Salivary Methotrexate as a Predictor of Oral Mucositis in Hematological Cancer Patients: A Phase II Randomized, Double‐Blind Clinical Trial

OBJECTIVE: To evaluate the efficacy of prophylactic photobiomodulation therapy (PBMT) in preventing oral mucositis (OM) and to assess serum and salivary methotrexate (MTX) levels as predictors of OM in adults receiving high-dose methotrexate (HD-MTX). METHODS: This phase II randomized, double-blind, placebo-controlled trial enrolled adults with hematological malignancies undergoing a first HD-MTX cycle at a tertiary cancer center in Brazil. Participants were randomized to PBMT or sham laser therapy, administered daily until MTX clearance or for up to five sessions. OM was assessed for 9 days using WHO criteria. Serum and salivary MTX concentrations were measured at 24, 48, and 72 h post-infusion, along with urinary pH and serum creatinine. RESULTS: Fifty-three patients were randomized (PBMT n = 26; placebo n = 27). PBMT significantly reduced ulcerative OM (grade ≥ 2) at 96 h (11.5% vs. 51.9%), yielding a 77.7% relative risk reduction and a number needed to treat of 2 (p < 0.01). Placebo recipients had an 8.97-fold higher odds of severe OM. Serum MTX was not associated with OM, whereas salivary MTX increased disproportionately over time and independently correlated with OM severity. CONCLUSIONS: PBMT significantly reduced OM incidence and severity in adults receiving HD-MTX. Salivary MTX is a promising non-invasive biomarker for OM risk. TRIAL REGISTRATION: Trial was prospectively registered in the Brazilian Registry of Clinical Trials (ReBec, No. 12218).