Article

Fatigue and sleep quality are associated with changes in inflammatory markers in breast cancer patients undergoing chemotherapy

Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093-0733, USA.
Brain Behavior and Immunity (Impact Factor: 6.13). 03/2012; 26(5):706-13. DOI: 10.1016/j.bbi.2012.02.001
Source: PubMed

ABSTRACT Fatigue and sleep disturbances are two of the most common and distressing symptoms reported by cancer patients. Fatigue and sleep are also correlated with each other. While fatigue has been reported to be associated with some inflammatory markers, data about the relationship between cancer-related sleep disturbances and inflammatory markers are limited. This study examined the relationship between fatigue and sleep, measured both subjectively and objectively, and inflammatory markers in a sample of breast cancer patients before and during chemotherapy. Fifty-three women with newly diagnosed stage I-III breast cancer scheduled to receive at least four 3-week cycles of chemotherapy participated in this longitudinal study. Fatigue was assessed with the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and objective sleep was measured with actigraphy. Three inflammatory markers were examined: Interleukin-6 (IL-6), Interleukin-1 receptor antagonist (IL-1RA) and C-reactive protein (CRP). Data were collected before (baseline) and during cycle 1 and cycle 4 of chemotherapy. Compared to baseline, more fatigue was reported, levels of IL-6 increased and IL-1RA decreased during chemotherapy. Reports of sleep quality remained poor. Mixed model analyses examining changes from baseline to each treatment time point revealed overall positive relationships between changes in total MFSI-SF scores and IL-6, between changes in total PSQI scores and IL-6 and IL-1RA, and between total wake time at night and CRP (all p's<0.05). These relationships suggest that cancer-related fatigue and sleep disturbances may share common underlying biochemical mechanisms.

