Probiotics

Probiotics

PEP Topic 
Radiation-Induced Diarrhea
Description 

Probiotics are live microorganisms that are capable of colonizing the intestinal tract, altering the microflora, and exerting a positive effect on the host. The mechanism(s) by which probiotics exert positive effects remains to be elucidated, but purported mechanisms include antagonizing pathogens through the production of antimicrobial or antibacterial compound, decreasing gut pH by stimulating lactic-acid-producing bacteria, preventing colonization of pathogenic microorganisms by competing for binding sites, improving immune function, competing with pathogens for nutrients and growth factors, producing lactase to aid lactose digestion, and signaling cells to stop production of virulence factors. Probiotics have been used to treat diarrhea and constipation. Preoperative probiotics were examined for prevention of infection in patients undergoing colorectal surgery.

Effectiveness Not Established

Research Evidence Summaries

Chitapanarux, I., Chitapanarux, T., Traisathit, P., Kudumpee, S., Tharavichitkul, E., & Lorvidhaya, V. (2010). Randomized controlled trial of live lactobacillus acidophilus plus bifidobacterium bifidum in prophylaxis of diarrhea during radiotherapy in cervical cancer patients. Radiation Oncology, 5, 31.

doi: 10.1186/1748-717X-5-31
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Study Purpose:

To determine if the combination of Lactobacillus acidophilus plus Bifidobacterium bifidum is effective in preventing diarrhea in patients with locally advanced cervical cancer receiving radiation therapy

Intervention Characteristics/Basic Study Process:

Patients were randomized to receive either L. acidophilus plus Bifidobacterium bifidum or placebo capsules. Beginning 7 days before and continuing throughout the entire time of receiving radiotherapy, participants took 2 capsules, 2 times each day before breakfast and dinner. Patients needing antidiarrheal medication were given loperamide (2 mg).

Sample Characteristics:

  • The study reported on 63 patients.
  • The median age was 52 years in the placebo group and 47 years in the study group.
  • The sample was 100% female.
  • All patients had International Federation of Gynecology and Obstetrics (FIGO) stage IIB-IIIB squamous cell carcinoma of the cervix and were scheduled to receive standard treatment for locally advanced cervical cancer (i.e., external beam whole pelvis radiation and brachytherapy plus weekly cisplatin at 40 mg/m2).

Setting:

The study was conducted in Thailand.

Phase of Care and Clinical Applications:

All patients were undergoing the active treatment phase of care.

Study Design:

This was a prospective, randomized, double-blind, placebo-controlled study.

Measurement Instruments/Methods:

The National Cancer Institute Common Toxicity Criteria, version 2, was used.

Results:

  • All patients experienced diarrhea; however, the difference in the severity of the diarrhea was significant (p = 0.002). In the placebo group, 55% of patients experienced grade 1 diarrhea, 42% experienced grade 2, and 3% experienced grade 3. In the study group, 91% experienced grade 1 diarrhea, 9% experienced grade 2, and none experienced grade 3.
  • The intervention group also had a significantly improved stool consistency (p < 0.001).  
  • In the placebo group, 32% of patients needed antidiarrheal medication, compared with only 9% of patients in the study drug group (p = 0.03).

Conclusions:

The prophylactic use of the combination of live L. acidophilus plus Bifidobacterium bifidum was shown to be effective in decreasing the severity of diarrhea.

Limitations:

  • The sample size was small sample with fewer than 100 patients.
  • Cultures were not performed on stool, which could have missed infectious causes of diarrhea. 
  • The use of antimicrobials was not mentioned as exclusion criteria.

Nursing Implications:

The prophylactic use of L. acidophilus plus Bifidobacterium bifidum may decrease the severity of diarrhea, improve stool consistency, and reduce the need for antidiarrheal medication in patients with locally advanced cervical cancer undergoing pelvic radiation with concomitant weekly cisplatin.  Further studies need to be done with larger samples.

