Clinical trial NCT06560879: Effectiveness of Probiotics for the Prevention of Gastrointestinal Toxicity in Children with Leukemia
Official title: Effectiveness of Probiotics for the Prevention of Gastrointestinal Toxicity and Changes in Gut Microbiota in Children with Acute Lymphoblastic Leukemia
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE2
Conditions: Probiotics
Gastrointestinal Diseases
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Lead sponsor: National Institute of Pediatrics, Mexico
Sponsor class: OTHER_GOV
First posted: 2024-08-19
Enrollment: 120
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: An experimental, longitudinal, prospective, prolective, analytical, concurrent, randomized, triple-blind: randomized controlled clinical trial
Primary purpose: PREVENTION

Brief summary: Background: Acute lymphoblastic leukemia (ALL) is a common malignant neoplasm in children. Although chemotherapy achieves remission in over 70% of cases, it can cause gastrointestinal toxicity in up to 32.5%. Some studies suggest that administering probiotics reduces this risk, but the evidence remains inconsistent.

Objective: To evaluate the effectiveness and safety of administering L. casei, L. rhamnosus or B. bifidum compared to a placebo for the prevention of gastrointestinal toxicity, decreased intestinal permeability, and changes in intestinal microbiota in pediatric patients diagnosed with acute lymphoblastic leukemia receiving chemotherapy.

Methods: A total of 120 participants aged 6 to 17 years, diagnosed with ALL and receiving consolidation phase chemotherapy without gastrointestinal comorbidities, will be included. Participants will be administered daily 2 capsules containing either 1) L. casei, 2) L. rhamnosus, 3) B. bifidum or 4) placebo daily for 8 weeks. The clinical status of the participants will be evaluated weekly by the oncology service to determine the presence of gastrointestinal toxicity and adverse events. Changes in intestinal permeability will be assessed by measuring beta-lactoglobulin in a blood sample using the ELISA technique, while changes in the intestinal microbiota will be analyzed by genomic sequencing at baseline and at the end of follow-up.

Statistical analysis: Descriptive analysis will use measures of central tendency and dispersion. For quantitative variables, the mean and standard deviation or median with minimum and maximum values will be calculated depending on the distribution type. Frequencies and proportions will be calculated for qualitative variables, presented in tabular and graphical form. To compare the quantitative variables between the four interventions, a multi-way ANOVA test will be used.

The risk of gastrointestinal toxicity and adverse events will be analyzed by calculating the relative risk and 95% confidence interval. Differences between the interventions will be analyzed using survival analysis with the Kaplan-Meier and Log-Rank tests. Sequencing data will be analyzed using the Qiime2 program, filtered to generate a phylogenetic tree using the Silva database. Corresponding plots will be generated for each taxonomic level. Alpha (intra-group) and Beta (inter-group) diversity will be presented by ordination plots using principal component analysis with the ANCOM program

Detailed description: Background Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by the uncontrolled proliferation of immature lymphoid cells. It is the most common neoplasm in children, representing up to 53.1% of all oncologic processes in Mexico \[1-6\]. Fortunately, with the current chemotherapeutic treatments, disease remission is achieved in 98% of cases; however, the chemotherapeutic treatments have side effects that can lead to gastrointestinal toxicity (7.7 to 32.5%), which is associated with up to 50% mortality.

Among the most common gastrointestinal manifestations resulting from this toxicity are mucositis, pancreatitis (2 to 8%), diarrhea (10 to 82%), and colitis associated with decreased Bacillus spp and Bidifobacterium spp, increasing the risk of necrosis and intestinal perforation of the terminal ileum and cecum. Hence, several studies have been conducted to identify agents that can reduce the incidence of gastrointestinal toxicity like as probiotics which are a group of saprophytic microorganisms (bacteria, viruses, fungi and protozoa) that live in equilibrium on the skin and mucous membranes, mainly in the intestine, have garnered attention.

Probiotics are known to have several beneficial functions such as promoting the absorption of carbohydrates, short-chain fatty acids and calcium; facilitating the synthesis of lipids and vitamins; modulate and reduce the concentration of inflammatory mediators in the intestinal mucosa; improve mucosal blood flow, thus reducing the risk of ischemic areas in the intestine; and strengthen the immune system.

