Inflammation and cancer-related fatigue: Mechanisms, contributing factors, and treatment implications

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Abstract

Fatigue is one of the most common and distressing side effects of cancer and its treatment, and may persist for years after treatment completion in otherwise healthy survivors. Guided by basic research on neuro-immune interactions, a growing body of research has examined the hypothesis that cancer-related fatigue is driven by activation of the pro-inflammatory cytokine network. In this review, we examine the current state of the evidence linking inflammation and cancer-related fatigue, drawing from recent human research and from experimental animal models probing effects of cancer and cancer treatment on inflammation and fatigue. In addition, we consider two key questions that are currently driving research in this area: what are the neural mechanisms of fatigue, and what are the biological and psychological factors that influence the onset and/or persistence of inflammation and fatigue in cancer patients and survivors? Identification of the mechanisms driving cancer-related fatigue and associated risk factors will facilitate the development of targeted interventions for vulnerable patients.

Highlight

► This review examines the current state of the evidence linking inflammation and cancer-related fatigue, and considers neural mechanisms and risk factors.

Introduction

Fatigue is increasingly recognized as one of the most common and distressing side effects of cancer and its treatment (Lawrence et al., 2004). Prevalence estimates of fatigue during cancer treatment range from 25% to 99% depending on the sample, type of treatment, and method of assessment (Servaes et al., 2002, Lawrence et al., 2004). Energy typically improves in the year after treatment completion, although a significant minority of patients continue to experience fatigue for months or years after successful treatment (Bower et al., 2000, Cella et al., 2001). Studies of long-term cancer survivors suggest that approximately one-quarter to one-third experience persistent fatigue for up to 10 years after cancer diagnosis (Bower et al., 2006, Servaes et al., 2006). Fatigue has a negative impact on work, social relationships, mood, and daily activities and causes significant impairment in overall quality of life (Andrykowski et al., 1998, Bower et al., 2000, Broeckel et al., 1998). Fatigue may also be a predictor of shorter survival in cancer patients (Groenvold et al., 2007).

Qualitative reports suggest that cancer-related fatigue is more severe, more enduring, and more debilitating than “normal” fatigue caused by lack of sleep or overexertion and is not relieved by adequate sleep or rest (Poulson, 2001). In addition, cancer-related fatigue involves mental, physical, and emotional components. One definition that captures several of the key features of cancer-related fatigue describes it as “a subjective state of overwhelming and sustained exhaustion and decreased capacity for physical and mental work that is not relieved by rest” (Cella et al., 1998).

Studies conducted over the past decade have begun to elucidate the biological underpinnings of cancer-related fatigue, with a focus on inflammation. This research is motivated by basic research on neural-immune signaling, which indicates that pro-inflammatory cytokines can signal the central nervous system to generate symptoms of fatigue and other behavioral changes in animals and healthy humans (Dantzer et al., 2008). In the cancer context, inflammation may be induced by common cancer treatments, including radiation and chemotherapy, or by the tumor itself. Previous reviews of this literature have generally supported a link between inflammation and behavioral symptoms in cancer patients, including fatigue (Miller et al., 2008a, Schubert et al., 2007, Seruga et al., 2008, Bower, 2007). This is a growing area of research that has seen important advances in methodological rigor (e.g., larger sample sizes, controls for confounders, advanced statistical methods) and examination of underlying mechanisms. In this review we will examine the current state of the evidence linking inflammation and cancer-related fatigue, drawing from recent human research and from experimental animal models probing effects of cancer and cancer treatment on inflammation and fatigue. We will then consider two key questions that are currently driving research in this area. First, what are the neural underpinnings of fatigue, and can they be discriminated from depression? Second, what are the biological and psychological factors that contribute to inflammation and fatigue during and after treatment? We conclude with implications for interventions and recommendations for future research.

Section snippets

Human and animal research on inflammation and cancer-related fatigue

We consider human and animal studies that have examined links between inflammation and fatigue at three stages of the cancer continuum: before, during, and after cancer treatment. The basic model guiding this area of research is that tumors and the treatments used to eradicate them can activate the proinflammatory cytokine network, leading to symptoms of fatigue via effects on the central nervous system (see Fig 1). In the pre-treatment period, the tumor itself may be a source for

Lessons from research on sickness behavior and depression

To date, there is limited understanding of the neural processes that may mediate effects of peripheral inflammation on behavioral outcomes, including fatigue, in cancer patients. However, insight into these effects can be gleaned from the large array of information that has accrued over the last 25 years on inflammation-induced sickness behavior and major depressive disorder (MDD). For example, careful research into IFN-α treatment has shown that 30–50% of patients on this therapy can develop a

Biobehavioral factors that influence inflammation and cancer-related fatigue

As described previously, the basic model underlying research on inflammation and cancer-related fatigue suggests that tumors and the treatments used to treat them activate pro-inflammatory cytokines, leading to fatigue. However, there is considerable variability in the extent of the inflammatory response and in the experience of fatigue in cancer populations. This is particularly evident in the post-treatment period, with some patients reporting high and persistent fatigue symptoms and other

Conclusions, recommendations, and implications for treatment

The evolving literature on cancer-related fatigue increasingly supports the hypothesis that inflammation is associated with fatigue symptoms in cancer populations. The evidence linking inflammation and fatigue in cancer survivors is particularly strong, with consistent findings emerging from large, well-controlled studies of breast cancer survivors. At this point, there are no well-established animal models of cancer-related fatigue, which limits our ability to probe the underlying mechanisms

Conflict of Interest

The authors of this manuscript have nothing to declare.

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