Delia, P., Sansotta, G., Donato, V., Frosina, P., Messina, G., De Renzis, C., & Famularo, G. (2007). Use of probiotics for prevention of radiation-induced diarrhea. World Journal of Gastroenterology, 13(6), 912–915.

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Study Purpose:

To examine the effect of probiotic use for prevention of radiation-induced diarrhea

Intervention Characteristics/Basic Study Process:

The experimental group received high-potency probiotics (VSL#3 in one sachet) three times per day beginning on the first day of radiation therapy until the end of scheduled cycles. The VSL #3 sachet contained 450 billions/gm of viable lyophilized bacteria, including 4 strains of lactobacilli (Lactobacilli casei, L. plantarum, L acidophilus, and L. delbruekii subsp. Bulgaricus); 3 strains of Bifidobacteria (B. longum, B. breve, and B. infantis) and 1 strain of Streptococcus salivarius subsp. thermophilus.

The control group received an identical-appearing placebo.

Sample Characteristics:

This study reported on 490 patients receiving adjuvant radiation therapy after surgery for sigmoid, rectal, or cervical cancer.

Study Design:

This was a double blind, randomized, placebo-controlled trial.

Measurement Instruments/Methods:

Efficacy endpoints included incidence and severity of radiation-induced diarrhea, the number of bowel movements (BMs) per day, and the time from start of study until need for loperamide.

Endpoints (clinical symptoms, use of medications, and any adverse events) were reviewed with patients weekly during scheduled radiation therapy treatments and again one month after completion.

Results:

  • In all, 97.5% of patients in the placebo group and 99.1% of patients in the experimental group completed study.
  • More patients in the placebo group had radiation-induced enteritis and colitis (p < 0.001).
  • The placebo group experienced more severe toxicity (grade 3 or 4) (p < 0.001) and had a higher mean daily number of BMs (p < 0.001).

Conclusions:

Use of a probiotic lactic-acid producing bacteria is a safe, easy, feasible approach to preventing radiation-induced diarrhea after surgery for abdominal and pelvic cancer.

Limitations:

  • Severity was assessed using World Health Organization (WHO) standards whereas other studies use National Cancer Institute (NCI) standards.
  • This study looked only looked at prevention of radiation-induced diarrhea. 
  • The study did not address safety in patients who are neutropenic.

Nursing Implications:

Probiotic lactic-acid-producing bacteria is safe for use in patients receiving radiation treatment, and it is not associated with bacteremia, sepsis, or septic shock. Lactobacilli lowers the production of proinflammatory cytokines and other effectors of inflammation and tissue injury. Probiotic bacteria upregulates the innate immune response in the gut and protects against invasive organisms. Further studies are needed on different probiotic preparations and mixtures.

Giralt, J., Regadera, J. P., Verges, R., Romero, J., de la Fuente, I., Biete, A., … Guarner, F. (2008). Effects of probiotic lactobacillus casei DN-114 001 in prevention of radiation-induced diarrhea: Results from multicenter, randomized, placebo-controlled nutritional trial. International Journal of Radiation Oncology, Biology, Physics, 71(4), 1213–1219.

doi: 10.1016/j.ijrobp.2007.11.009
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Study Purpose:

To determine whether a liquid yogurt containing Lactobacillus casei DN-114 reduces the incidence or the severity of diarrhea in patients with cervical carcinoma receiving radiation therapy with concomitant cisplatin or in patients with postoperative endometrial adenocarcinoma receiving radiation therapy

Intervention Characteristics/Basic Study Process:

Patients receiving conventional fractionation pelvic radiation therapy for cervical carcinoma (radiation therapy with weekly cisplatin) or for endometrial adenocarcinoma were randomly assigned to receive 96 mL of fermented liquid containing yogurt with Lactobacillus casei DN-114-001 or the same amount of placebo in 2-mg capsules, three times per day. Loperamide was used as necessary as rescue medication; no other antidiarrheal medications were permitted. Consumption of loperamide was recorded. Patients kept daily diaries.