Although research has been conducted on the use of probiotics to prevent or reduce the toxic effects of chemotherapy, the results are still inconclusive because the effect of probiotics has been analyzed in multiple combinations, which makes it difficult to distinguish the specific effects per phylum. This complicates the generation of standardized therapeutic schemes to improve the quality of care of these patients. If this project successfully identifies the effectiveness and safety of these probiotics, it will enable to development of new therapeutic strategies aimed at improving the quality of healthcare for these patients, reducing the frequency and severity of gastrointestinal complications secondary to the administration of chemotherapy.

Objective To evaluate the effectiveness and safety of the administration of Lactobacillus casei, Lactobacillus rhamnosus and Bifidobacterium bifidum compared to placebo in reducing the risk of gastrointestinal toxicity, decreasing intestinal permeability, and changing intestinal microbiota without the development of adverse effects in pediatric patients diagnosed with ALL receiving consolidation chemotherapy in the Oncology Service of the Instituto Nacional de Pediatría.

General Description of the Study

1. Participant selection and consent:

   * Participants meeting the study selection criteria will be selected.
   * Informed consent will be obtained from the participant's parents or guardians and, if appropriate, from the patient if older than 8 years of age. They will be informed about the benefits, complications and adverse effects of the interventions (Appendix 1-3).
   * If the parents or guardians prefer treatment outside the research project, the patient will be treated according to the established national protocols used in the Oncology Service of the Instituto Nacional de Pediatría.
   * Consent will also be obtained for the use of personal data as per Appendices 4 and 5. This data includes participant and parent names, birth date, sex, CURP, address, contact number, medical history, general habits, pathological conditions, social conditions, to be used exclusively for this research project.
   * Data will be handled with strict confidentiality, stored in an electronic database for five years by project personnel.
2. Initial Assessments:

   * A pediatric oncologist will perform a medical history, physical examination, anthropometry, fecal and serum sampling.
   * A nutritionist will evaluate the participant´s nutritional status and body composition.

   A) Physical examination:
   * Participant will remove outer clothing and shoes and sit on the examination table.
   * The pediatric oncologist will visually inspect for skin lesions using a lamp and tongue depressor if necessary.
   * Body temperature will be measured with a digital thermometer.
   * Participants will lie supine for palpation, percussion, and/or auscultation to assess cardiac, and abdominal conditions.

   B) Anthropometry
   * Weight will be measured three times using a Seca scale.
   * Height will be measured three times using a stadiometer.
   * Waist circumference will be measured at the midpoint between the lower edge of the last rib and the upper edge of the iliac crest.
   * Hip circumference will be measured 15 cm below the waist.
   * Arm circumference will be measured around the biceps muscle.
   * Thigh circumference will be measured around the upper third of the thigh.

   C) Nutritional Status

   - Height-for-Age (H-A), Weight-for-Age (W-A), Weight-for-Height (W-H), and Body Mass Index (BMI) indices will be classified according to NOM-008-SSA2-1993 standards.

   D) Body composition
   * Participants will remove metallic objects, empty their bladder, and lie supine on a non-conductive bed.
   * Electrode placement will be prepared with a cleansing towel and an electrically conductive towel.
   * Electrodes will be placed on hands and feet, and a multifrequency bioelectric impedance device will measure body composition at six different frequencies.
   * Data will be adjusted to WHO percentile curves.

   E) Fecal samples
   * Participants will collect stool samples at home using provided kits and instructions.
   * Samples will be transported in a cooler to the Instituto Nacional de Pediatría on the same day for analysis and will be stored in the freezer at -70°C until the end of the project.

   F) Serum samples
   * A 3 ml blood sample will be collected by peripheral venipuncture.
   * Serum samples will be processed to determine antibodies against beta-lactoglobulin using the sandwich enzyme immunoassay technique.

