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The effectiveness of probiotics in prevention and treatment of cancer therapy-induced oral mucositis: A systematic review and meta-analysis
Oral Oncology 102 (2020) 104559
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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Review
The effectiveness of probiotics in prevention and treatment of cancer therapy-induced oral mucositis: A systematic review and meta-analysis Zekai Shua, Peijing Lib,c, Bingqi Yud, Shuang Huangb,c, Yuanyuan Chenb,c,
T
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a
The 2nd Clinical Medical College of Zhejiang Chinese Medical University, China Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, China c Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, China d Zhejiang Hospital, China b
A R T I C LE I N FO
A B S T R A C T
Keywords: Probiotics Radiotherapy Chemotherapy Chemo-radiotherapy Oral mucositis Stomatitis Head and neck cancer
Oral mucositis (OM) is a common and troublesome adverse side effect of many cancer therapy modalities (chemotherapy, radiotherapy, and chemo-radiotherapy), which can cause pain, ulceration, dysphagia, malnutrition, even treatment interruption. Probiotics may be effective in preventing and treating of cancer therapyinduced OM. We performed a systematic review and meta-analysis of the effectiveness of probiotics in prevention and treatment of cancer therapy-induced OM. Four databases and one trial registry were searched as of the 12th of May 2019 to identify all eligible randomized controlled trials (RCT). Five studies involving 435 patients were included in this study. Methodological quality and outcomes were evaluated in every study included. Pooled results showed a moderate heterogeneity (P = 0.15, I2 = 44%). The pooled RRs indicated that the use of probiotics decreased the risk of OM for grade ≥3 (RR = 0.66, 95%CI = 0.54–0.81, P < 0.0001) as well as all grades (RR = 0.83, 95% CI = 0.72–0.97, P = 0.02). There was no significant difference between probiotics and placebo for cancer therapy completion rate (RR = 1.14, 95%CI = 0.65–2.00, P = 0.64). The subgroup analysis indicated that the use of probiotics was not statistically significant for patients receiving chemo-radiotherapy (RR = 0.52, 95% CI = 0.26–1.04, P = 0.07). In conclusion, probiotics may reduce the incidence and mitigate the severity of cancer therapy-induced OM. Further trials with a randomized, double-blind and multicentric study design are needed to confirm this effect. The PROSPERO registration number of this systematic review and meta-analysis is CRD42019130414.
Introduction Oral mucositis (OM) is an inflammation of oral mucosa and can cause erythema, ulceration, pain, dysphagia, and malnutrition, which can cause treatment interruption. OM is common among cancer patients who received chemotherapy and/or radiotherapy [1,2]. The incidence of OM is quite high in patients who receive intensive chemotherapy combined with hematopoietic stem cell transplant (HSCT) or those who underwent radiotherapy for head and neck cancer (HNC) [3,4]. It was reported that more than 85% of patients who are treated with HSCT and almost 100% of HNC patients who receive radiotherapy develop OM, and the incidence of severe OM (≥Grade 3) is 100% when patients receive intensive therapy of total body irradiation (TBI), along with cyclophosphamide chemotherapy-combined HSCT [3–5]. There are three grading scales in common use to evaluate the severity of OM. World Health Organization (WHO) grading scales,
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toxicity criteria of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/ EORTC) and National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). The latter two scales are more widely used. According to RTOG/EORTC criteria, grade 1–2 OM presents as irritation and patchy mucositis that may produce an inflammatory serosanguinous discharge, while grade 3–4 OM appears as confluent fibrinous mucositis, ulceration, hemorrhaging, or necrosis, causing severe pain and requiring narcotic analgesics [6]. The pain caused by severe OM can result in dysphagia and eventually lead to malnutrition, which can cause treatment interruption in patients [2]. A prospective study conducted by Elting found that about 63% of patients who do not develop OM still develop oral pain, and 38% of patients with mild OM (≤Grade 2) have difficulties in food intake [7]. To better understand OM and find ways to prevent and treat it, the mechanism of the disease has been widely studied. Researchers have
Corresponding author at: Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, China. E-mail address: [email protected] (Y. Chen).
https://doi.org/10.1016/j.oraloncology.2019.104559 Received 14 August 2019; Received in revised form 24 December 2019; Accepted 31 December 2019 1368-8375/ © 2020 Elsevier Ltd. All rights reserved.
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Inclusion criteria
found OM to be much more complicated than originally thought. As summarized by Sonis, the development of mucositis was a dynamic process typically divided into five stages: initiation, primary damage response, signal amplification, ulceration and healing [8,9]. In the initial stage, chemotherapy or radiotherapy caused both DNA and nonDNA damage to basal epithelial cells, and a cascade of reactive oxygen species (ROS) is triggered which directly damages cells, tissues, and blood vessels. In the primary damage response stage, mucositis is driven by three pathways activated by the ROS cascade: NF-κB pathway, the ceramide pathway and the matrix metalloproteinase pathway. In the signal amplification stage, a series of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, further damage the basal epithelial cells through positive feedback in the three pathways. In the ulceration stage, the loss of mucosal integrity facilitates the colonization of bacteria, which stimulates macrophagocytes to produce more pro-inflammatory cytokines and potentiates tissue injury. This stage causes extreme pain in patients. Lastly, in the healing stage, signals from submucosal extracellular matrix and mesenchyme promote cell proliferation and differentiation to reestablish the mucosal barrier. Although the mechanism is well studied, the management of OM is still challenging. Interventions including basic oral care, growth factors and cytokines, anti-inflammatory agents, cryotherapy, and low-level laser therapy are suggested according to Multinational Association of Supportive Care in Cancer/The International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines. However, only palifermin (keratinocyte growth factor-1) has been approved by the US Food and Drug Administration and the European Medicines Agency to mitigate OM in a very limited segment of the at-risk population [1,10]. Microorganisms play an important role in the ulceration stage and have been found correlated with the progression of OM in recent studies [11,12]. Researchers discovered that pathogens contributed to the development of OM by activating innate immunity through pathogen-associated molecular patterns (PAMPs) [13,14]. PAMPs secreted by pathogens can infiltrate the damaged mucosa and activate NK cells, mast cells, macrophagocytes, and dendritic cells by pattern recognition receptors (PRRs) [13,15,16]. After a series of signal transmissions, NF-κB and its downstream pro-inflammatory cytokines are activated [13]. In contrast, the probiotics can inhibit apoptosis of epithelial cells by combining with toll-like receptors (TLRs)—one type of PRRs [17]. The effectiveness of probiotics in OM has been proven by several clinical trials, but the results are still controversial. Therefore, the aim of this review is to evaluate the efficacy of probiotics for prevention and treatment of cancer therapy-induced OM.
Types of studies: Randomized controlled trials (RCTs). Types of participants: Cancer patients of any age who received chemotherapy, radiotherapy and chemo-radiotherapy, which could cause oral mucositis. Types of interventions: The intervention groups were treated with probiotic agents or products containing probiotics or probiotics combining with other drugs. The control groups were treated with a placebo, other standard agents, or nothing. Types of outcomes: Primary outcomes: 1. Incidence of oral mucositis (according to RTOG, CTCAE, WHO criteria); 2. Incidence of severe (≥Grade 3) OM (according to RTOG, CTCAE, WHO criteria); 3. Cancer therapy completion rates. Secondary outcomes: onset time of OM, which is not available for this review. Exclusion criteria 1. Studies that did not include outcomes needed in this review. 2. When multiple studies contain the same data, we excluded all studies except the one with the most comprehensive data. Data collection and analysis Selection of studies: We downloaded all titles and abstracts of studies that we searched by electronic searching and hand searching. All studies were imported into EndNote and duplicates were removed. Two independent reviewers examined the remaining references independently. Studies were excluded when they did not meet the inclusion criteria (based on titles and abstracts). After the review of titles and abstracts, two independent reviewers (Zekai Shu, Peijing Li) reviewed full texts of the remaining studies and evaluated the studies whether they could be used in our qualitative or quantitative analyses (meta-analysis). Any discrepancies were discussed and resolved by all group members. We stored the excluded studies and gave the reasons for the exclusion. Data extraction and management: Two independent reviewers extracted data into extraction documents, which were discussed by and made available to all group members. For every included study, we collected the following data: 1. Patients characteristics (age, gender, type of cancer, type of cancer therapy [chemotherapy, radiotherapy, chemo-radiotherapy], sites of researches); 2. The intervention of experimental and control arms (type, formulation, dose, regimen, duration); 3. The elements of risk of bias (generation of randomization sequence, allocation concealment, participants, investigators, outcomes assessors, and data assessors blinding, integrity of outcome data, selective outcome reporting); 4. The primary and secondary outcomes mentioned above. Assessment of risk of bias and studies quality: The Cochrane Collaboration’s tools for assessing risk of bias and studies quality [18] was used by two independent reviewers to evaluate the following sources of bias: generation of randomization sequence, allocation concealment, participants and investigators, outcomes assessors, data assessors blinding, integrity of outcome data, selective outcome reporting. RevMan v5.3 [20] was used to assist with the assessment of risk of bias. If any discrepancies came up, a third experienced viewer arbitrated the different opinions or a group discussion would be conducted. Assessment of reporting biases: If more than 10 studies were eligible for a quantitative analysis (meta-analysis), a funnel plot would be used to assess the reporting biases by using RevMan v5.3. In our review, there were not enough studies for this assessment. Assessment of heterogeneity: The heterogeneity was analyzed by χ2 test (α = 0.1) and I2 test. The randomized effect model would be used if p-value of χ2 test ≤0.1 and I2 > 50%. The fixed effect model would be used if p-value of χ2 test > 0.1 or I2 ≤ 50%. When facing heterogeneity, we performed the subgroup analysis to explore clinical
Materials & methods The study followed the methodology in the Cochrane Handbook [18] and the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement guidelines [19]. The PROSPERO registration number of this systematic review and meta-analysis is CRD42019130414.