Sample Characteristics:

  • The study reported on 85 patients.
  • The mean age was 60.91 years (SD = 11.80 years) in the intervention group and 59.34 years (SD = 12.77 years) for the placebo group.
  • All of the patients were female.
  • Patients had been diagnosed with endometrial adenocarcinoma requiring postoperative pelvic radiation therapy or advanced cervical squamous cell carcinoma requiring pelvic radiation therapy with concomitant weekly cisplatin.
  • Patients had European Cooperative Oncology Group (ECOG) performance statuses of less than 2.
  • Patients were excluded from the study if they
    • Had other types of pelvic tumors.
    • Were receiving treatment with chemotherapy agents other than cisplatin.
    • Had received prior chemotherapy or radiation therapy.
    • Were being treated with antimicrobials or immunosupressors at inclusion.
    • Had experienced any acute or chronic gastrointestinal (GI) condition associated with diarrhea in the month prior to recruitment.

Setting:

The study was conducted at multiple outpatient settings in Spain.

Phase of Care and Clinical Applications:

Patients were undergoing the active treatment phase of care.

Study Design:

This was a placebo-controlled, double-blind, randomized clinical trial in two parallel groups.

Measurement Instruments/Methods:

The Bristol Stool Scale, National Cancer Institute (NCI) Common Toxicity Criteria (CTC), and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - C30 were used.

Results:

  • No significant differences were found in
    • Development of grade 2 or worse diarrhea
    • Need for rescue medication (loperamide)
    • Withdrawal because of a lack of efficacy
    • Time to the first occurrence of grade 2 or 3 diarrhea
    • Time to the first occurrence of type 5 (soft) stools (Bristol Scale)
    • Quality-of-life questionnaire scores
    • Complications reported at 6 months.
  • The first incidence of type 6 (fluffy) stools (Bristol scale) was significantly shorter in the placebo group (median of 10 days) than in the intervention group (median of 14 days, (p = 0.048).
  • No adverse events were considered related to the study product.

Conclusions:

The use of a fermented liquid yogurt containing Lactobacillus casei DN-114-001 did not decrease the incidence of radiation-induced diarrhea.

Limitations:

  • The sample size was small, with fewer than 100 patients.
  • No intent-to-treat analysis was performed.
  • Accrual was terminated prematurely because of recruiting difficulties and did not reach calculated sample size to achieve 80% power.
  • 5-HT3 inhibitors were used to treat nausea/vomiting. Because these are associated with constipation, their use could have affected stool consistency.

Nursing Implications:

The probiotic Lactobacillus casei does not appear to decrease the incidence of radiation-induced diarrhea.

Timko, J. (2010). Probiotics as prevention of radiation-induced diarrhoea. Journal of Radiotherapy in Practice, 9(4), 201–208.

doi: 10.1017/S1460396910000087
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Study Purpose:

To evaluate the efficacy of probiotics in the prevention of radiation-induced diarrhea

Intervention Characteristics/Basic Study Process:

Patients who had undergone adjuvant, postoperative radiation to the abdominal or pelvic area, alone or in combination with chemotherapy, and were admitted to the hospital were randomized to one of two groups: “5” Strain Dophilus (L group) or Hylak Tropfen Forte drops (H group).

Sample Characteristics:

  • The study reported on 42 patients.
  • The median age of patients in the L group was 62 years with a range of 34–82 years, and the median age of patients in the H group was 67 years with a range of 43–83 years.     
  • The sample was 66% male and 33% female.
  • The majority of patients in the L group had colorectal cancer and the majority of patients in the H group had prostate or rectosigmoid junction cancer.
  • The number of patients in the L group with a body mass index (BMI) of normal weight was equal to the number of patients with an overweight BMI. In the H group, more patients had an overweight BMI than a normal BMI.
  • In the L group, 55% of patients also received chemotherapy. In the H group, 50% of patients also received chemotherapy.
     

Setting:

This study was conducted at a single-site, inpatient setting in Ruzomberok, Slovakia.