   Assessments will be conducted weekly for clinical condition, anthropometry, and body composition at weeks 1, 4, and 8, and fecal and serum samples at weeks 1 and 8.
3. Preparation of interventions:

   * Interventions will be prepared in a Baker Company Class II Type A2 vertical laminar flow hood.
   * The required amounts of lyophilized probiotic powder and microcrystalline cellulose will be mixed for 5 minutes (2:30 clockwise and 2:30 counterclockwise) at a speed of 25 rpm and encapsulated at a dose of: L. casei and L. rhamnosus at 2.5 billion CFU per capsule, B. bifidum at 1 billion CFU per capsule and placebo 300 mg of microcrystalline cellulose.
   * Each intervention will be stored in labeled sterile bags and refrigerated at 2 to 8°C.
   * Capsules will be quality checked for UFC content at Bacteriology Laboratory by dilution and sequencing, and any deviations will result in process adjustments.
4. Participant Allocation:

   * Participants will be randomly assigned to interventions using a computer-generated sequence, adjust in balanced blocks of five. (Appendix 7).
   * An external researcher will place intervention names in opaque envelopes, labeled with random numbers of the sequence.
   * Participants will draw a random number to be assigned to an intervention, communicated to the principal investigator.
5. Intervention Administration:

   * Participants will receive bottles with 14-16 capsules of the assigned intervention, stored in a cooler with refrigerated gel packs.
   * Participants will take one capsule before breakfast and one before lunch for one week, recording adherence in a logbook and repeating this process for eight weeks.
6. Clinical Evaluation:

   - Weekly clinical evaluations will be conducted for mucositis, diarrhea, colitis, flatulence, abdominal distention, and constipation, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) scale (V 4.02) \[39\]. If necessary, the pediatric oncologist will initiate treatment according to the Oncology service plan.
7. Data Collection:

   * If antibiotics are required or the chemotherapy consolidation phase is completed, participants will be eliminated from the study, and final assessments will be conducted.
   * Data from weekly clinical evaluations, nutritional assessments, and study follow-ups will be recorded in a data collection form (Appendix 8) and entered an electronic Excel database for statistical analysis using STATA 18 by a blinded researcher.

The sample size was calculated based on data from the study by Reyna-Figueroa, which reported a 0% incidence of diarrhea during the administration L. rhamnosus compared to 10% in participants who did not receive probiotics. Using the formula for proportions, with an alpha error of 0.05, 80% power, and estimating a loss rate of 20%, a sample size of 30 participants was determined for each of the four groups.

Statistical analysis A descriptive analysis will be performed using measures of central tendency to understand the characteristics of the studied sample and to determine the type of distribution of each variable using the Kolmogorov-Smirnoff normality test. For quantitative variables, the mean and standard deviation or median with minimum and maximum values will be calculated, depending on the type of distribution and summarized in tabular form; and data graphically represented by boxplot or bars chats as appropriate.

To compare the quantitative variables between the four interventions, a multi-way ANOVA test will be used. For qualitative variables, the chi-squared test will be used to compare the groups, adjusting for the nutritional status of the participants.

The risk of gastrointestinal toxicity and adverse events will be analyzed by the relative risk or Peto's odds ratio and 95% confidence interval. Differences between the interventions will be analyzed using survival analysis with the Kaplan-Meier and Log-Rank tests. Sequencing data will be analyzed using the Qiime2 program, filtered to generate a phylogenetic tree using the Silva database. Corresponding plots will be generated for each taxonomic level. Alpha (intra-group) and Beta (inter-group) diversity will be presented by ordination plots using principal component analysis with the ANCOM program.

Noted that patients who drop out of the study will have their results analyzed up to their last record, and all analyses will be conducted on an intention-to-treat basis.

Eligibility criteria: Inclusion Criteria:

* Patients older than 6 years and younger than 17 years with a recent diagnosis of acute lymphoblastic leukemia, confirmed by bone marrow aspirate and interpreted by a pediatric oncologist.
* Participants of both sexes
* Participants receiving treatment at the Oncology Service of the Instituto Nacional de Pediatría.
* Receiving chemotherapy according to national health protocols in the consolidation phase.
* Informed consent
* Informed assent for those older than 8 years.

