Metabolomic Alterations Associated with Adjunctive Hydrogen Gas Inhalation During Concurrent Chemoradiotherapy in Locally Advanced Head and Neck Cancer: A Pilot Study.

Background: H2 gas inhalation has been proposed as a selective modulator of reactive oxygen species (ROS), potentially mitigating treatment-related oxidative damage. This study investigated the effects of adjunctive H2 gas inhalation on serum metabolomic profiles and clinical toxicities in patients with LAHNC undergoing CCRT. Methods: Twenty patients were prospectively randomized to receive either standard CCRT alone (Group A) or CCRT combined with adjunctive H2 gas inhalation (Group B). Serum samples collected before and after treatment were analyzed using untargeted ultra-high-performance liquid chromatography coupled with ion mobility quadrupole time-of-flight high-resolution mass spectrometry (UHPLC-IM-QTOF-HRMS)-based metabolomics. Results: One patient in Group B discontinued participation, leaving 19 patients for the final analysis. Patients receiving adjunctive H2 gas inhalation tended to exhibit numerically lower frequencies of moderate treatment-related toxicities, fewer chemotherapy delays, and a shorter overall treatment duration than those receiving CCRT alone. Metabolomic profiling in the CCRT-alone group revealed exploratory alterations in metabolites associated with arginine metabolism, glutathione metabolism, and purine metabolism following treatment. Ornithine, uric acid, and tetrahydrodeoxycorticosterone were among the candidate discriminative metabolites with exploratory discriminatory performance after CCRT. In contrast, patients receiving adjunctive H2 gas inhalation showed a more limited pattern of pathway mapping, with exploratory evidence from an illustrative single-hit pathway assignment suggesting possible involvement of purine metabolism. Altered uric acid levels together with changes in several lipid-related metabolites may collectively reflect metabolic responses associated with treatment-related oxidative stress during CCRT. Consistent with these findings, direct between-group comparison of within-subject changes (Δ = post - pre) indicated a numerically smaller reduction in serum uric acid levels in the adjunctive H2 gas inhalation group; however, this difference did not reach statistical significance. Conclusions: Adjunctive H2 gas inhalation during CCRT may be associated with reduced moderate treatment-related toxicities and exploratory changes in systemic metabolic profiles in patients with LAHNC. However, the study was not designed to evaluate oncological outcomes, and the metabolomic findings, particularly the pathway-level interpretations, should be considered exploratory because several pathway assignments were based on only one or a few mapped metabolites, together with the limited sample size, patient heterogeneity, and lack of independent external validation. Further validation in larger, independent cohorts using comprehensive between-group metabolomic analyses is warranted.