Elevated Serum Cytokines Correlated with Altered Behavior, Serum Cortisol Rhythm, and Dampened 24-Hour Rest-Activity Patterns in Patients with Metastatic Colorectal Cancer

Abstract

Purpose: Incapacitating symptom burden in cancer patients contributes to poor quality of life (QOL) and can influence treatment outcomes because of poor tolerance to therapy. In this study, the role of circulating cytokines in the production symptoms in cancer patients is evaluated.Experimental Design: Eighty patients with metastatic colorectal cancer with either normal (group I, n = 40) or dampened (group II, n = 40) 24-hour rest/ /activity patterns measured by actigraphy were identified. Actigraphy patterns were correlated with QOL indices, serum cortisol obtained at 8:00 a.m. and 4:00 p.m. and with serum levels of transforming growth factor-A, tumor necrosis factor-A, and interleukin 6 (IL-6) obtained at 8:00 a.m. and analyzed in duplicate by ELISA. Cytokine levels and survival were also correlated.Results: Group II patients had significantly higher pre treatment levels of all three cytokines, displayed significantly poorer emotional and social functioning, had higher fatigue, more appetite loss, and poorer performance status compared with group I patients. Transforming growth factor-A (TGF-A) and IL-6 were significantly increased in the patients with WHO performance status >1 and in those with appetite loss. Fatigue was significantly associated with elevated TGF-A only. IL-6 was increased in those patients with extensive liver involvement and multiple organ replacement, and it was significantly correlated with dampened cortisol rhythm. In a multivariate analysis, IL-6 was correlated with poor treatment outcome.Conclusions: Significant correlations were found between serum levels of TGF-A and IL-6, circadian patterns in wrist activity and serum cortisol and tumor-related symptoms in patients with metastatic colorectal cancer. These data support the hypothesis that some cancer patient's symptoms of fatigue, poor QOL, and treatment outcome are related to tumor or host generated cytokines and could reflect cytokine effects on the circadian timing system. This interplay between cytokine signaling pathways, the hypothalamicpituitary-adrenal axis, the autonomic nervous system, and efferent pathways of the suprachiasmatic nucleus that control circadian physiology, opens the way to new rational interventions for symptom management in cancer patients.

Cross-talks between Circadian Timing System and Cell Division Cycle Determine Cancer Biology and Therapeutics

“…Significant correlations were found between serum levels of TGF-α and IL-6, circadian patterns in wrist activity, and serum cortisol and tumor-related symptoms in 80 patients with metastatic colorectal cancer. These data support clinically relevant links between tumor cytokines and the circadian timing system (Rich et al 2005;Rich 2007). …”

Chronomodulated Irinotecan, Oxaliplatin, and Leucovorin-Modulated 5-Fluorouracil as Ambulatory Salvage Therapy in Patients with Irinotecan- and Oxaliplatin-Resistant Metastatic Colorectal Cancer

“…In our study also, chronoIFLO was also safe in older patients with a PS score <2. The activity and acceptable tolerability of chronoIFLO could relate to persistent circadian physiology in MCRC patients with a good PS score, as revealed by strong 24-hour rhythms in rest/activity and plasma cortisol in these patients [33,38,39]. Conversely, ablated circadian physiology constituted a poor prognostic factor for patients with metastatic cancer from colorectal as well as breast origin [33,[38][39][40].…”

“…The activity and acceptable tolerability of chronoIFLO could relate to persistent circadian physiology in MCRC patients with a good PS score, as revealed by strong 24-hour rhythms in rest/activity and plasma cortisol in these patients [33,38,39]. Conversely, ablated circadian physiology constituted a poor prognostic factor for patients with metastatic cancer from colorectal as well as breast origin [33,[38][39][40]. Similarly, tumors grew faster in rodent models with circadian physiology that had been ablated through clock gene mutation or environmental alterations [41][42][43].…”

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

“…Animal studies have identified several ligands of interest, including TGF-a, prokinectin-2 (PK2; a molecule closely related to endocrine tissue VEGF), and cardiotropin-like cytokine (Clc; a molecule related to the proinflammatory cytokine interleukin 6). Although currently no clinical data support these associations in patients with RCC, clinical observations have linked elevated levels of TGF-a with fatigue, appetite loss, and flattened circadian rhythms in patients with metastatic colorectal cancer (17).…”