Search strategy Electronic searches: We searched PubMed, Embase, Web of Science, Cochrane Library comprehensively by using a combination of medical subject heading (MeSH) terms and free text for eligible studies, with publication time up to 12 May 2019. The details of search strategy are shown in the appendix: PubMed (Appendix A), Embase (Appendix B), Web of Science (Appendix C), and Cochrane Library (Appendix D). Searching other resources: We searched ClinicalTrials.gov for prospective trial registers for controlled trials, with publication time up to 12 May 2019. The details of this search strategy are in Appendix E.
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[32–36], of which 4 studies were included in meta-analysis [32–35]. The study flow diagram was presented in Fig. 1. The characteristics of the included studies and reasons for the excluded studies were presented in Table1 and 2. Included studies: Five studies involving 435 patients met the inclusion criteria [32–36], of which four studies were included in metaanalysis. The four studies compared probiotics with placebo. Two trials studied chemo-radiotherapy [32,34], one studied induction chemotherapy [35], and one study included 78% chemo-radiotherapy, 10% radiotherapy combining cetuximab and 12% radiotherapy combining neoadjuvant chemotherapy [33]. The fifth study could only be included in the qualitative analysis, since the study design was different from the above four studies [36]. Risk of bias and studies quality: The Cochrane Collaboration’s tools for assessing risk of bias and studies quality [18]. The quality problems were mainly due to blinding of participants and investigators in two studies [33,36], and the blinding of outcomes assessors was unknown. Details were presented in Table 3, Fig. 2 and Fig. 3.
heterogeneity, especially different types of cancer therapy (chemotherapy, radiotherapy and chemo-radiotherapy). Data synthesis: We used RevMan v5.3 for meta-analysis. For the primary outcome, relative risk (RR) with 95% confidence interval (CI) was used to estimate all comparisons. For the secondary outcome, we chose mean difference (MD) with 95% CI as a measure of effect. When studies were not eligible for meta-analysis, we summarized the results and made a qualitative analysis. We also performed subgroup metaanalyses based on the different types of cancer therapy (chemotherapy, radiotherapy, chemo-radiotherapy), using the method of analysis mentioned above. Results Eligible studies Up to 12th of May 2019, we identified 2616 records by electronic searching in PubMed, Embase, Web of Science, and Cochrane Library databases. 65 records were found by hand searches in ClinicalTrials.gov. Among them, we found 763 duplicate studies using Endnote and manual screening. After reading titles and abstracts of the remaining 1918 studies, we excluded 1902 studies that did not adopt the required criteria. After reviewing the full text of the remaining studies, 11 studies were excluded, of which, 8 records were clinical trial registration records that have no results posted [21–28], one was a single-arm study [29], one only focused on intestinal adverse events [30], and one was a conference abstract and did not tell whether it was a RCT [31]. Finally, 5 studies were eligible for this systematic review
Probiotics versus placebo Four studies were performed the meta-analysis, which allowed pooling of data (n = 368) [32–35]. As shown in Fig. 4A, the pooled RR for the incidence of severe OM favoured probiotics (RR = 0.66, 95%CI = 0.54–0.81, P < 0.0001). And the fixed effect model was used in the analysis because of the moderate heterogeneity (P = 0.15, I2 = 44%). The pooled RR for the incidence of OM was in favour of probiotics as well (RR = 0.83, 95%CI = 0.72–0.97, P = 0.02), as
Fig. 1. Study flow diagram. 3
4
Randomized Placebo-controlled trial
Sanctis, [33]; Italy
Probiotic group was instructed to receive oral lavage with kefir and swallow 250 ml of kefir twice a day after meals on the first 5 days of each 5-FU chemotherapy cycle VS placebo The LB CD2 lozenges contained not < 2 × 109 viable cells of L. brevis CD2 as the active ingredient. The daily dose was six lozenges per day, one every 2–3 h to be dissolved in the mouth and then swallowed. Hot beverages (e.g. tea, coffee, or milk) were avoided for at least half an hour before and after administration VS placebo
Patients received a median of six cycles of 5FU chemotherapy cycles
Patients received radiotherapy with/without Concomitant cisplatinum-based chemotherapy was administered using a weekly (40 mg/m2) or a 3-weekly (100 mg/ m2) schedule. Some participants were administered with Cetuximab. Radiation dose fraction was delivered with a prescribed total dose of 68–70 Gy and 50–54 Gy to the macroscopic disease and low-risk regions, respectively Control group: 75.0%; Probiotic group: 81.2%
Control group: 60(39–77); Probiotic group: 58.4(34–74)
15 ml AG013 (an oral rinse composed of a recombinant L. lactis strain) at 1、3、 6timesdaily from day 1 to 14 during induction chemotherapy cycle 2 VS placebo
Control group: 60.0%; Probiotic group: 70.6%
Control group: 87.5%; Probiotic group: 70.6%
Control group: 58(34–72); Probiotic group: 51(19–75)
Control group: 54(18–63); Probiotic group: 55.4(26–66)
Outcomes: 1. Incidence of oral mucositis; 2. Incidence of severe oral mucositis (≥Grade 3); 3. Cancer therapy completion rates
Topuz [36]; Turkey
25 patients with locally advanced head and neck cancer (LAHNC) were followed during induction cycle 1 developed ulcerative oral mucositis (UOM; World Health Organization Grade > 2) 40 patients with newly diagnosed Stage II, III or IV colorectal cancer. Baseline Eastern Cooperative Oncology Group performance Status (ECOG PS) of 0, 1 or 2 was required for study participation 71 patients with head and neck cancer (75 patients were screened, of which 4 patients were excluded and were not randomized)
2
1;2
2
1;2;3 Probiotic (Bifidobacterium longum, Lactobacillus lactis, and Enterococcus faecium) was supplied from the beginning to the end of treatment for up to 7 weeks (3 capsules 2 times a day) VS placebo
Control group: 60.0%; Probiotic group: 62.71%%
Control group: 50.4 ± 10.3; Probiotic group: 51.7 ± 9.8
99 patients(18–70 years) whose Karnofsky score ≥ 80 and had newly pathologically diagnosed locally advanced nasopharyngeal carcinoma and were undergoing CCRT
Randomized, DoubleBlind, PlaceboControlled trial
Chunling Jiang 2018; China
Randomized single-blind placebo-controlled(3 probiotics groups vs control group)trial Randomized Placebo-controlled trial
1;2;3
The daily dose(L. brevis CD2)was 6 lozenges per day, 1 lozenge every 2–3 h to be dissolved in the mouth and then swallowed VS placebo
Chemo-radiotherapy: All patients received radical radiotherapy at a dose of 70 Gy in 35 fractions over 7 weeks (at 5 fractions per week; standard fractionation) by linear accelerator, with parallel-opposed lateral fields and spinal cord shielding at 44 Gy. Concurrent chemotherapy consisted of cisplatin (DDP) 40 mg/m2 weekly for 7 doses (days 1, 8, 15, 22, 29, 36, 43) beginning on day 1 of radiation treatment Chemo-radiotherapy: Patients received 70 Gy of radiotherapy in 32 fractions (2.19 Gy/d, 5 d/wk), with the gross tumor volume and the clinical target volume receiving 60 Gy in 32 fractions for 45 days (total, 6–7 weeks). Intravenous infusions of cisplatin (100 mg/m2) were performed on days 1, 22, and 43. Induction chemotherapy cycle 2 with TPF or PF(d1-d14).
Control group: 91.9%; Probiotic group: 93.1%
Control group: 50.1 ± 10.0; Probiotic group: 52.4 ± 9.4
200 patients with a confirmed diagnosis of HNSCC stage II–IVA (resectable) attending the head and neck cancer clinic at the study center
Randomized double-blind placebo-controlled trial
AtulSharma 2011; India
Sewanti Atul Limaye [35]; America
Outcomes
Interventions
Type of cancer therapy
Sex (%, male)
Mean Age (Year)
Participants
Design
Author; Year; Country
Table 1 Characteristic of included studies.
