This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rich, T. Articles by Lévi, F. Search for Related Content PubMed PubMed Citation Articles by Rich, T. Articles by Lévi, F.

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

This article has been cited by other articles:

				S. K. Lutgendorf, A. Z. Weinrib, F. Penedo, D. Russell, K. DeGeest, E. S. Costanzo, P. J. Henderson, S. E. Sephton, N. Rohleder, J. A. Lucci III, et al. Interleukin-6, Cortisol, and Depressive Symptoms in Ovarian Cancer Patients J. Clin. Oncol., October 10, 2008; 26(29): 4820 - 4827. [Abstract] [Full Text] [PDF]

				D. Spiegel Losing Sleep Over Cancer J. Clin. Oncol., May 20, 2008; 26(15): 2431 - 2432. [Full Text] [PDF]

				A. H. Miller, S. Ancoli-Israel, J. E. Bower, L. Capuron, and M. R. Irwin Neuroendocrine-Immune Mechanisms of Behavioral Comorbidities in Patients With Cancer J. Clin. Oncol., February 20, 2008; 26(6): 971 - 982. [Abstract] [Full Text] [PDF]

				J. E. Bower Behavioral Symptoms in Patients With Breast Cancer and Survivors J. Clin. Oncol., February 10, 2008; 26(5): 768 - 777. [Abstract] [Full Text] [PDF]

				M. Fouladiun, U. Korner, L. Gunnebo, P. Sixt-Ammilon, I. Bosaeus, and K. Lundholm Daily Physical-Rest Activities in Relation to Nutritional State, Metabolism, and Quality of Life in Cancer Patients with Progressive Cachexia Clin. Cancer Res., November 1, 2007; 13(21): 6379 - 6385. [Abstract] [Full Text] [PDF]

				I. Iurisci, T. Rich, F. Levi, P. F. Innominato, N. Tinari, L. Irtelli, M. De Tursi, A. Grassadonia, and S. Iacobelli Relief of Symptoms After Gefitinib Is Associated With Improvement of Rest/Activity Rhythm in Advanced Lung Cancer J. Clin. Oncol., June 1, 2007; 25(16): e17 - e19. [Full Text] [PDF]

				J. L. Ryan, J. K. Carroll, E. P. Ryan, K. M. Mustian, K. Fiscella, and G. R. Morrow Mechanisms of Cancer-Related Fatigue Oncologist, May 1, 2007; 12(suppl_1): 22 - 34. [Abstract] [Full Text] [PDF]

				X.M. Li and F. Levi Circadian Physiology Is a Toxicity Target of the Anticancer Drug Gemcitabine in Mice J Biol Rhythms, April 1, 2007; 22(2): 159 - 166. [Abstract] [PDF]

				F. Levi, E. Filipski, I. Iurisci, X. M. Li, and P. Innominato Cross-talks between Circadian Timing System and Cell Division Cycle Determine Cancer Biology and Therapeutics Cold Spring Harb Symp Quant Biol, January 1, 2007; 72(0): 465 - 475. [Abstract] [PDF]

				D. Gholam, S. Giacchetti, C. Brezault-Bonnet, M. Bouchahda, D. Hauteville, R. Adam, B. Ducot, O. Ghemard, F. Kustlinger, C. Jasmin, et al. Chronomodulated Irinotecan, Oxaliplatin, and Leucovorin-Modulated 5-Fluorouracil as Ambulatory Salvage Therapy in Patients with Irinotecan- and Oxaliplatin-Resistant Metastatic Colorectal Cancer Oncologist, November 1, 2006; 11(10): 1072 - 1080. [Abstract] [Full Text] [PDF]

				S. Giacchetti, G. Bjarnason, C. Garufi, D. Genet, S. Iacobelli, M. Tampellini, R. Smaaland, C. Focan, B. Coudert, Y. Humblet, et al. Phase III Trial Comparing 4-Day Chronomodulated Therapy Versus 2-Day Conventional Delivery of Fluorouracil, Leucovorin, and Oxaliplatin As First-Line Chemotherapy of Metastatic Colorectal Cancer: The European Organisation for Research and Treatment of Cancer Chronotherapy Group J. Clin. Oncol., August 1, 2006; 24(22): 3562 - 3569. [Abstract] [Full Text] [PDF]