Correlation of Skeletal Muscle and Visceral adipose tissue Measured by Computed Tomography with neoadjuvant chemoradiotherapy related efficacy and toxicity in esophageal squamous cell carcinoma: a retrospective analysis from a large prospective cohort.

BACKGROUND: Despite being a standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC), neoadjuvant chemoradiotherapy (nCRT) followed by surgery was frequently associated with toxicities. Body composition was a potential factor influencing both the toxicity and efficacy of nCRT. The aim of this study was therefore to assess, within a large retrospective cohort derived from prospective trials, the associations of body composition measures-including skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) with nCRT-related toxicities and outcomes. MATERIALS AND METHODS: Patients with locally advanced ESCC who underwent standard nCRT between January 2019 and December 2024 were included in this retrospective analysis. Body composition parameters were derived from pre-treatment computed tomography (CT) scans at the third lumbar vertebra (L3). SMD was calculated as the mean radiation attenuation (Hounsfield units) of the muscle area. Based on established criteria, patients were stratified as having low or high SMI according to Martin's BMI-specific thresholds, while SMD and VAT were categorized into tertiles (low, intermediate, high). Hematologic toxicities and dose-limiting toxicities (DLT) were graded using CTCAE v5.0. Associations between body composition and toxicities/efficacy were analyzed using logistic regression. The relationship between body composition and absolute lymphocyte count (ALC) nadir and baseline lymphocyte subsets (CD4+, CD8+, CD3+) was also evaluated. RESULTS: This study included 297 patients (median age 66 years; 85.5% male; 72.4% stage III). Following nCRT, 278 patients underwent surgery, achieving a pathological complete response (pCR) rate of 42.8% and tumor regression grade (TRG) 0-1 of 72.3%. Grade ≥2 hematologic toxicity occurred in 80.5% (n=239) of patients, and 35.4% (n=105) experienced DLT. While body composition showed no significant association with pCR or TRG, multivariate analysis revealed that both high SMI (adjusted odds ratio [OR] 0.48, 95% confidence interval [CI] 0.26-0.89, P=0.02) and high VAT (adjusted OR 0.46, 95% CI 0.22-0.94, P=0.034) were independent protective factors against grade ≥2 hematologic toxicity. Additionally, high SMI was significantly associated with reduced risk of DLT (adjusted OR 0.56, 95% CI 0.34-0.92, P=0.023). Notably, patients with low VAT had significantly lower median ALC nadir and baseline CD4+ T-cell counts. CONCLUSION: In this cohort, pretreatment high SMI and high VAT were associated with reduced nCRT-related hematologic toxicities (grade ≥2) and DLT in patients with locally advanced ESCC. Pathological response (pCR/TRG 0-1) was not associated with body composition. The protective role of high VAT might be partially mediated by its association with higher lymphocyte nadirs and baseline CD4+ T-cell counts. Future studies should investigate long-term outcomes and assess whether prehabilitation strategies targeting SMI and VAT can mitigate toxicity without compromising treatment efficacy.