Short-term isolated leucine supplementation was not associated with improvements in muscle mass or function in patients with head and neck cancer: A randomized, double-blind, proof-of-concept trial with an elderly non-cancer comparator cohort

BACKGROUND & AIMS: Cancer cachexia is a multifactorial syndrome characterized by muscle mass loss, systemic inflammation, and anabolic resistance, negatively impacting patients' quality of life and survival. Leucine, an essential branched-chain amino acid (BCAA), has shown promising effects on protein synthesis, particularly in the elderly, but its effects in cancer patients remain underexplored. This study aimed to evaluate the short-term effects of isolated leucine supplementation on skeletal muscle mass and related outcomes in patients with head and neck cancer (HNC), in an elderly non-cancer cohort as a physiological comparator. METHODS: This randomized, double-blind, proof-of-concept trial was conducted with 41 participants, divided into two groups: 23 cancer patients and 18 non-cancer (NC) patients. Participants received either 6 g/day of isolated leucine or non-essential amino acids (NEAA) comparator for 4 weeks. The primary endpoint was the change in appendicular skeletal muscle mass index (ASMMI) assessed by dual-energy X-ray absorptiometry (DXA). Secondary and exploratory outcomes included skeletal muscle mass index assessed by bioelectrical impedance analysis (BIA), muscle strength, physical performance, phase angle, quality of life, nitrogen balance, and inflammatory markers. The 3-way ANOVA was used to assess pre- and post-supplementation effects. Multiple comparisons were performed using the Bonferroni test. A 2-way ANOVA or the Mann-Whitney test followed by Tukey's multiple comparisons, when appropriate, were applied. Pearson's correlation was used for parametric data, and Spearman's correlation for non-parametric data. RESULTS: ; p = 0.01). No significant between-group differences were observed in HNC patients. In CL group, ASMMI correlated strongly with PA (r = 0.821, p = 0.01) and moderately with CC (r = 0.673, p = 0.02). In CP group, ASMMI correlated with PA (r = 0.734, p = 0.02); in NCP group, SMMI correlated with HGS (r = 0.862, p = 0.01). Secondary outcomes, including muscle strength, gait speed, phase angle, and inflammatory markers, did not differ significantly between groups. Protein intake remained below recommended levels, and nitrogen balance was negative across cohorts. CONCLUSION: In this short-term, proof-of-concept study, isolated leucine supplementation was associated with modest gains in muscle mass in elderly individuals without cancer but was not linked with improvements in muscle mass or function in patients with HNC. These findings suggest that supplementation with isolated leucine supplementation alone is insufficient to counteract cancer-related muscle waste and should be investigated as part of multimodal interventions addressing nutrition, inflammation, and physical activity.