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

Departments of ¹ Radiation Oncology and ² Microbiology, University of Virginia Health System, Charlottesville, Virginia; ³ Institut National de la Sante et de la Recherche Medicale E0354 Chonothérapeutique des Cancers, Université Paris XI and Service de Cancérologie, Paul Brousse Hopital, Villejuif, France; ⁴ Laboratory of Molecular Oncology, Department of Oncology and Neurosciences, G. d'Annunzio University of Chieti, Chieti, Italy; and ⁵ European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium

Requests for reprints: Tyvin Rich, Department of Radiation Oncology, University of Virginia Health System, Charlottesville, VA. Phone: 434-924-5191; Fax: 434-982-3262; E-mail: tar4d{at}virginia.edu.

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-, tumor necrosis factor-, 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- (TGF-) 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- 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- 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 hypothalamic-pituitary-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.

Key Words: TGF- • IL-6 • actigraphy • HPA • quality of life

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