Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism?

Cleeland, Charles S.; Bennett, Gary J.; Dantzer, Robert; Dougherty, Patrick M.; Dunn, Adrian J.; Meyers, Christina A.; Miller, Andrew H.; Payne, Richard; Reuben, James M.; Wang, Xin Shelley; Lee, Bang Ning

doi:10.1002/cncr.11382

Cited by 471 publications

(362 citation statements)

References 60 publications

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“…Affective and constitutional symptoms in cancer patients show clustering patterns that suggest distinct and shared biological mechanisms in their production (8). Evidence from multiple disciplines (infectious disease, endocrinology, immunology, and neuroscience; ref.…”

Section: Discussionmentioning

confidence: 99%

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

Rich

Innominato

Boerner

et al. 2005

Clinical Cancer Research

228

178

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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.

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Section: Discussionmentioning

confidence: 99%

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

Rich

Innominato

Boerner

et al. 2005

Clinical Cancer Research

228

178

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“…This cluster effect has been compared with the pro-inflammatory-driven cytokine-induced sickness behavior seen in animal models. However, currently the role of systemic inflammation in the genesis of multiple cancer symptoms is not understood [7].…”

Section: Introductionmentioning

confidence: 99%

The Systemic Inflammatory Response and Its Relationship to Pain and Other Symptoms in Advanced Cancer

et al. 2013

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Introduction. Inflammation has been identified as a hallmark of cancer and may be necessary for tumorgenesis and maintenance of the cancer state. Inflammation‐related symptoms are common in those with cancer; however, little is known about the relationship between symptoms and systemic inflammation in cancer. The aim of the present study was to examine the relationship between symptoms and systemic inflammation in a large cohort of patients with advanced cancer. Methods. Data from an international cohort of patients with advanced cancer were analyzed. Symptoms and patient‐related outcomes were recorded using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire—Core Questionnaire. Systemic inflammation was assessed using C‐reactive protein levels. The relationship between these symptoms and systemic inflammation was examined using Spearman rank correlation (ρ) and the Mann‐Whitney U test. Results. Data were available for 1,466 patients across eight European countries; 1,215 patients (83%) had metastatic disease at study entry. The median survival was 3.8 months (interquartile range [IQR] 1.3–12.2 months). The following were associated with increased levels of inflammation: performance status (ρ = .179), survival (ρ = .347), pain (ρ = .154), anorexia (ρ = .206), cognitive dysfunction (ρ = .137), dyspnea (p= .150), fatigue (ρ = .197), physical dysfunction (ρ = .207), role dysfunction (ρ = .176), social dysfunction (ρ = .132), and poor quality of life (ρ = .178). All were statistically significant at p < .001. Conclusion. The results show that the majority of cancer symptoms are associated with inflammation. The strength of the potential relationship between systemic inflammation and common cancer symptoms should be examined further within the context of an anti‐inflammatory intervention trial.

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“…Several inflammatory mediators have been linked to altered central nervous system activity, including interleukin (IL)-1h, IL-6, and tumor necrosis factor-a (TNF-a; refs. 10,11), and alterations in proinflammatory cytokines have been found in fatigue-related disorders, such as depression and chronic fatigue syndrome (12 -14). Such results suggest that persistent unexplained fatigue in breast cancer survivors could stem from an underlying longterm alteration in inflammatory biology.…”

mentioning

confidence: 99%

Inflammatory Biomarkers for Persistent Fatigue in Breast Cancer Survivors

Collado-Hidalgo¹,

Bower

Ganz

et al. 2006

Clinical Cancer Research

347

263

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Purpose: This study seeks to define immunologic and inflammatory variables associated with persistent post-treatment fatigue in breast cancer survivors. Experimental Design: Leukocyte subsets, plasma inflammatory markers, and ex vivo proinflammatory cytokine production were assessed in 50 fatigued and nonfatigued breast cancer survivors recruited z2 years after successful primary therapy. Multivariate statistical analyses were used to define a composite immunologic biomarker of fatigue risk. Results: Fatigued breast cancer survivors were distinguished from nonfatigued survivors by increased ex vivo monocyte production of interleukin (IL)-6 and tumor necrosis factor-a following lipopolysaccharide stimulation, elevated plasma IL-1ra and soluble IL-6 receptor (sIL-6R/CD126), decreased monocyte cell-surface IL-6R, and decreased frequencies of activated T lymphocytes and myeloid dendritic cells in peripheral blood (all P < 0.05). An inverse correlation between sIL-6R and cell-surface IL-6R was consistent with inflammation-mediated shedding of IL-6R, and in vitro studies confirmed that proinflammatory cytokines induced such shedding. Multivariate linear discriminant function analysis identified two immunologic markers, the ratio of sIL-6R to monocyte-associated IL-6R and decreased circulating CD69 + T lymphocytes, as highly diagnostic of fatigue (P = 0.0005), with cross-validation estimates indicating 87% classification accuracy (sensitivity = 0.83; specificity = 0.83). Conclusion: These results extend links between fatigue and inflammatory markers to show a functional alteration in proinflammatory cytokine response to lipopolysaccharide and define a prognostic biomarker of behavioral fatigue.

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Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism?

Cited by 471 publications

References 60 publications

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

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

The Systemic Inflammatory Response and Its Relationship to Pain and Other Symptoms in Advanced Cancer

Inflammatory Biomarkers for Persistent Fatigue in Breast Cancer Survivors

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