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inevitable because multiple probiotic strains exist and can be combined in different proportions. In our opinion, although the heterogeneity is high, the benefit of probiotics for reducing the incidence of OM is still authentic, which is supported by our analysis and two trials included. In another study by Sewanti [35], 29% HNC patients who received probiotics experienced only 0 or 1 day of OM, whereas all placebo patients went through at least 2 days of OM. Moreover, in an excluded singlearm study conducted in HSCT patients, up to 22.6% patients did not develop OM and only 6.5% experienced severe OM, which further supports our conclusion [29]. The subgroup analysis was performed in chemo-radiotherapy studies. The two studies involved in this subgroup analysis both concluded that probiotics could mitigate severe OM in patients receiving chemoradiotherapy, but after merging these studies in our meta-analysis, we got the opposite result (RR = 0.52, 95%CI = 0.26–1.04, P = 0.07) (Fig. 4D). This was due to the use of a randomized effect model to account for the high heterogeneity (P = 0.05, I2 = 73%) due to much better outcomes in Jiang’s study compared to Sharma’s. In fact, we could get a positive result if a fixed model was utilized. In our opinion, probiotics may still do good to cancer patients treated by chemoradiotherapy, since two studies were well designed and the methodological quality was high (Table 3). However, further prospective trials are needed to confirm this finding. We also conducted a qualitative analysis after including Topuz’s study conducted in colorectal cancer patients treated with 5-FU chemotherapy [36]. However, the inclusion of Topuz’s study did not affect the results of the quantitative analyses above, because Topuz’s study design was different from the other four studies. We speculated that the negative result of Topuz’s study was due to the powerless and unspecific probiotics contained in kefir (a kind of a fermented milk complex) which was used in the study [36]. Currently, microorganisms are found to play important roles in OM and many other diseases, such as diarrhea induced by radiotherapy, idiopathic pulmonary fibrosis, even modulating anti-tumor response to anti–PD-1 immunotherapy [11,12,37–41]. A systematic review of Cochrane Library demonstrated that probiotics might benefit diarrhea patients resulted from pelvic radiotherapy [38]. The result is supported by another systematic review [39]. In this review, we proved that probiotics might reduce the incidence and severity of cancer therapyinduced OM, especially for HNC patients. Additional RCTs in larger populations with good study design and execution are needed to further support the conclusion.
Table 2 Reasons for excluded studies. Study & Registration ID
Reason for exclusion
S. Giammarco 2016 Sharma, A 2016 Lacouture, M.E 2016
Did not tell whether the study was a RCT Sigle-arm study
CTRI/2008/091/000117; CTRI/2013/02/003393; NCT01707641; NCT01545687; NCT01797952; NCT03112837; NCT03552458; NCT03785938
The study focused on intestine adverse events No results posted
shown in Fig. 4B, while the heterogeneity was high (P = 0.09, I2 = 65%). The analysis results didn’t favour probiotics for the cancer therapy completion rate (RR = 1.14, 95%CI = 0.65–2.00, P = 0.64), and the heterogeneity was high (P < 0.00001, I2 = 98%) (Fig. 4C). Clinical subgroup analysis We performed a subgroup analysis for the chemo-radiotherapy trials. The results didn’t favour probiotics in terms of the incidence of severe OM in chemo-radiotherapy (RR = 0.52, 95%CI = 0.26–1.04, P = 0.07), as shown in Fig. 4D. Testing for publication bias: The test for publication bias was not performed due to insufficient studies included. Discussion Summary of the evidence We performed a meta-analysis to evaluate the effectiveness of probiotics in prevention and treatment of cancer therapy-induced OM, including chemotherapy, radiotherapy, and chemo-radiotherapy. We included five studies involving 435 participants, and four studies were included in the meta-analysis. In clinical practice, the occurrence of OM seems inevitable. Therefore, the primary concern is how to prevent severe OM (≥Grade 3). As shown in Fig. 4A, the use of probiotics can reduce the incidence of severe OM (≥Grade 3), and the heterogeneity is moderate (P = 0.15, I2 = 44%). Probiotics also reduce the overall incidence of OM (Fig. 4B). Although the study design and quality are similar for all trials included, the heterogeneity is high (P = 0.09, I2 = 65%). The heterogeneity is calculated based on the degree of coincidence of confidence interval. But we can see that the beneficial effects of probiotics in Sharma’s study are much better than Jiang’s study (Fig. 4B). Three reasons may explain the result: 1. Different radiation technologies were used in two studies. Sharma’s study used a 2D radiotherapy technique, while Jiang’s study used intensity modulated radiation therapy (IMRT). IMRT can reduce oral radiation dose and protect oral better compared with 2D technique, which can dilute the effect of probiotics to some extent. It can explain why probiotics do no good to cancer therapy completion rate as well (RR = 1.14, 95%CI = 0.65–2.00, P = 0.64) (Fig. 4C), since IMRT has made OM no longer the factor causing treatment interruption. 2. Participants in two studies were not diagnosed with exactly the same type of cancer. For example, Sharma’s study contained different types of head and neck cancer, while only nasopharyngeal carcinoma patients were included in Jiang’s study. This caused the different oral dose distribution which generate different severities of OM [32,34]. 3. The ingredients of probiotics were not exactly the same between two studies. The probiotics ingredients in Sharma’s study were Lactobacillus brevis, while they were Lactobacillus, Bifidobacterium and Enterococcus in Jiang’s study. However, variance in probiotic ingredients between studies is currently
Safety issue of probiotics The term “probiotics” is defined as live microorganisms that benefits population and treat specific disease by improving microbial flora [42,43]. In spite of the benefits proven by clinical trials and animal models, there are no probiotic products approved for specific health issues by the US Food and Drug Administration (FDA) yet [43]. Probiotic products are regarded as drugs rather than nutritional supplements if used for a physiological effect, according to the FDA guidance on INDs (Investigation New Drug) in 2013 [44]. In 2001, the Agency for Healthcare Research and Quality (AHRQ) announced a report based on the research by the National Institutes of Health and the FDA which concluded that “the current literature is not well equipped to answer questions on the safety of probiotics in intervention studies with confidence [45]”. Theoretical risks of probiotics include systematic infections, deleterious metabolic activities, excessive immune stimulation, gene transfer, obesity, skin problem and gastrointestinal side effects [43,44]. The populations at risk include inpatients, immunosuppressed people, pregnant people, and those with the potential for translocation of probiotic across the bowel wall [44]. Since all HSCT patients are rendered immunosuppressed and some HNC patients develop neutropenia due to anti-cancer treatment, additional caution and comprehensively 5
6 High Risk: Open-Label
High Risk: Open-Label
Low Risk: Prior to starting RCHT or bioRT, enrolled patients were randomized (1:1) to standard oral care regimen with sodium bicarbonate mouthwash (control arm) or LB CD2 lozenges (intervention arm) through a computer-generated randomization list consisting of randomly permuted blocks of four patient numbers.
Sanctis [33]; Italy
High Risk: Open-Label
Unclear Risk
Unclear Risk
High Risk: The appearance and taste of kefire was different from 0.9% NaCl oral rinses
High Risk: The appearance and taste of kefire was different from 0.9% NaCl oral rinses
Unclear Risk
Unclear Risk
Unclear Risk
Unclear Risk
Unclear Risk
Topuz, [36]; Turkey
Unclear Risk
Unclear Risk
Sewanti Atul Limaye [35]; America
Unclear Risk
High Risk: The block size was known only to the statistician
Unclear Risk
Low Risk: Patients were randomly distributed into 6 blocks in a 2:1 ratio to receive probiotics or a placebo, the block size was known only to the statistician
Low Risk: Patients were randomly distributed into 6 blocks in a 2:1 ratio to receive probiotics or a placebo, the block size was known only to the statistician
Low Risk: The study subjects were unaware of the study arm they were on
Low Risk: An independent biostatistician analyzed the study data
Unclear Risk
Low Risk: The study products were pre-packaged by the sponsor as per the randomization codes and dispensed accordingly
Low Risk: The L. brevis CD2 lozenges and placebo were supplied by CD Pharma India Pvt. Ltd. and were identical in physical appearance, taste and color
Low Risk: Patients were randomly assigned to either of the treatment arms in a 1:1 ratio through a computer-generated randomization list consisting of randomly permuted blocks of 10 patient numbers Low Risk: The blinding codes for the seeds of the random numbers, the block length, and the random numbers, were sealed in envelopes and stored at Jiangxi Cancer Hospital. Blinding codes were not disclosed during the entire trial period Unclear Risk
Low Risk: Patients were randomly assigned to either of the treatment arms in a 1:1 ratio through a computer-generated randomization list consisting of randomly permuted blocks of 10 patient numbers Low Risk: The random assignment of patients was performed by Nanchang Medical University with a computergenerated random number code
Atul Sharma 2011; India
Chunling Jiang 2018; China
Data assessors
Outcomes assessors
Investigators
Participants
Allocation concealment
Generation of randomization sequence
Author; Year; Country
Table 3 Risk bias of included studies.
Low Risk: There was no selective reporting according to the clinical registration information posted (Clinical Trials number NCT03112837) Low Risk: Study group (n = 64) lost 6; Control group (n = 35) lost 0
Low Risk: 40 patients were enrolled, and 3 patients were ineligible for analysis. Low Risk: 75 patients were enrolled, and 7 patients were ineligible for analysis.
Low Risk: There was no selective reporting according to the clinical registration information posted (Clinical Trials number NCT01707641)
Low Risk: There was no selective reporting according to the clinical registration information posted (Clinical Trials number NCT00938080) Unclear Risk
Low Risk: There was no selective reporting according to the clinical registration information posted (Clinical Trials number CTRI/2008/ 091/000117) Low Risk: Study group (n = 101) lost 8; Control group (n = 99) lost 4
High Risk: Study group (n = 17) lost 3; Control group (n = 8) lost 3
Selective outcome reporting
Integrity of outcome data
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Fig. 2. Risk of bias graph for each included study.