Exclusion Criteria:

* Allergy to probiotics.
* Consumption of another probiotic
* Enteropathies affecting intestinal absorption (e.g., malabsorption syndrome, short bowel syndrome, intestinal malrotation, chronic nonspecific ulcerative colitis, Crohn's disease).
* Chronic diarrhea (\>15 days of duration)
* Presence of mucosal lesions
* Impossibility of enteral feeding
* Renal insufficiency
* Peritoneal dialysis
* Water and electrolyte disorders
* Surgical intestinal bypass (e.g., colostomy, ileostomy)
* Congenital metabolic disorders
* Septicemia
* Body temperature \> 38° C
* Received broad-spectrum antibiotics (piperacillin/tazobactam, fourth generation cephalosporins, aminoglycosides, carbapenem and/or metronidazole) within the past 30 days.

Primary outcomes:
measure: Prevention of Mucositis
timeFrame: 8 weeks
measure: Prevention of Diarrhea
timeFrame: 8 weeks
measure: Prevention of Colitis
timeFrame: 8 weeks
measure: Adverse events (flatulence)
timeFrame: 8 weeks
measure: Adverse events (distention)
timeFrame: 8 weeks
measure: Adverse events (constipation)
timeFrame: 8 weeks
measure: Adverse events (vomiting)
timeFrame: 8 weeks
Secondary outcomes:
measure: Blood Beta-Lactoglobulin Concentration
timeFrame: 8 weeks
measure: Changes in alpha and beta diversity of the intestinal microbiota
timeFrame: 8 weeks
measure: Adverse events (fever)
timeFrame: 8 weeks
measure: Adverse events (nausea)
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Mexico City
country: Mexico
facility: National Institute of Pediatrics
state: Coyoacan
Study officials:
affiliation: National Institute of Pediatrics
name: Sara Espinosa-Padilla, Ph.D.
role: STUDY_DIRECTOR
References:
citation: Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med. 1998 Aug 27;339(9):605-15. doi: 10.1056/NEJM199808273390907. No abstract available.
citation: Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, Ribeiro RC, Rubnitz JE, Raimondi SC, Onciu M, Coustan-Smith E, Kun LE, Jeha S, Cheng C, Howard SC, Simmons V, Bayles A, Metzger ML, Boyett JM, Leung W, Handgretinger R, Downing JR, Evans WE, Relling MV. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009 Jun 25;360(26):2730-41. doi: 10.1056/NEJMoa0900386.
citation: Rivera-Luna R, Velasco-Hidalgo L, Zapata-Tarres M, Cardenas-Cardos R, Aguilar-Ortiz MR. Current outlook of childhood cancer epidemiology in a middle-income country under a public health insurance program. Pediatr Hematol Oncol. 2017 Feb;34(1):43-50. doi: 10.1080/08880018.2016.1276236. Epub 2017 Mar 13.
citation: Moricke A, Zimmermann M, Valsecchi MG, Stanulla M, Biondi A, Mann G, Locatelli F, Cazzaniga G, Niggli F, Arico M, Bartram CR, Attarbaschi A, Silvestri D, Beier R, Basso G, Ratei R, Kulozik AE, Lo Nigro L, Kremens B, Greiner J, Parasole R, Harbott J, Caruso R, von Stackelberg A, Barisone E, Rossig C, Conter V, Schrappe M. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016 Apr 28;127(17):2101-12. doi: 10.1182/blood-2015-09-670729. Epub 2016 Feb 17.
citation: Barry E, Alvarez JA, Scully RE, Miller TL, Lipshultz SE. Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management. Expert Opin Pharmacother. 2007 Jun;8(8):1039-58. doi: 10.1517/14656566.8.8.1039.
citation: Schmiegelow K, Muller K, Mogensen SS, Mogensen PR, Wolthers BO, Stoltze UK, Tuckuviene R, Frandsen T. Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy. F1000Res. 2017 Apr 7;6:444. doi: 10.12688/f1000research.10768.1. eCollection 2017.
