Effectiveness of oral cryotherapy in preventing methotrexate-induced oral mucositis in pediatric patients with acute lymphoblastic leukemia: a randomized controlled trial
Mené sur 127 patients pédiatriques atteints d'une leucémie lymphoblastique aiguë, cet essai randomisé évalue l'efficacité d'une cryothérapie orale pour prévenir une mucite buccale induite par le méthotrexate
Purpose: 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).
Methods: 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.
Results: 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.
Conclusions: 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.
Supportive Care in Cancer , résumé, 2026