Earlier studies have found that probiotics could regulate epithelial function, maintain the integrity of the mucosal barrier, enhance host immunity and inhibit colonization of pathogenic bacteria [49]. Animal experiments have revealed that probiotics may protect epithelial cells by activating TLRs on the surfaces of macrophages and triggering a multi-cellular, adaptive immune signal cascade [17,50]. In detail, lipoteichoic acid (LTA) from Lactobacillus rhamnosus GG (LGG), a probiotic, could bind to TLR2 on pericryptal macrophages, which induces the production of the chemokine CXCL12. Then CXCL12 binds to CXCR4 on COX-2 expressing mesenchymal stem cells (MSCs), which induces MSCs to crypt epithelial stem cells in the lamina propria of intestinal mucosa. Finally, MSCs release PGE2 to protect epithelial stem cells from radiation injury [17]. Ciorba further found that the protective effects of LGG on epithelial cells was lost in Myd88-/-, TLR2-/- and COX2-/- mice. Therefore, we speculate that the protective mechanism of probiotics may arise through TLR-Myd88 pathway (Fig. 5). A study by Burdelya found that the mice could be protected from gastrointestinal and hematopoietic acute radiation syndromes by injection of CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to toll-like receptor5 (TLR5) and activates NF–κB signaling, before lethal total-body irradiation [51]. Another animal study revealed nonviable probiotics were equally effective as live microorganisms in ameliorating dextran sodium sulfate-induced colitis through the TLR9-Myd88 pathway and the protective effects were mediated by their DNA [52]. In summary, TLRs may be the key site for probiotics effectiveness and the effective ingredients of probiotics, such as LTA or DNA, may be extracted and utilized instead of live probiotics (Fig. 5). This can reduce the potential treatment side effects, such as sepsis mentioned above, and further improve the efficacy. Fig. 3. Risk of bias summary for each included study.
Strengths and limitations safety evaluation are needed before the application of probiotics. Among all side effects, the worst consequence for OM patients is sepsis, which may lead to treatment interruption and even life-threating. Of the five studies included in this analysis, no patients developed sepsis due to probiotics. However, three separate cases of sepsis caused by Lactobacillus in HSCT patients are reported [46–48]. And lactobacillus rhamnosus isolated from patients’ blood was found resistant to multiantibiotics, which makes it very difficult to manage [46,47]. In conclusion, we are still not ready to estimate whether it is safe or not for cancer patients to receive probiotics for OM based on current evidence because many factors matter, including probiotic strain type, dosage, time of usage, and the selection of patients under right physical condition.
Although our results supported the conclusion that the probiotics could reduce the incidence and mitigate the severity of cancer therapyinduced OM, some potential limitations should be mentioned. Firstly, the number of studies was small. Secondly, although OM was only induced by cancer therapy (chemotherapy, radiotherapy, and chemoradiotherapy), participants among studies were not diagnosed with exactly the same type of cancer, which might influence the reliability of the final results. Thirdly, the effective ingredients of probiotics were not exactly the same among studies. However, as this is the first systematic review and meta-analysis on this topic, which makes it meaningful and clinically valuable. As we know, recently microorganisms draw increasing attention from the scientific community and have been demonstrated to be important in many diseases [11,12,37,53]. However, just as the limitations listed above, the selection and combination of probiotics and target population vary among studies, which make it difficult to be eventually recommended in Clinical Practice Guidelines
Mechanism of probiotics The mechanism of the protection of probiotics is still unclear. 7
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Fig. 4. Forest plots comparing probiotics vs placebo: A. Incidence of severe oral mucositis; B. Incidence of oral mucositis; C. Cancer therapy completion rate; D. Incidence of severe oral mucositis in patients treated with chemo-radiotherapy.
extract and apply just the effective ingredients of probiotics, rather than the probiocs as a whole.
and approved for clinical application on OM. This review may help researchers with the selection of probiotics and inferring their effect on potentially beneficial patients, especially HNC patients.
Declaration of Competing Interest
Conclusion
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
This systematic review and meta-analysis showed that the probiotics may reduce the incidence and mitigate the severity of cancer therapyinduced OM, especially for HNC patients. However, considering the small number of clinical trials included, further randomized, doubleblind, multicentric trials in a larger population are warranted. This paper may help researchers improve the design of trials in the selection of probiotic strains and the patients with the potential to benefit from them. Due to the safety concerns of probiotics, it may be benefical to
Acknowledgements We acknowledged the contributions of all members in our research team to the article. 8
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Fig. 5. Mechanism of probiotics and pathogens involved in oral mucositis.
Appendix A. PubMed
#10 (#8 OR #9) #11 [ti, ab, kw] stomati* OR [ti, ab, kw] mouth mucosa OR [ti, ab, kw] oral mucositis OR [ti, ab, kw] mucositi* OR [ti, ab, kw] oromucositi* #12 (#10 OR #11) #13 (#7 AND #12)
#1 MeSH descriptor Probiotics explode all trees #2 MeSH descriptor Lactobacillales explode all trees #3 MeSH descriptor Lactococcus explode all trees #4 MeSH descriptor Bifidobacterium explode all trees #5 (#1 OR #2 OR #3 OR #4) #6 [Title/Abstract] probiotic* OR [Title/Abstract] lactobacill* OR [Title/Abstract] Lactococcus* OR [Title/Abstract] bifidobacteri* #7 (#5 OR #6) #8 MeSH descriptor Stomatitis explode all trees #9 MeSH descriptor Mouth Mucosa explode all trees
Appendix C. Web of Science #1 [topic] prbiotic* OR [topic] lactobacill* OR [topic] lactococcus* OR [topic] bifidobacteri* #2 [topic] stomiti* OR [topic] “mouth mucosa” OR [topic] “oral mucositis” OR [topic] mucositi* OR [topic] oromucositi* #3 (#1 AND #2)
#10 (#8 OR #9) #11 [Title/Abstract] stomati* OR [Title/Abstract] mouth mucosa OR [Title/Abstract] oral mucositis OR [Title/Abstract] mucositi* OR [Title/Abstract] oromucositi* #12 (10 OR #11) #13 (#5 AND #12)
Appendix D. Cochrane Library #1 MeSH descriptor Probiotics explode all trees #2 MeSH descriptor Lactobacillales explode all trees #3 MeSH descriptor Lactococcus explode all trees #4 MeSH descriptor Bifidobacterium explode all trees #5 (#1 OR #2 OR #3 OR #4) #6[ti, ab, kw] probiotic* OR [ti, ab, kw] lactobacill* OR [ti, ab, kw] lactococcus* OR [ti, ab, kw] bifidobacteri* #7 (#5 OR #6) #8 MeSH descriptor Stomatitis explode all trees #9 MeSH descriptor Mouth Mucosa explode all trees #10 (#8 OR #9) #11 [ti, ab, kw] stomati* OR [ti, ab, kw] mouth mucosa OR [ti, ab, kw] oral mucositis OR [ti, ab, kw] mucositi* OR [ti, ab, kw] oromucositi* #12 (#10 OR #11) #13 (#7 AND #12)
Appendix B. Embase #1 exp Probiotic agent/ #2 exp Lactobacillales/ #3 exp Lactococcus #4 exp Bifidobacteriales #5 (#1 OR #2 OR #3 OR #4) #6 [ti, ab, kw] probiotic* OR [ti, ab, kw] lactobacill* OR [ti, ab, kw] lactococcus* OR [ti, ab, kw] bifidobacteri* #7 (#5 OR #6) #8 exp Stomatitis #9 exp Mouth mucosa 9
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Appendix E. Clinical trials
nct01707641 2012. [24] Nct, A Phase III, Randomized, Double-Blind Study of Lactobacillus Brevis CD2 Lozenges Versus Placebo in the Prevention of Acute Oral Mucositis (OM) in Patients With Head and Neck Cancer Receiving Concurrent Radiotherapy and Chemotherapy. Clinicaltrials.gov [www.clinicaltrials.gov] 2012. [25] Nct, A Phase III Study of Efficacy of Lactobacillus CD2 Lozenges in Preventing HighDose Chemotherapy Induced Oral Mucositis in Patients Undergoing Myeloablative Hematopoietic Stem Cell Transplantation. https://clinicaltrials.gov/show/ nct01797952 2013. [26] Nct, Effect of live combined bifidobacterium, lactobacillus and enterococcus capsules on oral mucositis in nasopharyngeal carcinoma patients receiving radiotherapy. https://clinicaltrials.gov/show/nct03112837 2017. [27] Nct, Effects of Probiotics in Preventing Oral Mucositis. https://clinicaltrials.gov/ show/nct03552458 2018. [28] Nct, Mucositis and Infection Reduction With Liquid Probiotics in Children With Cancer. https://clinicaltrials.gov/show/nct03785938 2018. [29] Sharma A, Tilak T, Bakhshi S, Raina V, Kumar L, Chaudhary SP, et al. Lactobacillus brevis CD2 lozenges prevent oral mucositis in patients undergoing high dose chemotherapy followed by haematopoietic stem cell transplantation. ESMO Open 2016;1:e000138. https://doi.org/10.1136/esmoopen-2016-000138. [30] Lacouture ME, Keefe DM, Sonis S, Jatoi A, Gernhardt D, Wang T, et al. A phase II study (ARCHER 1042) to evaluate prophylactic treatment of dacomitinib-induced dermatologic and gastrointestinal adverse events in advanced non-small-cell lung cancer. Ann Oncol Off J European Soc Med Oncol 2016;27:1712–8. https://doi.org/ 10.1093/annonc/mdw227. [31] Giammarco S, Di Giovanni A, Metafuni E, Chiusolo P, Sica S. A pilot study on the efficacy of Lactobacillus brevis CD2 lozenges in preventing oral mucositis by highdose chemotherapy with autologous hematopoietic stem cell transplantation. Bone Marrow Transplant 2016;51:S588–9. https://doi.org/10.1038/bmt.2016.56. [32] Jiang C, Wang H, Xia C, Dong Q, Chen E, Qiu Y, et al. A randomized, double-blind, placebo-controlled trial of probiotics to reduce the severity of oral mucositis induced by chemoradiotherapy for patients with nasopharyngeal carcinoma. Cancer 2019;125:1081–90. https://doi.org/10.1002/cncr.31907. [33] De Sanctis V, Belgioia L, Cante D, La Porta MR, Caspiani O, Guarnaccia R, et al. Lactobacillus brevis CD2 for prevention of oral mucositis in patients with head and neck tumors: a multicentric randomized study. Anticancer Res 2019;39:1935–42. https://doi.org/10.21873/anticanres.13303. [34] Sharma A, Rath GK, Chaudhary SP, Thakar A, Mohanti BK, Bahadur S. 