A Phase II Randomized Clinical Trial and Mechanistic Studies Using Improved Probiotics to Prevent Oral Mucositis Induced by Concurrent Radiotherapy and Chemotherapy in Nasopharyngeal Carcinoma

Abstract

Earlier evidence has proven that probiotic supplements can reduce concurrent chemoradiotherapy (CCRT)-induced oral mucositis (OM) in nasopharyngeal cancer (NPC). The incidence of severe OM (grade 3 or higher) was the primary endpoint in this study. We first enrolled 85 patients with locally advanced NPC who were undergoing CCRT. Of them, 77 patients were finally selected and randomized (1:1) to receive either a probiotic cocktail or placebo. To investigate the protective effects and the mechanism of probiotic cocktail treatment on OM induced by radiotherapy and chemotherapy, we randomly divided the rats into the control (C) group, the model (M) group, and the probiotic (P) group. After treatment, samples from the tongue, blood, and fecal and proximal colon tissues on various days (7th, 14th, and 21st days) were collected and tested for the inflammatory response, cell apoptosis, intestinal permeability, and intestinal microbial changes. We found that patients taking the probiotic cocktail showed significantly lower OM. The values of the incidence of 0, 1, 2, 3, and 4 grades of OM in the placebo group and in the probiotic cocktail group were reported to be 0, 14.7, 38.2, 32.4, and 14.7% and 13.9, 36.1, 25, 22.2, and 2.8%, respectively. Furthermore, patients in the probiotic cocktail group showed a decrease in the reduction rate of CD3+ T cells (75.5% vs. 81%, p < 0.01), CD4+ T cells (64.53% vs. 79.53%, p < 0.01), and CD8+ T cells (75.59 vs. 62.36%, p < 0.01) compared to the placebo group. In the rat model, the probiotic cocktail could ameliorate the severity of OM, decrease the inflammatory response, cause cell apoptosis and intestinal permeability, and restore the structure of gut microbiota to normalcy. In conclusion, the modified probiotic cocktail significantly reduces the severity of OM by enhancing the immune response of patients with NPC and modifying the structure of gut microbiota.Clinical Trial Registration: The Clinical Trial Registration should be the NCT03112837.

Microbiome First Medicine in Health and Safety

“…Table 4 illustrates examples from human clinical trials [ 131 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 ]. Not surprisingly, the best outcomes occur when there is a clear understanding of the specific microbes, genes, metabolic changes, and installation conditions that are needed to support microbiome-driven physiological benefits.…”

Chemotherapy-Induced Intestinal Microbiota Dysbiosis Impairs Mucosal Homeostasis by Modulating Toll-like Receptor Signaling Pathways

“…In a phase II randomized clinical trial on the effectiveness of a probiotic cocktail on oral mucositis in advanced nasopharyngeal cancer patients undergoing concurrent chemoradiotherapy, similar results were found. For instance, the relative abundance of probiotics, such as Lactobacillus, Bifidobacterium and Akkermansia, decreased, while the abundance of harmful bacteria, such as Clostridium, Enterococcus, and Enterobacter increased [25]. A systematic review by Yixia and colleagues summarized that a chemotherapy regimen (including one or more of 5-fluorouracil/FU, capecitabine, oxaliplatin, irinotecan and folinic acid) and surgery may lead to distinct alterations in the gut microbiota composition in colorectal cancer patients particularly in Proteobacteria phylum [26].…”

“…As reviewed by Badgeley et al, supplementation with probiotics has several benefits for cancer patients such as enhancing cancer cell apoptosis, reducing chemotherapy toxicity and modulating host immune response [93]. A phase II randomized clinical trial recently conducted by Xia et al confirmed that a probiotic cocktail can reduce concurrent chemoradiotherapy-induced oral mucositis in nasopharyngeal cancer patients [25]. Interestingly, fecal microbiota transplantation could be used to treat severe Clostridioides difficile colitis in a pediatric patient with non-Hodgkin lymphoma [94].…”

The science of mucositis

“…For this to be realised, appropriate infrastructure such as tissue and biome banking, and comprehensive data collection with skilled bioinformatics (likely with artificial intelligence and machine learning capacity) is needed to identify meaningful biomarkers with clinical utility. Although sequencing the microbiota genome (through technology such as 16S rRNA) is a relatively new approach to mucositis research, it has already yielded exciting findings that could be applied to personalised medicine and has the advantage of being a modifiable risk factor through microbial-related therapies such as ultra-narrow antibiotics, prebiotics, second-generation probiotics, and metabolites now being investigated in clinical trials [21][22][23]. Consequently, one of the major opportunities going forward is to begin to assess the impact of multiple mechanistic variables-genomics, proteomics, metabolomics, microbiomics-simultaneously in a systems biology approach to enact true personalised medicine in supportive care.…”