sepsis, dysbacteria and hypersensitivity (especially in high risk populations such as those who are immunocompromised or have central lines in situ)
Search methods for identification of studies
We will conduct a broad search to ensure maximum recall of the relevant literature. A comprehensive search of different electronic databases using a combination of free text and MESH terms will be undertaken to identify potential studies for inclusion in the review. There will be no restriction on language. The databases used in the retrieval process will be the Cochrane Central Register of Controlled Trails (CENTRAL), the Cochrane Gynaecological Cancer Review Group Specialised Register, MEDLINE and EMBASE. For the MEDLINE search strategy see Appendix 1.
For databases other than MEDLINE, we will adapt the MEDLINE search strategy accordingly. We will search databases until present day. We will use the 'related articles' feature in PubMed the for all included studies to identify any other studies that might have been missed by our search. We will update and conduct the search prior to completion of the review to identify newly published articles.
Searching other resources
We will also search prospective trial registers for controlled trials in progress, e.g. ClinicalTrials.gov (http://clinicaltrials.gov/).
If possible, we will contact principal trial authors for further information related to their study and any other published and unpublished studies. We will also screen all reference lists of included studies for additional studies.
Data collection and analysis
Selection of studies
We will download all titles and abstracts retrieved by electronic searching to a reference management database and remove duplicates. Two review authors (FvdW, PH) will examine the remaining references independently. Those studies which clearly do not meet the inclusion criteria will be excluded. The full-text articles of potentially eligible studies will be obtained and each review author will independently assess whether the study meets the inclusion criteria. Any difference in opinion will be arbitrated by a third author (RS). We will document the excluded studies and state the reasons for exclusion according to the guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Data extraction and management
Two review authors (FvdW, PH) will independently extract data. Data will be entered into the Cochrane Collaboration's statistical software, Review Manager 2013, by one author (FvdW or PH) and checked for correctness by another (PH or FvdW).
For each included study, we will collect data on the characteristics of the patients (age, gender distribution, diarrhoea severity, previous treatment) and interventions (type, formulation, dose, duration, regimen), outcomes and duration of follow-up.
For time to event data, we will extract the log of the hazard ratio [log(HR)] and its standard error from trial reports; if these are not reported, we will attempt to estimate the log(HR) and its standard error (SE) using the methods of Parmar 1998.
For dichotomous outcomes (e.g. adverse events or the presence of diarrhoea), we will extract the number of patients in each treatment arm who experienced the outcome of interest and the number of patients assessed at endpoint, in order to estimate a relative risk (RR).
For continuous outcomes (e.g. QoL measures), we will extract the final value and standard deviation (SD) of the outcome of interest and the number of patients assessed at the endpoint in each treatment arm at the end of follow-up, in order to estimate the mean difference between treatment arms and its standard error.
Where possible, we will extract all data relevant to an intention-to-treat (ITT) analysis, in which participants will be analysed in groups to which they were assigned.
We will note the time points at which outcomes were collected and reported and, if necessary, analyse them separately.
Assessment of risk of bias in included studies
Two review authors (FvdW, PH) will independently assess the risk of bias of all included RCTs using the Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011); differences will be resolved by discussion or by appeal to a third review author (RS).
We will summarise results in both a 'risk of bias graph' and a 'risk of bias summary'. We will interpret results of meta-analyses in light of the findings of the risk of bias assessments.
Measures of treatment effect
We will express results as RRs with 95% confidence intervals (CIs) for dichotomous outcomes. For time to event data, we will use the HR if possible. For continuous outcomes we will calculate mean differences (MDs) with 95% CIs.
Dealing with missing data
In case outcome data are missing, we will contact trial authors and request for further information related to their study.
Assessment of heterogeneity
We will evaluate the presence of clinical heterogeneity by comparing the participants' characteristics and the methodology across studies (Data synthesis). We will assess statistical heterogeneity by visual inspection of the forest plots along with consideration of the test for heterogeneity and the I
Assessment of reporting biases
If more than 10 included studies are available, we will use funnel plots to assess the potential for small study effects such as publication bias. .
For statistical analyses we will use Review Manager 2013.
We will combine results of studies that are clinically homogeneous. For dichotomous outcomes, we will pool the RR; for time-to-event data, we will pool HRs using the generic inverse variance method; for continuous outcomes, we will pool MDs if all studies measured the outcome on the same scale, otherwise standardised mean differences (SMDs) will be pooled.
In case studies contain multiple treatment groups, we will divide the 'shared' comparison group into the number of treatment groups and comparisons between each treatment group and the split comparison group will be treated as independent comparisons.
We will use the randomeffects model with inverse variance weighting for all meta-analyses (DerSimonian 1986).
If meta-analysis is not possible, we will summarise the results qualitatively.
Subgroup analysis and investigation of heterogeneity
We will conduct subgroup analyses to investigate possible differences between groups. We will consider factors such as age, stage, type of intervention and length of follow-up in interpreting any heterogeneity.
We will perform sensitivity analyses by excluding studies at high risk of bias and studies with more than 10% missing outcome data.
We would like to thank the Cochrane Gynaecological and Orphan Cancer Review Group for the advice and support that they have provided, in particular Clare Jess, Managing Editor and Jane Hayes Information Manager/TSC. Also we would like to thank the peer reviewers: Mario Cruciani; Ruth Payne; Karen Moody and Arno Mank.
The original protocol for this review was designed and written by Ting Wang, Lili Luo, Taixiang Wu, Qinghua Zhou and published in December 2010. In 2013, the Review Group asked us to take over this protocol and prepare the review after multiple attempts (both by the CRG and us) to contact the original authors had failed. We are much indebted to the original author team for their preparation of the protocol.
The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Gynaecological Cancer Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.
Appendix 1. MEDLINE (Ovid) search strategy
1 exp Neoplasms/
2 (neoplasm* or cancer* or tumor* or tumour* or malignan* or carcinom*).mp.
3 1 or 2
4 exp Diarrhea/
8 6 or 4 or 7 or 5
9 exp Probiotics/
13 exp Lactobacillus/
17 saccharomyces boulardii.mp.
18 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17
19 3 and 8 and 18
21 controlled clinical trial.pt.
24 drug therapy.fs.
28 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27
29 19 and 28
mp=title, original title, abstract, name of substance word, subject heading word, unique identifier; pt=publication type; ab=abstract; fs=floating subheading
Protocol first published: Issue 11, 2010
Contributions of authors
Review protocol amendment:
Amending the protocol: Rob Scholten, Pauline Heus, Fleur van de Wetering
Commented on draft protocol: Leen Verleye, Geertjan van Tienhoven
Original author team:
Conceiving the review idea Ting Wang, Qinghua Zhou
Designing the review. Qinghua Zhou
Writing the protocol: Ting Wang, Qinghua Zhou
Designing search strategies:Ting Wang, Lili Luo with assistance from Jane Hayes of the CGCRG
Providing a methodological perspective: Taixiang Wu, Qinghua Zhou
Coordinating the review: Qinghua Zhou,Ting Wang
Declarations of interest
Sources of support
- None, Not specified.
- The Belgian Health Care Knowledge Centre (KCE), Belgium.The Belgian Health Care Knowledge Centre (KCE) commissioned and supported a series of systematic reviews for the guideline "Supportive treatment for cancer. Part 2: prevention and treatment of adverse events related to chemotherapy and/or radiotherapy for adults with cancer". This protocol was one of the research questions of this guideline.