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-alpha [TNF-alpha]), immunomodulatory (IL-10 and interferon-gamma [IFN-gamma]), 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 </= 0.05), IL-6 (P </= 0.02), TNF-alpha (P </= 0.05), IFN-gamma (P </= 0.05), and VEGF (P < 0.03). Before and after RT, higher REE, weight loss >/=5%, and intake reduction >/=25% were associated with advanced stage, histologic grades 2/3, higher IL-1ra, IL-6, TNF-alpha, IFN-gamma, 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-alpha, IFN-gamma, 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-alpha) by themselves predicted increased REE (hazard ratio [HR]: 8.25; 95% CI: 2.74-26.47; P < 0.002), greater weight loss (HR: 8.15; 95% CI: 2.22-25.40; P < 0.002), and intake reductions (HR: 7.15; 95% CI: 2.25-16.11; 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-gamma, VEGF, and pro-cachectic cytokines, all of which may cause higher metabolic rates, poor intake, and nonresponse to RT.