TY - JOUR
T1 - Association of fatigue and depression with circulating levels of proinflammatory cytokines and epidermal growth factor receptor ligands
T2 - A correlative study of a placebo-controlled fatigue trial
AU - Rich, Tyvin
AU - Zhao, Fengmin
AU - Cruciani, Ricardo A.
AU - Cella, David
AU - Manola, Judith
AU - Fisch, Michael J.
N1 - Funding Information:
The authors wish to acknowledge the work of Dr. Mehmet Koc and the laboratory facilities of Dr. Jeffery Lisiak at the University of Virginia for the cytokine assays. This study was conducted by the Eastern Cooperative Oncology Group and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA49957, CA39229, and CA104362 from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. These data were previously presented at the Annual Meeting of the American Society of Clinical Oncology in 2011.
Publisher Copyright:
© 2017 Rich et al.
PY - 2017/1/31
Y1 - 2017/1/31
N2 - 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.
AB - 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.
KW - Cancer
KW - Circadian-signaling pathways
KW - Depression
KW - Fatigue
KW - Placebo effect
KW - Proinflammatory cytokine
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U2 - 10.2147/CMAR.S115835
DO - 10.2147/CMAR.S115835
M3 - Article
C2 - 28203105
AN - SCOPUS:85011954023
SN - 1179-1322
VL - 9
SP - 1
EP - 10
JO - Cancer Management and Research
JF - Cancer Management and Research
ER -