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[41] Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359:97–103. https://doi.org/10.1126/science.aan4236. [42] Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014;11:506–14. https://doi.org/10.1038/nrgastro. 2014.66. [43] Sotoudegan F, Daniali M, Hassani S, Nikfar S, Abdollahi M. Reappraisal of probiotics' safety in human. Food Chem Toxicol 2019;129:22–9. https://doi.org/10. 1016/j.fct.2019.04.032. [44] Doron S, Snydman DR. Risk and safety of probiotics. Clin Infect Dis 2015;60(Suppl 2):S129–34. https://doi.org/10.1093/cid/civ085. [45] Hempel S, Newberry S, Ruelaz A, Wang Z, Miles JN, Suttorp MJ, et al. Safety of probiotics used to reduce risk and prevent or treat disease. Evid Rep Technol Assess (Full Rep) 2011:1–645. [46] Robin F, Paillard C, Marchandin H, Demeocq F, Bonnet R, Hennequin C. Lactobacillus rhamnosus meningitis following recurrent episodes of bacteremia in a child undergoing allogeneic hematopoietic stem cell transplantation. J Clin Microbiol 2010;48:4317–9. https://doi.org/10.1128/jcm.00250-10. [47] Koyama S, Fujita H, Shimosato T, Kamijo A, Ishiyama Y, Yamamoto E, et al. Septicemia from lactobacillus rhamnosus GG, from a probiotic enriched Yogurt, in a
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Review
The effectiveness of probiotics in prevention and treatment of cancer therapy-induced oral mucositis: A systematic review and meta-analysis Zekai Shua, Peijing Lib,c, Bingqi Yud, Shuang Huangb,c, Yuanyuan Chenb,c,
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a
The 2nd Clinical Medical College of Zhejiang Chinese Medical University, China Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, China c Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, China d Zhejiang Hospital, China b
A R T I C LE I N FO
A B S T R A C T
Keywords: Probiotics Radiotherapy Chemotherapy Chemo-radiotherapy Oral mucositis Stomatitis Head and neck cancer
Oral mucositis (OM) is a common and troublesome adverse side effect of many cancer therapy modalities (chemotherapy, radiotherapy, and chemo-radiotherapy), which can cause pain, ulceration, dysphagia, malnutrition, even treatment interruption. Probiotics may be effective in preventing and treating of cancer therapyinduced OM. We performed a systematic review and meta-analysis of the effectiveness of probiotics in prevention and treatment of cancer therapy-induced OM. Four databases and one trial registry were searched as of the 12th of May 2019 to identify all eligible randomized controlled trials (RCT). Five studies involving 435 patients were included in this study. Methodological quality and outcomes were evaluated in every study included. Pooled results showed a moderate heterogeneity (P = 0.15, I2 = 44%). The pooled RRs indicated that the use of probiotics decreased the risk of OM for grade ≥3 (RR = 0.66, 95%CI = 0.54–0.81, P < 0.0001) as well as all grades (RR = 0.83, 95% CI = 0.72–0.97, P = 0.02). There was no significant difference between probiotics and placebo for cancer therapy completion rate (RR = 1.14, 95%CI = 0.65–2.00, P = 0.64). The subgroup analysis indicated that the use of probiotics was not statistically significant for patients receiving chemo-radiotherapy (RR = 0.52, 95% CI = 0.26–1.04, P = 0.07). In conclusion, probiotics may reduce the incidence and mitigate the severity of cancer therapy-induced OM. Further trials with a randomized, double-blind and multicentric study design are needed to confirm this effect. The PROSPERO registration number of this systematic review and meta-analysis is CRD42019130414.
Introduction Oral mucositis (OM) is an inflammation of oral mucosa and can cause erythema, ulceration, pain, dysphagia, and malnutrition, which can cause treatment interruption. OM is common among cancer patients who received chemotherapy and/or radiotherapy [1,2]. The incidence of OM is quite high in patients who receive intensive chemotherapy combined with hematopoietic stem cell transplant (HSCT) or those who underwent radiotherapy for head and neck cancer (HNC) [3,4]. It was reported that more than 85% of patients who are treated with HSCT and almost 100% of HNC patients who receive radiotherapy develop OM, and the incidence of severe OM (≥Grade 3) is 100% when patients receive intensive therapy of total body irradiation (TBI), along with cyclophosphamide chemotherapy-combined HSCT [3–5]. There are three grading scales in common use to evaluate the severity of OM. World Health Organization (WHO) grading scales,
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toxicity criteria of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/ EORTC) and National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). The latter two scales are more widely used. According to RTOG/EORTC criteria, grade 1–2 OM presents as irritation and patchy mucositis that may produce an inflammatory serosanguinous discharge, while grade 3–4 OM appears as confluent fibrinous mucositis, ulceration, hemorrhaging, or necrosis, causing severe pain and requiring narcotic analgesics [6]. The pain caused by severe OM can result in dysphagia and eventually lead to malnutrition, which can cause treatment interruption in patients [2]. A prospective study conducted by Elting found that about 63% of patients who do not develop OM still develop oral pain, and 38% of patients with mild OM (≤Grade 2) have difficulties in food intake [7]. To better understand OM and find ways to prevent and treat it, the mechanism of the disease has been widely studied. Researchers have
Corresponding author at: Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, China. E-mail address: [email protected] (Y. Chen).
https://doi.org/10.1016/j.oraloncology.2019.104559 Received 14 August 2019; Received in revised form 24 December 2019; Accepted 31 December 2019 1368-8375/ © 2020 Elsevier Ltd. All rights reserved.
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Inclusion criteria
found OM to be much more complicated than originally thought. As summarized by Sonis, the development of mucositis was a dynamic process typically divided into five stages: initiation, primary damage response, signal amplification, ulceration and healing [8,9]. In the initial stage, chemotherapy or radiotherapy caused both DNA and nonDNA damage to basal epithelial cells, and a cascade of reactive oxygen species (ROS) is triggered which directly damages cells, tissues, and blood vessels. In the primary damage response stage, mucositis is driven by three pathways activated by the ROS cascade: NF-κB pathway, the ceramide pathway and the matrix metalloproteinase pathway. In the signal amplification stage, a series of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, further damage the basal epithelial cells through positive feedback in the three pathways. In the ulceration stage, the loss of mucosal integrity facilitates the colonization of bacteria, which stimulates macrophagocytes to produce more pro-inflammatory cytokines and potentiates tissue injury. This stage causes extreme pain in patients. Lastly, in the healing stage, signals from submucosal extracellular matrix and mesenchyme promote cell proliferation and differentiation to reestablish the mucosal barrier. Although the mechanism is well studied, the management of OM is still challenging. Interventions including basic oral care, growth factors and cytokines, anti-inflammatory agents, cryotherapy, and low-level laser therapy are suggested according to Multinational Association of Supportive Care in Cancer/The International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines. However, only palifermin (keratinocyte growth factor-1) has been approved by the US Food and Drug Administration and the European Medicines Agency to mitigate OM in a very limited segment of the at-risk population [1,10]. Microorganisms play an important role in the ulceration stage and have been found correlated with the progression of OM in recent studies [11,12]. Researchers discovered that pathogens contributed to the development of OM by activating innate immunity through pathogen-associated molecular patterns (PAMPs) [13,14]. PAMPs secreted by pathogens can infiltrate the damaged mucosa and activate NK cells, mast cells, macrophagocytes, and dendritic cells by pattern recognition receptors (PRRs) [13,15,16]. After a series of signal transmissions, NF-κB and its downstream pro-inflammatory cytokines are activated [13]. In contrast, the probiotics can inhibit apoptosis of epithelial cells by combining with toll-like receptors (TLRs)—one type of PRRs [17]. The effectiveness of probiotics in OM has been proven by several clinical trials, but the results are still controversial. Therefore, the aim of this review is to evaluate the efficacy of probiotics for prevention and treatment of cancer therapy-induced OM.
