Named Series: Fatigue, Brain, Behavior, and Immunity
Sleep disturbance, cytokines, and fatigue in women with ovarian cancer

https://doi.org/10.1016/j.bbi.2012.04.003Get rights and content

Abstract

Pro-inflammatory cytokines, such as interleukin-6 (IL-6), have been implicated in the underlying processes contributing to sleep regulation and fatigue. Despite evidence for sleep difficulties, fatigue, and elevations in IL-6 among women with ovarian cancer, the association between these symptoms and IL-6 has not been investigated. To address this knowledge gap, we examined relationships between sleep disturbance, fatigue, and plasma IL-6 in 136 women with ovarian cancer prior to surgery. These relationships were also examined in 63 of these women who were disease-free and not receiving chemotherapy one year post-diagnosis. At both time-points, higher levels of IL-6 were significantly associated with sleep disturbances (p < 0.05), controlling for potentially confounding biological and psychosocial covariates. Higher IL-6 was significantly associated with fatigue prior to surgery (p < 0.05); however, when sleep disturbance was included in the model, the relationship was no longer significant. IL-6 was not significantly associated with fatigue at one year. Changes in sleep over time were significantly associated with percent change in IL-6 from pre-surgery to one year, adjusting for covariates (p < 0.05). These findings support a direct association of IL-6 with sleep disturbances in this population, whereas the relationship between IL-6 and fatigue prior to surgery may be mediated by poor sleep. As this study is the first to examine cytokine contributions to sleep and fatigue in ovarian cancer, further research is warranted to clarify the role of biological correlates of sleep and fatigue in this population.

Highlight

► We examined relationships at two time points between sleep, fatigue, and interleukin-6 (IL-6) in ovarian cancer patients. ► Higher levels of IL-6 were associated with greater sleep disturbance at pre-surgery and one year post diagnosis. ► The association between IL-6 and fatigue at pre-surgery was no longer significant when controlling for sleep. ► Changes in sleep over time were associated with percent change in IL-6 from pre-surgery to one year.

Introduction

High levels of both sleep disturbances and fatigue have been documented in women with ovarian cancer (Clevenger et al., under review, Anderson and Hacker, 2008, Sandadi et al., 2011). The co-occurrence of these symptoms in oncology patients has been well established (Roscoe et al., 2007) and both of these symptoms have been associated with poor quality of life in ovarian (Sandadi et al., 2011, Clevenger et al., under review, Holzner et al., 2003) and other cancer populations (Fiorentino and Ancoli-Israel, 2007, Ancoli-Israel et al., 2001).

Although inflammatory cytokines have been associated with both fatigue and sleep disturbances, the role of inflammatory cytokines with respect to these burdensome symptoms has not been investigated in ovarian cancer, a disease characterized by high levels of systemic pro-inflammatory cytokines that are thought to be tumor-derived (Tempfer et al., 1997). Pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are implicated in the regulation of sleep (Opp and Toth, 2003), modulation of sleep architecture (Kapás et al., 1992, Opp et al., 1991), and appear to be involved in circadian regulation of sleep as well (Guess et al., 2009, Vgontzas et al., 2005). Sleep deprivation increases monocyte production of IL-6 (Irwin et al., 2006), and a daytime nap decreases IL-6 in individuals with nighttime sleep loss (Vgontzas et al., 2007), leading to suggestions of a bi-directional feedback loop between sleep and cytokine expression (Irwin, 2002).

Presence of fatigue has been described as a “pre-diagnostic symptom” for ovarian cancer, as it is one of the most commonly reported recurring symptoms prior to diagnosis of ovarian cancer (Goff et al., 2004, Goff et al., 2000). Though fatigue may be a consequence of poor sleep, cancer-related fatigue has been described as unique as it is persistent, intense, longer in duration, and not alleviated by rest as compared to more traditional fatigue (Bower, 2007). Tumor- and/or treatment-associated cytokines have a proposed role in cancer-related fatigue via effects on central nervous system pathways that elicit vegetative behaviors (Collado-Hidalgo et al., 2006, Bower et al., 2002, Scott et al., 2002, Dantzer, 2001). Supporting such hypotheses are findings that fatigued breast cancer survivors demonstrated significantly higher elevations of cytokines including IL-1ra, TNF-α, sTNF-RII, IL-6 and neopterin than non-fatigued survivors (Bower et al., 2002, Collado-Hidalgo et al., 2006, Bower, 2007), and circulating levels of IL-6, IL-1ra, and neopterin have been associated with fatigue in a quantitative review of cancer patients (Schubert et al., 2007).

Although the presence of sleep disturbances and fatigue has been well documented in women with ovarian cancer, biological and psychological mechanisms which may contribute to fatigue and sleep problems in ovarian cancer are poorly understood. To better understand these mechanisms, this study examined associations between circulating levels of IL-6, and self-reported symptoms of fatigue and disturbed sleep in ovarian cancer patients. We hypothesized that higher levels of IL-6 would be associated with greater fatigue and greater sleep disturbance, and that IL-6 would be associated with fatigue, independent of sleep disturbance. These hypotheses were examined prior to surgery, when effects of tumor-derived cytokines would not be confounded with the effects of chemotherapy, and at one year following surgery when participating patients had completed adjuvant treatment and showed no evidence of disease. We also investigated whether changes over time in IL-6 would be associated with changes over time in sleep and fatigue.

Section snippets

Participants

Women with a pelvic mass suspicious for ovarian cancer were recruited at a pre-surgical clinic visit as part of a larger study examining psychosocial factors, pro-angiogenic biomarkers and cancer progression. Exclusion criteria included use of systemic corticosteroid medication in the previous month, history of previous cancer, current pregnancy, inability to accurately answer questions (dementia), presence of a comorbid condition with known effects on the immune system, age less than 18 years,

Participant characteristics

At baseline, the 136 participants were primarily married, non-Hispanic Caucasians with a mean age of 60.4 years. The majority of participants had advanced stage and high grade disease (Table 1). As seen in Table 2, levels of IL-6 dropped substantially from pre-surgery to one year (p < 0.001). Mean levels of fatigue also decreased from pre-surgery to one year (p = 0.03). However, global sleep disturbance decreased only minimally over this time period (p = 0.41), with means at one year remaining above

Discussion

Ovarian cancer patients report sleep disturbances which do not significantly improve between pre-surgery and one year follow up, and elevated levels of IL-6 in peripheral blood were associated with poorer sleep at both time points. These relationships were independent of potentially confounding clinical covariates as well as depressive mood and thought intrusions. Fatigue symptoms significantly decreased from pre-surgery to one year. The relationship between IL-6 and fatigue was significant at

Acknowledgments

We gratefully acknowledge Bridget Zimmerman, Ph.D. for statistical assistance, and Katherine Collins, B.A. for assistance in data collection.

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    This research was funded in part by support from NIH Grants CA104825 and CA140933 to SL.

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