Phase of Care and Clinical Applications:

All patients were undergoing the active treatment phase of care.

Study Design:

This was a randomized, parallel-group, nonplacebo controlled trial.

Measurement Instruments/Methods:

Patient diaries were used to record the number and consistency of stools, presence of bleeding or abdominal pain, and use of antidiarrheals or antibiotics.

Results:

  • Patients in the L group had a higher number of daily bowel movements (BMs) (n = 4.16, range = 1.2–9.7) than in the H group (n = 2.52, range = 0.7–5.3).
  • In the second week, the weekly number of BMs was significantly higher in the L group (p < 0.01) compared to the H group.
  • The number of BMs in the H group increased at week 3.
  • A significant increase was reported in the number of BMs in patients receiving only radiation versus radiation plus chemotherapy.
  • Fewer patients in the L group (27%) required an antidiarrheal (specifically diphenoxylate) compared to the H group (55%).
  • Fewer patients in the L group (9%) required antibiotics versus in the H group (25%).
  • Abdominal pain was similar between groups with 25% of patients reporting the side effect in the L group compared to 22% in the H group.
  • One subject in the H group reported blood in the stool at day 9.

Conclusions:

Probiotics  may be effective in the prevention of radiation-induced diarrhea.

Limitations:

  • The sample size was small, with fewer than 100 patients.
  • A control group was not included.
  • Patients' diets and the radiation technique could have varied between groups.

Nursing Implications:

The use of probiotics may have some benefit in the prevention of radiation-induced diarrhea; however, more studies (including control arms) are needed.

Urbancsek, H., Kazar, T., Mezes, I., & Neumann, K. (2001). Results of a double-blind, randomized study to evaluate the efficacy and safety of Antibiophilus in patients with radiation-induced diarrhoea. European Journal of Gastroenterology and Hepatology, 13(4), 391–396.

http://dx.doi.org/
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Study Purpose:

To determine the efficacy and tolerability of Lactobacillus rhamnosus (marketed as Antibiophilus) in treating radiation-induced diarrhea

Intervention Characteristics/Basic Study Process:

Patients in the treatment group were instructed to use Antibiophilus sachets containing 1.5 grams of Lactobacillus rhamnosus. Patients in the control group used identically appearing placebo sachets containing 700 mg corn starch, 797 mg microcrystalline cellulose, 1.37 mg iron oxide, 1.13 mg orange coloring agent, and 1 mg caramel aroma. Both groups used the sachets three times per day and were asked to document the date and time of any rescue medication.

Sample Characteristics:

Patients were between 19–75 years old and had developed diarrhea within 4 weeks of receiving radiation therapy to the abdomen. The experimental group contained 102 patients, and the control group contained 103 patients.

Study Design:

This was a randomized, double-blind, parallel group study.

Measurement Instruments/Methods:

  • The primary endpoint to assess efficacy was the time to and frequency of rescue medication for diarrhea. 
  • Secondary endpoints were the number of bowel movements and diarrhea grading (0 for no diarrhea, 1 for mild, 2 for moderate, and 3 for severe).

Results:

  • A greater percentage of patients in the control group (48%) required rescue medication compared to the experimental group (35%), but the difference was not statistically significant (p = 0.064).
  • The control group experienced a greater average number of bowel movements per day (3.2) compared to the experimental group (2.4), but the difference was not statistically significant (p < 0.10).
  • Diarrhea was graded at a higher severity for the control group (1) compared to the experimental group (0.7), but the difference was not statistically significant.
  • Although the results suggested a superior efficacy for diarrhea treatment in the experimental group, the results failed to show a statistically significant difference for any of the measured variables. Despite this lack of statistically significant differences, the authors concluded that antibiophilus therapy yielded a favorable benefit-to-risk ratio.

Limitations:

  • The study population was limited to patients who were already experiencing diarrhea. The study did not provide any data regarding prevention of diarrhea.
  • The endpoints were based on patients' subjective reports.