citation: Gorschluter M, Marklein G, Hofling K, Clarenbach R, Baumgartner S, Hahn C, Ziske C, Mey U, Heller R, Eis-Hubinger AM, Sauerbruch T, Schmidt-Wolf IG, Glasmacher A. Abdominal infections in patients with acute leukaemia: a prospective study applying ultrasonography and microbiology. Br J Haematol. 2002 May;117(2):351-8. doi: 10.1046/j.1365-2141.2002.03434.x.
citation: Inaba H, Pei D, Wolf J, Howard SC, Hayden RT, Go M, Varechtchouk O, Hahn T, Buaboonnam J, Metzger ML, Rubnitz JE, Ribeiro RC, Sandlund JT, Jeha S, Cheng C, Evans WE, Relling MV, Pui CH. Infection-related complications during treatment for childhood acute lymphoblastic leukemia. Ann Oncol. 2017 Feb 1;28(2):386-392. doi: 10.1093/annonc/mdw557.
citation: Ribeiro ILA, Limeira RRT, Dias de Castro R, Ferreti Bonan PR, Valenca AMG. Oral Mucositis in Pediatric Patients in Treatment for Acute Lymphoblastic Leukemia. Int J Environ Res Public Health. 2017 Nov 28;14(12):1468. doi: 10.3390/ijerph14121468.
citation: Raja RA, Schmiegelow K, Albertsen BK, Prunsild K, Zeller B, Vaitkeviciene G, Abrahamsson J, Heyman M, Taskinen M, Harila-Saari A, Kanerva J, Frandsen TL; Nordic Society of Paediatric Haematology and Oncology (NOPHO) group. Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol. Br J Haematol. 2014 Apr;165(1):126-33. doi: 10.1111/bjh.12733. Epub 2014 Jan 15.
citation: Hudson MM, Ness KK, Gurney JG, Mulrooney DA, Chemaitilly W, Krull KR, Green DM, Armstrong GT, Nottage KA, Jones KE, Sklar CA, Srivastava DK, Robison LL. Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA. 2013 Jun 12;309(22):2371-2381. doi: 10.1001/jama.2013.6296.
citation: Strauss AJ, Su JT, Dalton VM, Gelber RD, Sallan SE, Silverman LB. Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol. 2001 Jun 15;19(12):3066-72. doi: 10.1200/JCO.2001.19.12.3066.
citation: Zawitkowska J, Lejman M, Zaucha-Prazmo A, Drabko K, Plonowski M, Bulsa J, Romiszewski M, Mizia-Malarz A, Koltan A, Derwich K, Karolczyk G, Ociepa T, Cwiklinska M, Trelinska J, Owoc-Lempach J, Niedzwiecki M, Kiermasz A, Kowalczyk J. Grade 3 and 4 Toxicity Profiles During Therapy of Childhood Acute Lymphoblastic Leukemia. In Vivo. 2019 Jul-Aug;33(4):1333-1339. doi: 10.21873/invivo.11608.
citation: Boussios S, Pentheroudakis G, Katsanos K, Pavlidis N. Systemic treatment-induced gastrointestinal toxicity: incidence, clinical presentation and management. Ann Gastroenterol. 2012;25(2):106-118.
citation: Ruiz-Esquide G, Nervi B, Vargas A, Maiz A. [Treatment and prevention of cancer treatment related oral mucositis]. Rev Med Chil. 2011 Mar;139(3):373-81. Epub 2011 Aug 25. Spanish.
citation: Moscardo Guilleme C, Fernandez Delgado R, Sevilla Navarro J, Astigarraga Aguirre I, Rives Sola S, Sanchez de Toledo Codina J, Fuster Soler JL, Parra Ramirez L, Molina Garicano J, Gonzalez Martinez B, Madero Lopez L. [Update on L-asparaginase treatment in paediatrics]. An Pediatr (Barc). 2013 Nov;79(5):329.e1-329.e11. doi: 10.1016/j.anpedi.2013.03.015. Epub 2013 May 31. Spanish.
citation: El-Mahallawy HA, El-Din NH, Salah F, El-Arousy M, El-Naga SA. Epidemiologic profile of symptomatic gastroenteritis in pediatric oncology patients receiving chemotherapy. Pediatr Blood Cancer. 2004 Apr;42(4):338-42. doi: 10.1002/pbc.10394.
citation: Maroun JA, Anthony LB, Blais N, Burkes R, Dowden SD, Dranitsaris G, Samson B, Shah A, Thirlwell MP, Vincent MD, Wong R. Prevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer: a consensus statement by the Canadian Working Group on Chemotherapy-Induced Diarrhea. Curr Oncol. 2007 Feb;14(1):13-20. doi: 10.3747/co.2007.96.