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    • "To examine the relationship among chemotherapy, methylation status, inflammation and fatigue, outcome variables used were fatigue , as measured by MFI score, and log-transformed concentrations of sTNFR2 and IL-6, based on their association with fatigue in previous studies including our own (Bower et al., 2011; Liu et al., 2012; Torres et al., 2013). Each outcome was tested for association with chemotherapy and with methylation level (b-values) of CpG sites passing Bonferroni significance in the chemotherapy-methylation association tests. "
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    ABSTRACT: Inflammation has been associated with fatigue during and after various types of breast cancer treatments. We examined whether prior chemotherapy was associated with DNA methylation patterns that could explain persisting inflammation and/or fatigue in women treated for breast cancer. Prior to breast radiation therapy, DNA was extracted from peripheral blood mononuclear cells (PBMCs) of 61 Stage 0-IIIA breast cancer patients who had received partial mastectomy with or without chemotherapy. DNA methylation was assessed at >485,000 CpG sites across the genome along with fatigue and plasma inflammatory markers previously associated with fatigue. Compared to non-chemotherapy-treated women, women who had received chemotherapy exhibited significantly decreased methylation at eight CpG sites (p<1.03x10-7) including four in exon 11 of transmembrane protein 49 (TMEM49), which demonstrated the largest decreases in methylation. Lower methylation at each identified CpG site was associated with increased plasma soluble tumor necrosis factor receptor 2 (sTNFR2) and interleukin (IL)-6 and mediated the relationship between chemotherapy and increases in these inflammatory biomarkers adjusting for multiple clinical and treatment characteristics. sTNFR2, but not CpG methylation status, was correlated with fatigue. Six months after breast radiation therapy, DNA methylation, inflammatory biomarkers and fatigue assessments were repeated in a subset of subjects (N=39). Reduced methylation in 4 of the 8 identified CpG sites was still observed in chemotherapy versus non-chemotherapy-treated patients, albeit with some decay indicating the dynamic and potentially reversible nature of the changes. Reduced methylation in these 4 CpG sites also continued to correlate with either increased sTNFR2 or IL-6, but not fatigue. In conclusion, prior chemotherapy treatment was associated with decreased methylation of CpG sites in DNA from PBMCs of breast cancer patients, which correlated with increased inflammatory markers prior to and 6 months after radiation therapy. Persisting epigenetic changes secondary to chemotherapy may be one factor that contributes to inflammation and its consequences including cancer-related fatigue in vulnerable breast cancer patients.
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    • "In other studies, the depressive coping style of patients with lung cancer correlated with decreased survival (Faller, 1999), and major depression was associated with worse survival in patients with non-small cell lung carcinoma (Pirl et al., 2012). Chemotherapy is associated with increased pro-infl ammatory cytokine levels, which may persist for quite a long time, and these increases may be associated with fatigue and sleep disturbance during chemotherapy treatment (Liu et al., 2012a, 2012b; Mills et al., 2004, 2008; Wang et al., 2010). "
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    ABSTRACT: Abstract The prevalence of depressive symptoms in patients with cancer exceeds that observed in the general population and depression is associated with a poorer prognosis in cancer patients. The increased prevalence is not solely explained by the psychosocial stress associated with the diagnosis. Pro-inflammatory cytokines, which induce sickness behaviour with symptoms overlapping those of clinical depression, are validated biomarkers of increased inflammation in patients with cancer. A growing literature reveals that chronic inflammatory processes associated with stress may also underlie depression symptoms in general, and in patients with cancer in particular. Therapeutic modalities, which are frequently poorly tolerated, are used in the treatment of cancer. These interventions are associated with inflammatory reactions, which may help to explain their toxicity. There is evidence that antidepressants can effectively treat symptoms of depression in cancer patients though the database is meager. Novel agents with anti-inflammatory properties may be effective alternatives for patients with treatment-resistant depression who exhibit evidence of increased inflammation.
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    • "Cytotoxic chemotherapy induces inflammatory cytokine production in macrophages in vitro and when administered to rodents (Elsea et al., 2008; Sauter et al., 2011; Wong et al., 2012; Wood et al., 2006). In clinical studies, elevated blood levels of IL-6 correlate with fatigue in cancer patients exposed to cytotoxic chemotherapy (Liu et al., 2012; Schubert et al., 2007). In addition, treatment for malignant melanoma with the cytokine interferon-α induces fatigue that is not responsive to antidepressant therapy (Capuron et al., 2002). "
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    ABSTRACT: Fatigue is the most common symptom related to cytotoxic chemotherapeutic treatment of cancer. Peripheral inflammation associated with cytotoxic chemotherapy is likely a causal factor of fatigue. The neural mechanisms by which cytotoxic chemotherapy associated inflammation induces fatigue behavior are not known. This lack of knowledge hinders development of interventions to reduce or prevent this disabling symptom. Infection induced fatigue/lethargy in rodents is mediated by suppression of hypothalamic orexin activity. Orexin is critical for maintaining wakefulness and motivated behavior. Though there are differences between infection and cytotoxic chemotherapy in some symptoms, both induce peripheral inflammation and fatigue. Based on these similarities we hypothesized that cytotoxic chemotherapy induces fatigue by disrupting orexin neuron activity. We found that a single dose of a cytotoxic chemotherapy cocktail (cyclophosphamide, adriamycin, 5-fluorouracil-CAF) induced fatigue/lethargy in mice and rats as evidenced by a significant decline in voluntary locomotor activity measured by telemetry. CAF induced inflammatory gene expression-IL-1R1 (p<0.001), IL-6 (p<0.01), TNFα (p<0.01), and MCP-1 (p<0.05) -in the rodent hypothalamus 6 to 24 hours after treatment during maximum fatigue/lethargy. CAF decreased orexin neuron activity as reflected by decreased nuclear cFos localization in orexin neurons 24 hours after treatment (p<0.05) and by decreased orexin-A in cerebrospinal fluid 16 hours after treatment (p<0.001). Most importantly, we found that central administration of1 μg orexin-A restored activity in CAF-treated rats (p<0.05). These results demonstrate that cytotoxic chemotherapy induces hypothalamic inflammation and that suppression of hypothalamic orexin neuron activity has a causal role in cytotoxic chemotherapy-induced fatigue in rodents.
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