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Association of fatigue and depression with circulating levels of proinflammatory cytokines and epidermal growth factor receptor ligands: a correlative study of a placebo-controlled fatigue trial

Authors Rich T, Zhao F, Cruciani RA, Cella D, Manola J, Fisch MJ

Received 26 June 2016

Accepted for publication 28 November 2016

Published 31 January 2017 Volume 2017:9 Pages 1—10

DOI https://doi.org/10.2147/CMAR.S115835

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Akshita Wason

Peer reviewer comments 3

Editor who approved publication: Dr Kenan Onel


Tyvin Rich,1,* Fengmin Zhao,2,* Ricardo A Cruciani,3 David Cella,4 Judith Manola,2 Michael J Fisch5

1Hampton University Proton Therapy Institute, Hampton, VA, 2Dana-Farber Cancer Institute, Boston, MA, 3Beth Israel Medical Center, New York, NY, 4Northwestern University Feinberg School of Medicine, Chicago, IL, 5The University of Texas MD Anderson Cancer Center, Houston, TX, USA

*These authors contributed equally to this work

Context: The biology of fatigue and depression in cancer patients is poorly understood. Hypotheses regarding cytokines and growth factors related to sickness behavior and disruption of circadian signaling have been proposed.
Objectives: We prospectively examined proinflammatory cytokines (e.g., sickness behavior model) and epidermal growth factor receptor (EGFR) ligands (e.g., circadian disruption model) in the serum of cancer patients enrolled in a clinical trial testing levocarnitine for fatigue.
Methods: Serum samples were collected at baseline and week 4. Cytokine/growth factor analyses were performed with a Luminex analyzer. The Brief Fatigue Index and the Center for Epidemiologic Studies Depression Index were used to measure fatigue and depression severity. The association between cytokine and symptoms was examined using logistic models.
Results: Among 101 analyzable patients, all ten cytokines/growth factors examined were highly elevated at baseline and all significantly decreased at week 4 (p<0.001) regardless of treatment intervention. At baseline, the odds of severe fatigue significantly increased for patients with higher level of interleukin-1 receptor antagonist (IL-1Ra), whereas patients with higher levels of IL-1Ra, tumor necrosis factor-α, interleukin (IL)-6, IL-8, interferon-γ, transforming growth factor α, and vascular endothelial growth factor had higher odds of severe depression. At week 4, fatigue (p=0.023) and depression (p=0.007) responders had less decrease in IL-1 level than the corresponding non-responders.
Conclusion: In this correlative analysis of a fatigue clinical trial, levels of fatigue were significantly associated with levels of IL-1 and IL-1Ra. Circadian-signaling pathways related to EGFR signaling were correlated with depression as were other cytokines. A major placebo effect was associated with a global decrease in cytokine and growth factors. These data provide further basis for testing hypotheses regarding the mechanisms of fatigue and depression in cancer patients.

Keywords: fatigue, depression, proinflammatory cytokine, circadian-signaling pathways, cancer, placebo effect

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