Effects of Immunonutrients for Oral Mucositis Secondary to Cancer Therapy: A Systematic Review and Bayesian Network Meta-Analysis

Background Oral mucositis (OM) is the most common acute complication among patients with cancer and adversely affects treatment outcomes and quality of life. However, effective management strategies remain limited. This systematic review and network meta-analysis (NMA) aimed to evaluate the efficacy of immunonutrients in alleviating OM secondary to cancer therapy. Methods A comprehensive literature search was conducted in PubMed, Embase, Web of Science, and Cochrane Library to identify randomised controlled trials (RCTs) comparing immunonutrient treatments for OM secondary to cancer therapy. A Bayesian random-effects model was used in a network meta-analysis to compare the effects of different immunonutrients on OM incidence, with subgroup analyses for mild (MOM) and severe (SOM) oral mucositis. Exploratory meta-regression analyses were performed to explore whether age, anticancer treatments, control group composition, cancer types and administration routes were associated with variations in the effects of immunonutrient interventions on OM incidence. Additionally, pairwise meta-analysis was conducted to evaluate the overall effects of immunonutrients on secondary outcomes, including weight changes, pain intensity, and symptom duration. Results The analysis included 47 RCTs involving 3,583 patients and evaluating 7 interventions. Network meta-analysis suggested that glutamine, zinc, and probiotics were associated with reduced overall OM incidence compared with placebo: glutamine (RR = 0.56, 95%CI: 0.27-0.93), zinc (RR = 0.52, 95%CI: 0.22-0.98), and probiotics (RR = 0.52, 95%CI: 0.23-0.91). However, these findings for overall OM were attenuated in the risk-of-bias sensitivity analysis and should therefore be interpreted cautiously. The evidence supporting zinc was less certain given its borderline confidence interval and low certainty according to GRADE. In contrast, more consistent evidence was observed for severe oral mucositis (SOM), with glutamine (RR = 0.32, 95%CI: 0.19-0.51) and probiotics (RR = 0.56, 95%CI: 0.37-0.76) associated with a reduced incidence of SOM. Immunonutrients were associated with significant pain reduction on the NRS (MD = −1.71; 95% CI: −1.97 to −1.45, P < 0.001) and VAS (MD = −1.39; 95% CI: −2.12 to −0.67, P < 0.001), as well as reduced duration of both OM (MD = −1.95 days, 95%CI: −2.78 to −1.13, P < 0.001) and SOM (MD = −3.93 days, 95%CI: −6.53 to -1.33, P = 0.003). Conclusion These findings suggest that immunonutrients may have a potential role in supportive oncology care. However, the evidence for reducing overall OM incidence should be interpreted cautiously due to reduced robustness after sensitivity analyses. More consistent evidence supports the potential role of glutamine and probiotics in preventing severe oral mucositis. Exploratory meta-regression analyses suggested potentially greater benefits of glutamine among adults, patients receiving concurrent chemoradiotherapy, and those with head and neck cancers. Additionally, immunonutrient interventions were associated with improvements in pain relief and OM duration, underscoring their therapeutic value in supportive oncology care.