Nursing Implications:

This study involved a large sample. Although the results suggested a superior efficacy for diarrhea treatment in the experimental group, the results failed to show a statistically significant difference for any of the measured variables. 

Systematic Review/Meta-Analysis

Fuccio, L., Guido, A., Eusebi, L. H., Laterza, L., Grilli, D., Cennamo, V., … Bazzoli, F. (2009). Effects of probiotics for the prevention and treatment of radiation-induced diarrhea. Journal of Clinical Gastroenterology, 43(6), 506–513.

doi: 10.1097/MCG.0b013e3181a1f59c
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Purpose:

To evaluate the effectiveness of probiotic supplementation for the prevention and treatment of radiation-induced diarrhea

Search Strategy:

Databases searched were PubMed, EMBASE, Cochrane Library, Google Scholar, and online clinical trials registers (Cochrane Central Register of Conrolled Trials, metaRegister of Controlled Trials, National Institutes of Health) until January 2009. Other relevant trials were identified from the reference list of selected articles. Abstracts presented up to 2008 at the United European Gastroenterology Week meetings, American Society for Therapeutic Radiology and Oncology Annual Meetings, and American Gastroenterological Association Digestive Disease Week were searched manually.

Search keywords were diarrhea, probiotics, radiotherapy, radiation therapy, Lactobacilli, Bifidobacteria, Enterococci, VSL no. 3, pelvic tumors, and abdominal tumors.

Studies were included in the review if they were randomized, controlled trials with at least two parallel groups that evaluated the effectiveness of probiotic supplementation to prevent or treat radiation-induced diarrhea.

Studies were excluded if they were review articles, involved nonradiation-induced diarrhea, or covered radiation-induced gastrointestinal (GI) symptoms other than diarrhea.

Literature Evaluated:

The abstracts of 58 articles were reviewed. Fifty evaluated the effects of probiotic supplementation for conditions other than radiation therapy and were eliminated. Of the remaining eight, three were duplicate reports and one studied radiation-induced chronic bowel discomfort rather than diarrhea.

The remaining four studies were selected for this review. Three were randomized controlled trials evaluating probiotic supplementation for the prevention of radiation-induced diarrhea, and one trial evaluated probiotic supplementation for the treatment of radiation-induced diarrhea.

Sample Characteristics:

Three studies evaluated the use of probiotic supplementation to prevent radiation-induced diarrhea. A total of 632 individuals initially were randomized to the studies; the final sample sizes were 21, 85, and 482. The study using probiotic supplementation to treat radiation-induced diarrhea had a sample size of 205 patients, with 102 receiving the intervention and 103 receiving a placebo.

Results:

  • Probiotic supplementation was well-tolerated in the prevention and treatment trials.
  • The three trials addressing probiotic supplementation for the prevention of radiation-induced diarrhea did not collectively show significant differences between the intervention and control groups.
  • The study addressing treatment also did not show significant differences between the intervention and placebo groups.

Conclusions:

The few available studies on the use of probiotics to prevent or treat radiation-induced diarrhea do not allow for firm conclusions to be drawn regarding the benefits of this intervention.

Limitations:

The studies included in the systematic review and meta-analysis used different single strains and different doses of probiotics.

Nursing Implications:

More studies using preparations containing several strains of probiotics and studies looking at comparisons between different probiotics are needed.

Salari, P., Nikfar, S., & Abdollahi, M. (2012). A meta-analysis and systematic review on the effect of probiotics in acute diarrhea. Inflammation & Allergy Drug Targets, 11(1), 3–14.

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Purpose:

To clarify the efficacy of probiotics in children and adults

Search Strategy:

  • Databases searched were PubMed, Web of Science, Scopus, and the Cochrane Database.
  • Search keywords were probiotics and diarrhea.
  • Studies were included in the review if they were randomized clinical trials (RCTs) and involved children.
  • Studies were excluded if they were uncontrolled trials or the results did not address study goals.

Literature Evaluated:

  • A total of 1,228 references were retrieved.
  • The Jadad scale quality rating was used to evaluate the literature.

