[18 F]FDG PET unveils a cachexia-specific multiorgan metabolic phenotype and identifies patients with poor prognosis in locally advanced rectal cancer.

Abstract

PURPOSE: Cancer cachexia is a debilitating syndrome that profoundly impacts survival, yet its systemic metabolic characteristics and prognostic drivers in locally advanced rectal cancer (LARC) remain poorly defined. This study aimed to comprehensively profile the host’s metabolic response in LARC-associated cachexia using [18 F]FDG PET-CT and to evaluate its prognostic implications. METHODS: In this retrospective analysis, 131 LARC patients were stratified by cachexia status. Receiver operating characteristic (ROC) analysis was used to identify the most discriminative metabolic parameters. Structural equation modeling was applied to assess the mediating role of systemic metabolism between primary tumor metabolic tumor volume (MTV) and cachexia. Survival analysis was conducted using Kaplan–Meier curves and Cox proportional hazards models, with overall survival (OS) as the primary endpoint. RESULTS: Cachectic patients displayed a distinct systemic metabolic profile. First, a coordinated reduction in aortic, hepatic, and pancreatic FDG uptake emerged as a hallmark of systemic metabolic suppression. Conversely, adipose tissue exhibited a paradoxical hypermetabolism that was not only preserved but markedly accentuated across all depots after normalization to aortic uptake, revealing a consistent and systemic shift in metabolic partitioning. Path analysis within our model revealed significant direct paths from hypometabolism in the aorta and pancreas to cachexia. The effect of primary tumor MTV was channeled through both direct and indirect routes, with subcutaneous fat metabolism exhibiting the most substantial mediating effect. Critically, survival analysis pinpointed subcutaneous fat glucose uptake (SubFat SUVmax) from this metabolic network, validating it in multivariate analysis as a powerful independent prognostic factor that surpassed the clinical diagnosis of cachexia. CONCLUSION: This study delineates a comprehensive metabolic landscape of cachexia in LARC, revealing a systemic energy imbalance in which adipose tissue hypermetabolism acts as both a key pathophysiological mediator and a superior prognostic biomarker compared to clinical cachexia diagnosis. These findings support a shift from phenotypic to metabolic stratification in the management of cancer cachexia.