Types of studies: Randomized controlled trials (RCTs). Types of participants: Cancer patients of any age who received chemotherapy, radiotherapy and chemo-radiotherapy, which could cause oral mucositis. Types of interventions: The intervention groups were treated with probiotic agents or products containing probiotics or probiotics combining with other drugs. The control groups were treated with a placebo, other standard agents, or nothing. Types of outcomes: Primary outcomes: 1. Incidence of oral mucositis (according to RTOG, CTCAE, WHO criteria); 2. Incidence of severe (≥Grade 3) OM (according to RTOG, CTCAE, WHO criteria); 3. Cancer therapy completion rates. Secondary outcomes: onset time of OM, which is not available for this review. Exclusion criteria 1. Studies that did not include outcomes needed in this review. 2. When multiple studies contain the same data, we excluded all studies except the one with the most comprehensive data. Data collection and analysis Selection of studies: We downloaded all titles and abstracts of studies that we searched by electronic searching and hand searching. All studies were imported into EndNote and duplicates were removed. Two independent reviewers examined the remaining references independently. Studies were excluded when they did not meet the inclusion criteria (based on titles and abstracts). After the review of titles and abstracts, two independent reviewers (Zekai Shu, Peijing Li) reviewed full texts of the remaining studies and evaluated the studies whether they could be used in our qualitative or quantitative analyses (meta-analysis). Any discrepancies were discussed and resolved by all group members. We stored the excluded studies and gave the reasons for the exclusion. Data extraction and management: Two independent reviewers extracted data into extraction documents, which were discussed by and made available to all group members. For every included study, we collected the following data: 1. Patients characteristics (age, gender, type of cancer, type of cancer therapy [chemotherapy, radiotherapy, chemo-radiotherapy], sites of researches); 2. The intervention of experimental and control arms (type, formulation, dose, regimen, duration); 3. The elements of risk of bias (generation of randomization sequence, allocation concealment, participants, investigators, outcomes assessors, and data assessors blinding, integrity of outcome data, selective outcome reporting); 4. The primary and secondary outcomes mentioned above. Assessment of risk of bias and studies quality: The Cochrane Collaboration’s tools for assessing risk of bias and studies quality [18] was used by two independent reviewers to evaluate the following sources of bias: generation of randomization sequence, allocation concealment, participants and investigators, outcomes assessors, data assessors blinding, integrity of outcome data, selective outcome reporting. RevMan v5.3 [20] was used to assist with the assessment of risk of bias. If any discrepancies came up, a third experienced viewer arbitrated the different opinions or a group discussion would be conducted. Assessment of reporting biases: If more than 10 studies were eligible for a quantitative analysis (meta-analysis), a funnel plot would be used to assess the reporting biases by using RevMan v5.3. In our review, there were not enough studies for this assessment. Assessment of heterogeneity: The heterogeneity was analyzed by χ2 test (α = 0.1) and I2 test. The randomized effect model would be used if p-value of χ2 test ≤0.1 and I2 > 50%. The fixed effect model would be used if p-value of χ2 test > 0.1 or I2 ≤ 50%. When facing heterogeneity, we performed the subgroup analysis to explore clinical
Materials & methods The study followed the methodology in the Cochrane Handbook [18] and the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement guidelines [19]. The PROSPERO registration number of this systematic review and meta-analysis is CRD42019130414.
Search strategy Electronic searches: We searched PubMed, Embase, Web of Science, Cochrane Library comprehensively by using a combination of medical subject heading (MeSH) terms and free text for eligible studies, with publication time up to 12 May 2019. The details of search strategy are shown in the appendix: PubMed (Appendix A), Embase (Appendix B), Web of Science (Appendix C), and Cochrane Library (Appendix D). Searching other resources: We searched ClinicalTrials.gov for prospective trial registers for controlled trials, with publication time up to 12 May 2019. The details of this search strategy are in Appendix E.
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[32–36], of which 4 studies were included in meta-analysis [32–35]. The study flow diagram was presented in Fig. 1. The characteristics of the included studies and reasons for the excluded studies were presented in Table1 and 2. Included studies: Five studies involving 435 patients met the inclusion criteria [32–36], of which four studies were included in metaanalysis. The four studies compared probiotics with placebo. Two trials studied chemo-radiotherapy [32,34], one studied induction chemotherapy [35], and one study included 78% chemo-radiotherapy, 10% radiotherapy combining cetuximab and 12% radiotherapy combining neoadjuvant chemotherapy [33]. The fifth study could only be included in the qualitative analysis, since the study design was different from the above four studies [36]. Risk of bias and studies quality: The Cochrane Collaboration’s tools for assessing risk of bias and studies quality [18]. The quality problems were mainly due to blinding of participants and investigators in two studies [33,36], and the blinding of outcomes assessors was unknown. Details were presented in Table 3, Fig. 2 and Fig. 3.
heterogeneity, especially different types of cancer therapy (chemotherapy, radiotherapy and chemo-radiotherapy). Data synthesis: We used RevMan v5.3 for meta-analysis. For the primary outcome, relative risk (RR) with 95% confidence interval (CI) was used to estimate all comparisons. For the secondary outcome, we chose mean difference (MD) with 95% CI as a measure of effect. When studies were not eligible for meta-analysis, we summarized the results and made a qualitative analysis. We also performed subgroup metaanalyses based on the different types of cancer therapy (chemotherapy, radiotherapy, chemo-radiotherapy), using the method of analysis mentioned above. Results Eligible studies Up to 12th of May 2019, we identified 2616 records by electronic searching in PubMed, Embase, Web of Science, and Cochrane Library databases. 65 records were found by hand searches in ClinicalTrials.gov. Among them, we found 763 duplicate studies using Endnote and manual screening. After reading titles and abstracts of the remaining 1918 studies, we excluded 1902 studies that did not adopt the required criteria. After reviewing the full text of the remaining studies, 11 studies were excluded, of which, 8 records were clinical trial registration records that have no results posted [21–28], one was a single-arm study [29], one only focused on intestinal adverse events [30], and one was a conference abstract and did not tell whether it was a RCT [31]. Finally, 5 studies were eligible for this systematic review
Probiotics versus placebo Four studies were performed the meta-analysis, which allowed pooling of data (n = 368) [32–35]. As shown in Fig. 4A, the pooled RR for the incidence of severe OM favoured probiotics (RR = 0.66, 95%CI = 0.54–0.81, P < 0.0001). And the fixed effect model was used in the analysis because of the moderate heterogeneity (P = 0.15, I2 = 44%). The pooled RR for the incidence of OM was in favour of probiotics as well (RR = 0.83, 95%CI = 0.72–0.97, P = 0.02), as
Fig. 1. Study flow diagram. 3
4
Randomized Placebo-controlled trial
Sanctis, [33]; Italy
Probiotic group was instructed to receive oral lavage with kefir and swallow 250 ml of kefir twice a day after meals on the first 5 days of each 5-FU chemotherapy cycle VS placebo The LB CD2 lozenges contained not < 2 × 109 viable cells of L. brevis CD2 as the active ingredient. The daily dose was six lozenges per day, one every 2–3 h to be dissolved in the mouth and then swallowed. Hot beverages (e.g. tea, coffee, or milk) were avoided for at least half an hour before and after administration VS placebo
Patients received a median of six cycles of 5FU chemotherapy cycles
Patients received radiotherapy with/without Concomitant cisplatinum-based chemotherapy was administered using a weekly (40 mg/m2) or a 3-weekly (100 mg/ m2) schedule. Some participants were administered with Cetuximab. Radiation dose fraction was delivered with a prescribed total dose of 68–70 Gy and 50–54 Gy to the macroscopic disease and low-risk regions, respectively Control group: 75.0%; Probiotic group: 81.2%
Control group: 60(39–77); Probiotic group: 58.4(34–74)
15 ml AG013 (an oral rinse composed of a recombinant L. lactis strain) at 1、3、 6timesdaily from day 1 to 14 during induction chemotherapy cycle 2 VS placebo
Control group: 60.0%; Probiotic group: 70.6%
Control group: 87.5%; Probiotic group: 70.6%
Control group: 58(34–72); Probiotic group: 51(19–75)
Control group: 54(18–63); Probiotic group: 55.4(26–66)
Outcomes: 1. Incidence of oral mucositis; 2. Incidence of severe oral mucositis (≥Grade 3); 3. Cancer therapy completion rates
Topuz [36]; Turkey
25 patients with locally advanced head and neck cancer (LAHNC) were followed during induction cycle 1 developed ulcerative oral mucositis (UOM; World Health Organization Grade > 2) 40 patients with newly diagnosed Stage II, III or IV colorectal cancer. Baseline Eastern Cooperative Oncology Group performance Status (ECOG PS) of 0, 1 or 2 was required for study participation 71 patients with head and neck cancer (75 patients were screened, of which 4 patients were excluded and were not randomized)
2
1;2
2
1;2;3 Probiotic (Bifidobacterium longum, Lactobacillus lactis, and Enterococcus faecium) was supplied from the beginning to the end of treatment for up to 7 weeks (3 capsules 2 times a day) VS placebo
Control group: 60.0%; Probiotic group: 62.71%%
Control group: 50.4 ± 10.3; Probiotic group: 51.7 ± 9.8
99 patients(18–70 years) whose Karnofsky score ≥ 80 and had newly pathologically diagnosed locally advanced nasopharyngeal carcinoma and were undergoing CCRT
Randomized, DoubleBlind, PlaceboControlled trial
Chunling Jiang 2018; China
Randomized single-blind placebo-controlled(3 probiotics groups vs control group)trial Randomized Placebo-controlled trial
1;2;3
The daily dose(L. brevis CD2)was 6 lozenges per day, 1 lozenge every 2–3 h to be dissolved in the mouth and then swallowed VS placebo
Chemo-radiotherapy: All patients received radical radiotherapy at a dose of 70 Gy in 35 fractions over 7 weeks (at 5 fractions per week; standard fractionation) by linear accelerator, with parallel-opposed lateral fields and spinal cord shielding at 44 Gy. Concurrent chemotherapy consisted of cisplatin (DDP) 40 mg/m2 weekly for 7 doses (days 1, 8, 15, 22, 29, 36, 43) beginning on day 1 of radiation treatment Chemo-radiotherapy: Patients received 70 Gy of radiotherapy in 32 fractions (2.19 Gy/d, 5 d/wk), with the gross tumor volume and the clinical target volume receiving 60 Gy in 32 fractions for 45 days (total, 6–7 weeks). Intravenous infusions of cisplatin (100 mg/m2) were performed on days 1, 22, and 43. Induction chemotherapy cycle 2 with TPF or PF(d1-d14).
