Effectiveness of oral cryotherapy in preventing methotrexate-induced oral mucositis in pediatric patients with acute lymphoblastic leukemia: a randomized controlled trial.

To evaluate whether oral cryotherapy (OC) using ice-cold saline reduces the incidence and severity of high-dose methotrexate (HD-MTX)-induced oral mucositis (OM) in children with acute lymphoblastic leukemia (ALL). This single-center, open-label, parallel-group randomized controlled trial (RCT) enrolled children aged 3-18 years with ALL undergoing consolidation therapy with HD-MTX. Participants were randomly assigned (1:1) to either OC (ice-cold saline oral rinses) or standard oral care alone. HD-MTX was administered at doses of 3 g/m2 or 5 g/m2 over 24 h. The primary outcome was the incidence of OM of any grade (WHO grade ≥ I) within 14 days. Secondary outcomes included OM incidence (WHO grade ≥ II), OM duration, and mucositis-free survival by day 14. The primary analysis was conducted according to the per-protocol (PP) principle and included 118 participants with available outcome data; nine participants were excluded after randomization because of poor compliance (OC, n = 7; control, n = 2). The impact of missing outcome data was assessed using complete intention-to-treat (ITT) worst-case analysis, reference-based imputation, and tipping-point sensitivity analysis. A total of 127 patients were randomized. The primary day 14 analysis included 118 participants with available outcome assessments, with 59 participants in each group. The incidence of any-grade OM was significantly lower in the OC group (22.0% vs. 44.1%; P = 0.019). The incidence of OM of WHO grade ≥ II was also significantly lower in the OC group (6.8% vs. 23.7%; P = 0.021), corresponding to a substantial relative risk reduction. After multivariable adjustment, OC remained associated with a lower OM risk (adjusted odds ratio [OR], 0.37; 95% confidence interval [CI], 0.16-0.85; adjusted Cox hazard ratio [HR], 0.42; 95% CI, 0.21-0.84). The results of the reference-based imputation analysis were consistent with those of the primary analysis. However, OM duration did not differ significantly between groups (4.00 vs. 5.00 days; P = 0.318). Subgroup analyses revealed that the protective effect of OC was most pronounced in children older than 6 years (HR 0.25; P for interaction = 0.046) and those receiving MTX at 5 g/m2 (HR 0.22; P for interaction = 0.038). No serious OC-related adverse events were observed. OC using ice-cold saline effectively reduces the day 14 incidence and severity of HD-MTX-induced OM and improves mucositis-free survival in pediatric ALL. These findings were supported by the reference-based imputation analysis. This intervention appears to be safe and feasible; however, confirmation through ITT analyses and multicenter trials using age-stratified randomization is required before its routine clinical implementation. ChiCTR2300078327.