How relevant are cytokines in colorectal cancer wasting?

Purpose: The purpose of this article was to investigate the influence of inflammatory cytokines, pro-cachectic (interleukin [IL]-1 receptor agonist [IL-1ra], IL-6, and tumor necrosis factor-α [TNF-α]), immunomodulatory (IL-10 and interferon-γ [IFN-γ]), and pro-angiogenic (vascular endothelial growth factor [VEGF]), on resting energy expenditure (REE), weight, and nutritional intake and to explore potential interactions between their circulating concentrations and colorectal cancer stage/histologic differentiation and response to radiotherapy (RT). Patients and methods: This was a prospective longitudinal study in 101 patients evaluated before and after neoadjuvant RT, including REE (indirect calorimetry), percent weight loss, usual/current diet (diet history and 24-hour recall), serum concentrations of cytokines (enzyme-linked immunosorbent assay), and RT response. Results: Stages III/IV were often associated with histologic grades 2/3 (P < 0.01), albeit both characteristics independently were associated with higher concentrations of IL-1ra (P ĝ‰Currency sign 0.05), IL-6 (P ĝ‰Currency sign 0.02), TNF-α (P ĝ‰Currency sign 0.05), IFN-γ3 (P ĝ‰Currency sign 0.05), and VEGF (P < 0.03). Before and after RT, higher REE, weight loss ĝ‰¥5%, and intake reduction ĝ‰¥25% were associated with advanced stage, histologic grades 2/3, higher IL-1ra, IL-6, TNF-α, IFN-γ, and VEGF, and nonresponse to RT (P ≤ 0.003). A general linear model analysis showed that stages III/IV, histologic grades 2/3, and higher IL-1ra, IL-6, TNF-α, IFN-γ, and VEGF were major determinants of REE increase, weight loss, and intake reduction. In predictive value analyses, higher baseline pro-cachectic cytokines (IL-1ra + IL-6 + TNF-α) by themselves predicted increased REE (hazard ratio [HR]: 8.25; 95% CI: 2.74ĝ€"26.47; P < 0.002), greater weight loss (HR: 8.15; 95% CI: 2.22ĝ€"25.40; P < 0.002), and intake reductions (HR: 7.15; 95% CI: 2.25ĝ€"16.11; P < 0.004) after RT. Conclusion: This study confirms the fact that wasting in colorectal cancer is correlated with tumor burden and histologic aggressiveness and suggests that both characteristics lead to overproduction of IFN-γ, VEGF, and pro-cachectic cytokines, all of which may cause higher metabolic rates, poor intake, and nonresponse to RT.