Control group: 91.9%; Probiotic group: 93.1%
Control group: 50.1 ± 10.0; Probiotic group: 52.4 ± 9.4
200 patients with a confirmed diagnosis of HNSCC stage II–IVA (resectable) attending the head and neck cancer clinic at the study center
Randomized double-blind placebo-controlled trial
AtulSharma 2011; India
Sewanti Atul Limaye [35]; America
Outcomes
Interventions
Type of cancer therapy
Sex (%, male)
Mean Age (Year)
Participants
Design
Author; Year; Country
Table 1 Characteristic of included studies.
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inevitable because multiple probiotic strains exist and can be combined in different proportions. In our opinion, although the heterogeneity is high, the benefit of probiotics for reducing the incidence of OM is still authentic, which is supported by our analysis and two trials included. In another study by Sewanti [35], 29% HNC patients who received probiotics experienced only 0 or 1 day of OM, whereas all placebo patients went through at least 2 days of OM. Moreover, in an excluded singlearm study conducted in HSCT patients, up to 22.6% patients did not develop OM and only 6.5% experienced severe OM, which further supports our conclusion [29]. The subgroup analysis was performed in chemo-radiotherapy studies. The two studies involved in this subgroup analysis both concluded that probiotics could mitigate severe OM in patients receiving chemoradiotherapy, but after merging these studies in our meta-analysis, we got the opposite result (RR = 0.52, 95%CI = 0.26–1.04, P = 0.07) (Fig. 4D). This was due to the use of a randomized effect model to account for the high heterogeneity (P = 0.05, I2 = 73%) due to much better outcomes in Jiang’s study compared to Sharma’s. In fact, we could get a positive result if a fixed model was utilized. In our opinion, probiotics may still do good to cancer patients treated by chemoradiotherapy, since two studies were well designed and the methodological quality was high (Table 3). However, further prospective trials are needed to confirm this finding. We also conducted a qualitative analysis after including Topuz’s study conducted in colorectal cancer patients treated with 5-FU chemotherapy [36]. However, the inclusion of Topuz’s study did not affect the results of the quantitative analyses above, because Topuz’s study design was different from the other four studies. We speculated that the negative result of Topuz’s study was due to the powerless and unspecific probiotics contained in kefir (a kind of a fermented milk complex) which was used in the study [36]. Currently, microorganisms are found to play important roles in OM and many other diseases, such as diarrhea induced by radiotherapy, idiopathic pulmonary fibrosis, even modulating anti-tumor response to anti–PD-1 immunotherapy [11,12,37–41]. A systematic review of Cochrane Library demonstrated that probiotics might benefit diarrhea patients resulted from pelvic radiotherapy [38]. The result is supported by another systematic review [39]. In this review, we proved that probiotics might reduce the incidence and severity of cancer therapyinduced OM, especially for HNC patients. Additional RCTs in larger populations with good study design and execution are needed to further support the conclusion.
Table 2 Reasons for excluded studies. Study & Registration ID
Reason for exclusion
S. Giammarco 2016 Sharma, A 2016 Lacouture, M.E 2016
Did not tell whether the study was a RCT Sigle-arm study
CTRI/2008/091/000117; CTRI/2013/02/003393; NCT01707641; NCT01545687; NCT01797952; NCT03112837; NCT03552458; NCT03785938
The study focused on intestine adverse events No results posted
shown in Fig. 4B, while the heterogeneity was high (P = 0.09, I2 = 65%). The analysis results didn’t favour probiotics for the cancer therapy completion rate (RR = 1.14, 95%CI = 0.65–2.00, P = 0.64), and the heterogeneity was high (P < 0.00001, I2 = 98%) (Fig. 4C). Clinical subgroup analysis We performed a subgroup analysis for the chemo-radiotherapy trials. The results didn’t favour probiotics in terms of the incidence of severe OM in chemo-radiotherapy (RR = 0.52, 95%CI = 0.26–1.04, P = 0.07), as shown in Fig. 4D. Testing for publication bias: The test for publication bias was not performed due to insufficient studies included. Discussion Summary of the evidence We performed a meta-analysis to evaluate the effectiveness of probiotics in prevention and treatment of cancer therapy-induced OM, including chemotherapy, radiotherapy, and chemo-radiotherapy. We included five studies involving 435 participants, and four studies were included in the meta-analysis. In clinical practice, the occurrence of OM seems inevitable. Therefore, the primary concern is how to prevent severe OM (≥Grade 3). As shown in Fig. 4A, the use of probiotics can reduce the incidence of severe OM (≥Grade 3), and the heterogeneity is moderate (P = 0.15, I2 = 44%). Probiotics also reduce the overall incidence of OM (Fig. 4B). Although the study design and quality are similar for all trials included, the heterogeneity is high (P = 0.09, I2 = 65%). The heterogeneity is calculated based on the degree of coincidence of confidence interval. But we can see that the beneficial effects of probiotics in Sharma’s study are much better than Jiang’s study (Fig. 4B). Three reasons may explain the result: 1. Different radiation technologies were used in two studies. Sharma’s study used a 2D radiotherapy technique, while Jiang’s study used intensity modulated radiation therapy (IMRT). IMRT can reduce oral radiation dose and protect oral better compared with 2D technique, which can dilute the effect of probiotics to some extent. It can explain why probiotics do no good to cancer therapy completion rate as well (RR = 1.14, 95%CI = 0.65–2.00, P = 0.64) (Fig. 4C), since IMRT has made OM no longer the factor causing treatment interruption. 2. Participants in two studies were not diagnosed with exactly the same type of cancer. For example, Sharma’s study contained different types of head and neck cancer, while only nasopharyngeal carcinoma patients were included in Jiang’s study. This caused the different oral dose distribution which generate different severities of OM [32,34]. 3. The ingredients of probiotics were not exactly the same between two studies. The probiotics ingredients in Sharma’s study were Lactobacillus brevis, while they were Lactobacillus, Bifidobacterium and Enterococcus in Jiang’s study. However, variance in probiotic ingredients between studies is currently
Safety issue of probiotics The term “probiotics” is defined as live microorganisms that benefits population and treat specific disease by improving microbial flora [42,43]. In spite of the benefits proven by clinical trials and animal models, there are no probiotic products approved for specific health issues by the US Food and Drug Administration (FDA) yet [43]. Probiotic products are regarded as drugs rather than nutritional supplements if used for a physiological effect, according to the FDA guidance on INDs (Investigation New Drug) in 2013 [44]. In 2001, the Agency for Healthcare Research and Quality (AHRQ) announced a report based on the research by the National Institutes of Health and the FDA which concluded that “the current literature is not well equipped to answer questions on the safety of probiotics in intervention studies with confidence [45]”. Theoretical risks of probiotics include systematic infections, deleterious metabolic activities, excessive immune stimulation, gene transfer, obesity, skin problem and gastrointestinal side effects [43,44]. The populations at risk include inpatients, immunosuppressed people, pregnant people, and those with the potential for translocation of probiotic across the bowel wall [44]. Since all HSCT patients are rendered immunosuppressed and some HNC patients develop neutropenia due to anti-cancer treatment, additional caution and comprehensively 5
6 High Risk: Open-Label
High Risk: Open-Label
Low Risk: Prior to starting RCHT or bioRT, enrolled patients were randomized (1:1) to standard oral care regimen with sodium bicarbonate mouthwash (control arm) or LB CD2 lozenges (intervention arm) through a computer-generated randomization list consisting of randomly permuted blocks of four patient numbers.
Sanctis [33]; Italy
High Risk: Open-Label
Unclear Risk
Unclear Risk
High Risk: The appearance and taste of kefire was different from 0.9% NaCl oral rinses
High Risk: The appearance and taste of kefire was different from 0.9% NaCl oral rinses
Unclear Risk
Unclear Risk
Unclear Risk
Unclear Risk
Unclear Risk
Topuz, [36]; Turkey
Unclear Risk
Unclear Risk
Sewanti Atul Limaye [35]; America
Unclear Risk
High Risk: The block size was known only to the statistician
Unclear Risk
Low Risk: Patients were randomly distributed into 6 blocks in a 2:1 ratio to receive probiotics or a placebo, the block size was known only to the statistician
Low Risk: Patients were randomly distributed into 6 blocks in a 2:1 ratio to receive probiotics or a placebo, the block size was known only to the statistician
Low Risk: The study subjects were unaware of the study arm they were on
Low Risk: An independent biostatistician analyzed the study data
Unclear Risk
Low Risk: The study products were pre-packaged by the sponsor as per the randomization codes and dispensed accordingly
Low Risk: The L. brevis CD2 lozenges and placebo were supplied by CD Pharma India Pvt. Ltd. and were identical in physical appearance, taste and color
Low Risk: Patients were randomly assigned to either of the treatment arms in a 1:1 ratio through a computer-generated randomization list consisting of randomly permuted blocks of 10 patient numbers Low Risk: The blinding codes for the seeds of the random numbers, the block length, and the random numbers, were sealed in envelopes and stored at Jiangxi Cancer Hospital. Blinding codes were not disclosed during the entire trial period Unclear Risk
Low Risk: Patients were randomly assigned to either of the treatment arms in a 1:1 ratio through a computer-generated randomization list consisting of randomly permuted blocks of 10 patient numbers Low Risk: The random assignment of patients was performed by Nanchang Medical University with a computergenerated random number code
Atul Sharma 2011; India
Chunling Jiang 2018; China
Data assessors
Outcomes assessors
Investigators
Participants
Allocation concealment
Generation of randomization sequence
Author; Year; Country
Table 3 Risk bias of included studies.