Sample Characteristics:

  • The final review involved 20 studies with total sample of 3,867 patients. Sample sizes ranged from 69–913 patients.
  • Most trials involved children. Two studies were included regarding radiation-induced diarrhea and one trial involved chemotherapy-related diarrhea. These studies were not included in the meta-analysis.

Results:

The effect size for probiotics compared to placebo in 19 trials related to duration of diarrhea was -0.67 (95% confidence interval [CI] = -0.95–0.38) in favor of probiotics. Heterogeneity was statistically significant. Findings included evaluation of duration of diarrhea, hours of fever, duration of hospitalization, duration of vomiting, and number of stools per day. Authors reviewed subsets of information for children, adults, cases of amebiasis and clostridium difficile, HIV, and radiation or chemotherapy.

Conclusions:

Taken as a whole, authors concluded insufficient evidence exists for the efficacy of probiotics for different types of diarrhea in children or adults.

Limitations:

  • Very few of the trials were relevant to oncology.
  • Trials involved both children and adults. However, only the trials involving children were included in the meta-analysis. 
  • High heterogeneity existed among the studies. 
  • Variations in specific probiotics may have influenced results.
  • The authors noted the need for agreement among researchers in defining measurements including what constitutes the end of diarrhea.

Nursing Implications:

These findings did not provide strong support for the use of probiotics for prevention or management of diarrhea in patients receiving radiation or chemotherapy. Overall evidence in all groups was limited by a number of factors. The specific type, dosages, and timing of probiotic use varied.

Guideline/Expert Opinion

Gibson, R.J., Keefe, D.M., Lalla, R.V., Bateman, E., Blijlevens, N., Fijlstra, M., … Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). (2013). Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Supportive Care in Cancer, 21(1), 313–326.

doi: 10.1007/s00520-012-1644-z
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Purpose & Patient Population:

To systematically review current evidence for prevention and treatment of gastrointestinal (GI) mucositis in adults and children receiving cancer treatment and to update relevant Multinational Association of Supportive Care in Cancer (MASCC) guidelines

Type of Resource/Evidence-Based Process:

This was an evidence-based guideline developed based on a systematic review of the literature with rating of levels of evidence and identification of study flaws.

Database searched was MEDLINE.

Search keywords were numerous and included all known possible interventions tested.

Inclusion and exclusion criteria were not stated in this article but provided elsewhere in the journal.

Phase of Care and Clinical Applications:

  • Patients were undergoing the active treatment phase of care.
  • The study has clinical applicability for pediatrics.

Results Provided in the Reference:

A total of 1,336 papers were initially retrieved; of these, 146 were reviewed for development of the guidelines.

Guidelines & Recommendations:

  • Probiotics with Lactobacillus spp. may be beneficial for prevention of chemotherapy- and radiotherapy-induced diarrhea in patients with pelvic malignancies. Two studies with positive results were cited.
  • Amifostine may reduce esophagitis because of concomitant radiation and chemotherapy. It is not recommended in other situations because of conflicting evidence.
  • Mesalazine, 5-aminosalicylic acid (5-ASA), and olsalazine are not recommended because they have been associated with increased diarrhea compared to placebo.
  • Sucralfate is not recommended for diarrhea prevention because it is associated with increased GI side effects, including rectal bleeding.
  • Oral sulfasalazine given at 500 mg twice daily is recommended to reduce incidence and severity of radiation-induced enteropathy.
  • No guideline was provided for glutamine, but three new studies were sited that showed promising results.
  • If loperamide has not resulted in diarrhea control with standard or high-dose chemotherapy in HCTY patients, 100 mcg or greater of subcutaneous octreotide twice daily is recommended.

Limitations:

This review had a limited search strategy, as only one database was searched. In addition, most of the suggestions and recommendations provided were based on low-level evidence by the rating system used.

Nursing Implications:

These guidelines provide some suggestions for management of oral mucositis and diarrhea in patients with cancer. They also provide information regarding evidence for mucositis in the entire GI tract.


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