citation: Ahern PP, Maloy KJ. Understanding immune-microbiota interactions in the intestine. Immunology. 2020 Jan;159(1):4-14. doi: 10.1111/imm.13150. Epub 2019 Nov 27.
citation: Icaza-Chavez ME. [Gut microbiota in health and disease]. Rev Gastroenterol Mex. 2013 Oct-Dec;78(4):240-8. doi: 10.1016/j.rgmx.2013.04.004. Epub 2013 Nov 28. Spanish.
citation: Hawrelak JA, Myers SP. The causes of intestinal dysbiosis: a review. Altern Med Rev. 2004 Jun;9(2):180-97.
citation: Forsgard RA, Marrachelli VG, Korpela K, Frias R, Collado MC, Korpela R, Monleon D, Spillmann T, Osterlund P. Chemotherapy-induced gastrointestinal toxicity is associated with changes in serum and urine metabolome and fecal microbiota in male Sprague-Dawley rats. Cancer Chemother Pharmacol. 2017 Aug;80(2):317-332. doi: 10.1007/s00280-017-3364-z. Epub 2017 Jun 23.
citation: Hakim H, Dallas R, Wolf J, Tang L, Schultz-Cherry S, Darling V, Johnson C, Karlsson EA, Chang TC, Jeha S, Pui CH, Sun Y, Pounds S, Hayden RT, Tuomanen E, Rosch JW. Gut Microbiome Composition Predicts Infection Risk During Chemotherapy in Children With Acute Lymphoblastic Leukemia. Clin Infect Dis. 2018 Aug 1;67(4):541-548. doi: 10.1093/cid/ciy153.
citation: Touchefeu Y, Montassier E, Nieman K, Gastinne T, Potel G, Bruley des Varannes S, Le Vacon F, de La Cochetiere MF. Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis - current evidence and potential clinical applications. Aliment Pharmacol Ther. 2014 Sep;40(5):409-21. doi: 10.1111/apt.12878. Epub 2014 Jul 11.
citation: Reyna-Figueroa J, Barron-Calvillo E, Garcia-Parra C, Galindo-Delgado P, Contreras-Ochoa C, Lagunas-Martinez A, Campos-Romero FH, Silva-Estrada JA, Limon-Rojas AE. Probiotic Supplementation Decreases Chemotherapy-induced Gastrointestinal Side Effects in Patients With Acute Leukemia. J Pediatr Hematol Oncol. 2019 Aug;41(6):468-472. doi: 10.1097/MPH.0000000000001497.
citation: Wei D, Heus P, van de Wetering FT, van Tienhoven G, Verleye L, Scholten RJ. Probiotics for the prevention or treatment of chemotherapy- or radiotherapy-related diarrhoea in people with cancer. Cochrane Database Syst Rev. 2018 Aug 31;8(8):CD008831. doi: 10.1002/14651858.CD008831.pub3.
citation: Alexander JL, Wilson ID, Teare J, Marchesi JR, Nicholson JK, Kinross JM. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol. 2017 Jun;14(6):356-365. doi: 10.1038/nrgastro.2017.20. Epub 2017 Mar 8.
citation: Redman MG, Ward EJ, Phillips RS. The efficacy and safety of probiotics in people with cancer: a systematic review. Ann Oncol. 2014 Oct;25(10):1919-1929. doi: 10.1093/annonc/mdu106. Epub 2014 Mar 11.
citation: Lu D, Yan J, Liu F, Ding P, Chen B, Lu Y, Sun Z. Probiotics in preventing and treating chemotherapy-induced diarrhea: a meta-analysis. Asia Pac J Clin Nutr. 2019;28(4):701-710. doi: 10.6133/apjcn.201912_28(4).0005.
citation: Rodriguez JM, Murphy K, Stanton C, Ross RP, Kober OI, Juge N, Avershina E, Rudi K, Narbad A, Jenmalm MC, Marchesi JR, Collado MC. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis. 2015 Feb 2;26:26050. doi: 10.3402/mehd.v26.26050. eCollection 2015.
citation: Van den Nieuwboer M, Brummer RJ, Guarner F, Morelli L, Cabana M, Claasen E. The administration of probiotics and synbiotics in immune compromised adults: is it safe? Benef Microbes. 2015 Mar;6(1):3-17. doi: 10.3920/BM2014.0079.