Oncology · Medical Literature
Effectiveness of oral cryotherapy in preventing methotrexate-induced oral mucositis in pediatric patients with acute lymphoblastic leukemia: a randomized controlled trial.
Abstract
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.
Clinical relevance
Does oral cryotherapy using ice-cold saline rinses, added to standard oral care, reduce the incidence and severity of high-dose methotrexate-induced oral mucositis in pediatric patients (aged 3–18 years) with acute lymphoblastic leukemia undergoing consolidation therapy? __SNAPSHOT__ {"studyDesign":"Single-center, open-label, parallel-group randomized controlled trial (RCT) with per-protocol (PP) primary analysis and complete intention-to-treat (ITT) worst-case sensitivity analysis","setting":"Single center; country not reported in the available abstract","sampleSize":"127 randomized (9 excluded post-randomization for poor compliance: OC n=7, control n=2); PP analysis n=118. Arm-level allocation not explicitly reported in the abstract beyond the 1:1 ratio.","population":"Children aged 3–18 years with acute lymphoblastic leukemia (ALL) undergoing consolidation chemotherapy with high-dose methotrexate (HD-MTX) at 3 g/m² or 5 g/m² over 24 hours","intervention":"Oral cryotherapy (OC): ice-cold saline oral rinses in addition to standard oral care, administered during HD-MTX infusion","comparator":"Standard oral care alone","primaryOutcome":"Incidence of oral mucositis of any grade (WHO grade ≥ I) within 14 days post HD-MTX","followUp":"14 days post HD-MTX administration","fundingSource":"Not reported in the available abstract"}
Key findings
Only the abstract (truncated) was available for review; complete quantitative results — including absolute and relative incidence rates, risk ratios or odds ratios, confidence intervals, p-values, NNT, OM duration data, and mucositis-free survival curves — were not present in the provided text and are therefore not reported. The abstract confirms that the primary analysis was per-protocol (n=118), with nine participants excluded post-randomization primarily due to poor compliance, predominantly in the OC arm (OC: n=7 excluded; control: n=2 excluded). The study also pre-specified a complete ITT worst-case sensitivity analysis to assess the impact of missing outcome data. Secondary outcomes included WHO grade ≥ II OM incidence, OM duration, and mucositis-free survival by day 14. No adverse event data were available from the abstract. No values were calculable from the information provided.
Practice implications
IMPORTANT LIMITATION: Only a truncated abstract was available; the results section was not provided, and no outcome data, effect estimates, or conclusions can be attributed to this study. As such, it is not possible to determine whether oral cryotherapy was effective, ineffective, or harmful in this population, nor to assess the magnitude or clinical importance of any observed effect. The study design (1:1 RCT, PP + ITT analysis, WHO grading, 14-day follow-up) is methodologically appropriate for the question. The differential dropout rate due to poor compliance — 7 of the OC participants versus 2 controls excluded post-randomization — raises a clinically important concern about the feasibility and tolerability of ice-cold saline rinses in young children, particularly those aged 3–7 years, who may be less able to cooperate with prolonged oral rinsing. This mirrors a known challenge in the pediatric cryotherapy literature. The population (ALL consolidation, HD-MTX at 3–5 g/m²) is clinically relevant and underrepresented in prior cryotherapy RCTs, most of which enrolled adult or HSCT populations. Results, when published in full, should be interpreted in the context of the open-label design (blinding of participants and caregivers was not feasible), single-center conduct, and the biological plausibility of vasoconstriction-mediated mucosal protection during a 24-hour infusion (which differs mechanistically from short-bolus agents like 5-fluorouracil, where cryotherapy evidence is strongest). __LIMITATIONS__ 1. Only a truncated abstract was available; results, effect sizes, adverse events, and conclusions could not be reviewed. 2. Open-label design: performance bias cannot be excluded, as participants and caregivers knew treatment allocation. 3. Single-center study limits generalizability across institutions, countries, and different HD-MTX protocols. 4. Differential post-randomization exclusion due to poor compliance (7 OC vs. 2 control) introduces potential selection bias in the PP analysis; the planned ITT worst-case analysis partially addresses this. 5. The biological rationale for cryotherapy during a 24-hour HD-MTX infusion is less established than for bolus chemotherapy agents; the duration and frequency of ice-cold saline rinses relative to the infusion schedule are not described in the abstract. 6. Age range of 3–18 years spans developmentally diverse patients; compliance and tolerability in children aged 3–6 years may differ substantially from adolescents, and subgroup analyses by age are not described. 7. HD-MTX dose heterogeneity (3 g/m² vs. 5 g/m²) may confound mucositis incidence; whether analyses were stratified by dose is not reported. 8. Follow-up limited to 14 days may not capture late or prolonged mucositis episodes. 9. Funding source not reported; potential conflicts of interest cannot be assessed. __BOTTOM_LINE_CATEGORY__ low_certainty __BOTTOM_LINE__ This RCT addresses a clinically meaningful gap — whether ice-cold saline oral cryotherapy reduces HD-MTX-induced oral mucositis in pediatric ALL — but the full results are not available from the provided abstract, precluding any evidence-based practice recommendation. The notable compliance-related dropout rate in the OC arm (7/~64 OC patients excluded) signals a feasibility concern that clinicians should consider regardless of efficacy findings. Full publication review is required before this intervention can be adopted, modified, or rejected in pediatric HD-MTX consolidation protocols.