Zinc supplementation shows potential in reducing severe radiation-induced oral mucositis in head and neck cancer patientsZinc Mouthwash May Reduce Severe Mouth Sores From Radiation

Radiation-induced oral mucositis (RIOM) frequently causes severe pain and treatment interruptions in patients with head and neck cancer. While earlier guidelines suggested zinc supplementation, updated MASCC/ISOO guidelines downgraded it to 'No Guideline Possible' due to highly conflicting evidence. This study aims to resolve these inconsistencies by evaluating zinc's prophylactic efficacy and investigating whether the route of administration determines its clinical benefit. Following PRISMA guidelines and INPLASY registration (INPLASY202620063), we searched PubMed, Embase, and the Cochrane Library through February 2026. We included randomized controlled trials (RCTs) comparing prophylactic zinc versus placebo or standard care in head and neck cancer patients receiving radiotherapy. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool. The primary outcome was severe (Grade 3-4) RIOM incidence. Data from five RCTs (332 patients) were pooled using a random-effects model. Overall, zinc significantly reduced severe mucositis risk (RR = 0.35, 95% CI: 0.17-0.73, = 0.005). Crucially, an exploratory subgroup analysis revealed a striking divergence based on delivery route. Topical zinc mouthwash demonstrated encouraging protection (RR = 0.16, 95% CI: 0.05-0.49, = 0.001) with zero heterogeneity ( = 0%). In contrast, systemic zinc yielded borderline, inconsistent benefits (RR = 0.52, 95% CI: 0.27-1.01, = 0.055, = 37%). In conclusion, the localized pool of contemporary evidence clearly demonstrates that the systemic oral ingestion of zinc supplements does not provide a reliable prophylactic benefit against severe radiation-induced oral mucositis in head and neck cancer care. Conversely, topical zinc mouthwashes exhibit an encouraging protective trend; however, the severe paucity of available randomized trials and low cumulative patient volume preclude definitive clinical verification. While these exploratory findings suggest that topical administration may provide a more consistent protective trend compared to systemic routes, they should be interpreted as hypothesis-generating rather than definitive. Future large-scale, multi-center RCTs are strictly warranted to validate these promising route-specific benefits before formal guideline integration.