Low Risk: There was no selective reporting according to the clinical registration information posted (Clinical Trials number NCT03112837) Low Risk: Study group (n = 64) lost 6; Control group (n = 35) lost 0
Low Risk: 40 patients were enrolled, and 3 patients were ineligible for analysis. Low Risk: 75 patients were enrolled, and 7 patients were ineligible for analysis.
Low Risk: There was no selective reporting according to the clinical registration information posted (Clinical Trials number NCT01707641)
Low Risk: There was no selective reporting according to the clinical registration information posted (Clinical Trials number NCT00938080) Unclear Risk
Low Risk: There was no selective reporting according to the clinical registration information posted (Clinical Trials number CTRI/2008/ 091/000117) Low Risk: Study group (n = 101) lost 8; Control group (n = 99) lost 4
High Risk: Study group (n = 17) lost 3; Control group (n = 8) lost 3
Selective outcome reporting
Integrity of outcome data
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Fig. 2. Risk of bias graph for each included study.
Earlier studies have found that probiotics could regulate epithelial function, maintain the integrity of the mucosal barrier, enhance host immunity and inhibit colonization of pathogenic bacteria [49]. Animal experiments have revealed that probiotics may protect epithelial cells by activating TLRs on the surfaces of macrophages and triggering a multi-cellular, adaptive immune signal cascade [17,50]. In detail, lipoteichoic acid (LTA) from Lactobacillus rhamnosus GG (LGG), a probiotic, could bind to TLR2 on pericryptal macrophages, which induces the production of the chemokine CXCL12. Then CXCL12 binds to CXCR4 on COX-2 expressing mesenchymal stem cells (MSCs), which induces MSCs to crypt epithelial stem cells in the lamina propria of intestinal mucosa. Finally, MSCs release PGE2 to protect epithelial stem cells from radiation injury [17]. Ciorba further found that the protective effects of LGG on epithelial cells was lost in Myd88-/-, TLR2-/- and COX2-/- mice. Therefore, we speculate that the protective mechanism of probiotics may arise through TLR-Myd88 pathway (Fig. 5). A study by Burdelya found that the mice could be protected from gastrointestinal and hematopoietic acute radiation syndromes by injection of CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to toll-like receptor5 (TLR5) and activates NF–κB signaling, before lethal total-body irradiation [51]. Another animal study revealed nonviable probiotics were equally effective as live microorganisms in ameliorating dextran sodium sulfate-induced colitis through the TLR9-Myd88 pathway and the protective effects were mediated by their DNA [52]. In summary, TLRs may be the key site for probiotics effectiveness and the effective ingredients of probiotics, such as LTA or DNA, may be extracted and utilized instead of live probiotics (Fig. 5). This can reduce the potential treatment side effects, such as sepsis mentioned above, and further improve the efficacy. Fig. 3. Risk of bias summary for each included study.
Strengths and limitations safety evaluation are needed before the application of probiotics. Among all side effects, the worst consequence for OM patients is sepsis, which may lead to treatment interruption and even life-threating. Of the five studies included in this analysis, no patients developed sepsis due to probiotics. However, three separate cases of sepsis caused by Lactobacillus in HSCT patients are reported [46–48]. And lactobacillus rhamnosus isolated from patients’ blood was found resistant to multiantibiotics, which makes it very difficult to manage [46,47]. In conclusion, we are still not ready to estimate whether it is safe or not for cancer patients to receive probiotics for OM based on current evidence because many factors matter, including probiotic strain type, dosage, time of usage, and the selection of patients under right physical condition.
Although our results supported the conclusion that the probiotics could reduce the incidence and mitigate the severity of cancer therapyinduced OM, some potential limitations should be mentioned. Firstly, the number of studies was small. Secondly, although OM was only induced by cancer therapy (chemotherapy, radiotherapy, and chemoradiotherapy), participants among studies were not diagnosed with exactly the same type of cancer, which might influence the reliability of the final results. Thirdly, the effective ingredients of probiotics were not exactly the same among studies. However, as this is the first systematic review and meta-analysis on this topic, which makes it meaningful and clinically valuable. As we know, recently microorganisms draw increasing attention from the scientific community and have been demonstrated to be important in many diseases [11,12,37,53]. However, just as the limitations listed above, the selection and combination of probiotics and target population vary among studies, which make it difficult to be eventually recommended in Clinical Practice Guidelines
Mechanism of probiotics The mechanism of the protection of probiotics is still unclear. 7
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Fig. 4. Forest plots comparing probiotics vs placebo: A. Incidence of severe oral mucositis; B. Incidence of oral mucositis; C. Cancer therapy completion rate; D. Incidence of severe oral mucositis in patients treated with chemo-radiotherapy.
extract and apply just the effective ingredients of probiotics, rather than the probiocs as a whole.
and approved for clinical application on OM. This review may help researchers with the selection of probiotics and inferring their effect on potentially beneficial patients, especially HNC patients.
Declaration of Competing Interest
Conclusion
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
This systematic review and meta-analysis showed that the probiotics may reduce the incidence and mitigate the severity of cancer therapyinduced OM, especially for HNC patients. However, considering the small number of clinical trials included, further randomized, doubleblind, multicentric trials in a larger population are warranted. This paper may help researchers improve the design of trials in the selection of probiotic strains and the patients with the potential to benefit from them. Due to the safety concerns of probiotics, it may be benefical to
Acknowledgements We acknowledged the contributions of all members in our research team to the article. 8
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Fig. 5. Mechanism of probiotics and pathogens involved in oral mucositis.
Appendix A. PubMed
#10 (#8 OR #9) #11 [ti, ab, kw] stomati* OR [ti, ab, kw] mouth mucosa OR [ti, ab, kw] oral mucositis OR [ti, ab, kw] mucositi* OR [ti, ab, kw] oromucositi* #12 (#10 OR #11) #13 (#7 AND #12)
#1 MeSH descriptor Probiotics explode all trees #2 MeSH descriptor Lactobacillales explode all trees #3 MeSH descriptor Lactococcus explode all trees #4 MeSH descriptor Bifidobacterium explode all trees #5 (#1 OR #2 OR #3 OR #4) #6 [Title/Abstract] probiotic* OR [Title/Abstract] lactobacill* OR [Title/Abstract] Lactococcus* OR [Title/Abstract] bifidobacteri* #7 (#5 OR #6) #8 MeSH descriptor Stomatitis explode all trees #9 MeSH descriptor Mouth Mucosa explode all trees
Appendix C. Web of Science #1 [topic] prbiotic* OR [topic] lactobacill* OR [topic] lactococcus* OR [topic] bifidobacteri* #2 [topic] stomiti* OR [topic] “mouth mucosa” OR [topic] “oral mucositis” OR [topic] mucositi* OR [topic] oromucositi* #3 (#1 AND #2)
#10 (#8 OR #9) #11 [Title/Abstract] stomati* OR [Title/Abstract] mouth mucosa OR [Title/Abstract] oral mucositis OR [Title/Abstract] mucositi* OR [Title/Abstract] oromucositi* #12 (10 OR #11) #13 (#5 AND #12)
Appendix D. Cochrane Library #1 MeSH descriptor Probiotics explode all trees #2 MeSH descriptor Lactobacillales explode all trees #3 MeSH descriptor Lactococcus explode all trees #4 MeSH descriptor Bifidobacterium explode all trees #5 (#1 OR #2 OR #3 OR #4) #6[ti, ab, kw] probiotic* OR [ti, ab, kw] lactobacill* OR [ti, ab, kw] lactococcus* OR [ti, ab, kw] bifidobacteri* #7 (#5 OR #6) #8 MeSH descriptor Stomatitis explode all trees #9 MeSH descriptor Mouth Mucosa explode all trees #10 (#8 OR #9) #11 [ti, ab, kw] stomati* OR [ti, ab, kw] mouth mucosa OR [ti, ab, kw] oral mucositis OR [ti, ab, kw] mucositi* OR [ti, ab, kw] oromucositi* #12 (#10 OR #11) #13 (#7 AND #12)
Appendix B. Embase #1 exp Probiotic agent/ #2 exp Lactobacillales/ #3 exp Lactococcus #4 exp Bifidobacteriales #5 (#1 OR #2 OR #3 OR #4) #6 [ti, ab, kw] probiotic* OR [ti, ab, kw] lactobacill* OR [ti, ab, kw] lactococcus* OR [ti, ab, kw] bifidobacteri* #7 (#5 OR #6) #8 exp Stomatitis #9 exp Mouth mucosa 9
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Appendix E. Clinical trials
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