Longitudinal Associations Between Inflammation and Multi‐Dimensional Fatigue up to 2 Years After Colorectal Cancer Diagnosis

ABSTRACT

Cancer‐related fatigue (CRF) is a prevalent symptom among colorectal cancer (CRC) survivors. While inflammation is a proposed underlying mechanism, longitudinal evidence including pre‐treatment assessments remains scarce. Within the population‐based PROCORE study, newly diagnosed CRC patients provided blood samples and completed questionnaires at diagnosis ( n  = 411; 60.6% male; age = 67.0 years), 12‐ ( n  = 304), and 24‐month follow‐up ( n  = 252). Eleven inflammatory biomarkers (CRP, IFN‐γ, IL‐1α, IL‐1β, IL‐6, IL‐8, IL‐10, IL‐17A, IL‐22, sTNFRI, and sTNFRII) were assayed; CRF was measured with the Multidimensional Fatigue Inventory. Hybrid linear mixed models disentangled between‐ and within‐subject associations, controlling for sociodemographic (e.g., age), clinical (e.g., cancer treatment), and lifestyle covariates (e.g., BMI), sleep quality, and pain. A normative age‐ and sex matched sample ( n  = 204; 52.5% male; age = 64.3 years) was included for comparison. Soluble TNF receptors (sTNFRI/II) were most robustly and positively associated with nearly all fatigue dimensions. CRP was positively associated with mental and physical fatigue; IL‐8 positively associated with multiple domains including reduced motivation; and IFN‐γ positively associated with general fatigue and reduced activity. Lower IL‐1α was associated with more mental fatigue. Between‐subject effects mirrored overall results; within‐subject effects were more selective. Associations were most consistently observed for mental fatigue. In controls, less associations were significant; CRP was the most robust marker and positively associated with general fatigue, reduced activity, and reduced motivation. CRC survivors exhibited a broader, mostly TNF‐α driven inflammatory signature of fatigue than controls. Findings highlight inflammation as a potential target underlying CRF, informing survivorship care strategies.