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Mechanisms of Cancer Related Fatigue

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Pathobiology of Cancer Regimen-Related Toxicities

Abstract

One of the most prevalent and distressing symptoms associated with cancer and cancer therapy is fatigue. Fatigue significantly impairs patients’ quality of life and in some cases may last years following treatment. Despite a clear need, there is currently no pharmaceutical therapy approved to treat fatigue. Development of treatments for fatigue would benefit from an understanding of the mechanisms driving fatigue. While the mechanism of fatigue is unknown, recent research has led to several plausible hypotheses. This chapter reviews the hypothesized mechanisms of fatigue and the strength of evidence for each. There are multiple factors that are likely to influence fatigue including tumor burden, treatment, and psychological reactions associated with cancer diagnosis. Each of these influences has several physiological effects which may act independently or may converge on related pathways to produce fatigue. Anemia, cytokine dysregulation, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, serotonin dysregulation, adenosine triphosphate depletion, and impaired neurogenesis are all possible outcomes of cancer and cancer treatment which may impact fatigue. Of these, the interplay between cytokines and the HPA axis are particularly intriguing. The influence of cytokines on behavior has been extensively studied in animal models which have demonstrated that an increase in proinflammatory cytokines leads to a suite of symptoms called “sickness behaviors” which are similar to human symptoms of fatigue (i.e., listlessness, lethargy, and decreased consumatory behavior). Cytokines are partially regulated by the HPA axis. The HPA axis is part of the neuroendocrine system which controls reactions to stressors and regulates homeostasis of body processes including the immune system, mood, and energy storage. Given the large number of stressors related to a diagnosis of cancer, patients may experience dysregulation of the HPA axis due to chronic stress. Therefore, increases in cytokines, combined with deregulation of cytokines from the HPA axis, and chronic activation of the HPA axis may cause fatigue. Clinically, this hypothesis is supported by evidence of elevated cytokines and abnormal levels of the stress hormone cortisol in cancer patients. However, further evidence is needed to conclusively determine the mechanisms of fatigue.

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  1. Biomodels, LLC, Watertown, MA, USA

    Jonathan A. Zombeck Ph.D.

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  1. Brigham and Women’s Hospital, Francis Street 75, Boston, 01778, Massachusetts, USA

    Stephen T. Sonis

  2. Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, South Australia, Australia

    Dorothy M. Keefe

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Zombeck, J.A. (2013). Mechanisms of Cancer Related Fatigue. In: Sonis, S., Keefe, D. (eds) Pathobiology of Cancer Regimen-Related Toxicities. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5438-0_12

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