Time-dependent efficacy of zinc supplements in preventing oral mucositis after chemoradiotherapy: a meta-analysis

To evaluate the effect of zinc supplements in preventing chemotherapy and radiotherapy-related oral mucositis (OM) in cancer patients.

We retrieved randomized controlled trials (RCTs) on the prevention of OM after chemotherapy and radiotherapy using zinc supplements. These studies were sourced from nine databases, including PubMed, Embase, Cochrane, Web of Science, Scopus, and SinoMed, covering the period from their inception to October 2025. Two researchers independently screened studies and extracted data. The Cochrane risk of bias tool was used to assess the quality of the included studies, and Stata 16.0 software was used for analysis.

A total of 16 randomized controlled trials (RCTs) comprising 17 comparison groups and involving approximately 1076 patients were included. Zinc supplementation significantly delayed the onset of OM (MD = 1.37, 95% CI: 0.78 to 1.95, P < 0.001). Regarding the overall incidence of OM, zinc significantly reduced the risk at both 2 weeks (RR = 0.69) and 7-9 weeks (RR = 0.33) of treatment. For severe OM (grade ≥ 3), zinc exhibited a significant protective effect at both 2 weeks and 5-6 weeks of treatment (RR = 0.26 for both time points). Subgroup analyses revealed key dose duration, and administration route effects: (1) In the early phase of treatment (2 weeks), topical zinc demonstrated a beneficial trend in reducing both the incidence and severity of OM; (2) in the mid-to-late phase (5-6 weeks), oral administration of moderate to high doses (≥ 150 mg/day) was markedly effective in preventing severe OM (RR = 0.07, 95% CI: 0.02 to 0.36), showing superior efficacy compared to topical application; (3) zinc supplementation significantly alleviated pain scores at 3 and 6 weeks of treatment (MD = -1.82 and -2.02, respectively), as well as xerostomia symptoms at 6 weeks (MD = -0.60, 95% CI: -0.81 to -0.40, P < 0.001).

Zinc supplementation is safe and effective, demonstrating a significant time-dependent, bimodal therapeutic effect: it reduces the incidence of OM during the second and the seventh to ninth weeks and significantly decreases the occurrence of severe OM in the second and fifth to sixth weeks. Additionally, zinc supplementation offers certain benefits in alleviating oral pain and xerostomia. A phased intervention strategy is recommended: in the early stage, combine zinc with topical agents to control symptoms, and in the mid-to-late stages, administer oral medium-to-high doses (≥ 150 mg/day) to prevent severe OM, particularly in patients with head and neck tumors.