Fatigue is a common distressing effect of cancer.1 It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors alike. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”2 CRF differs from fatigue reported by individuals without cancer in that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, with estimates ranging between 25% and 99%.2,3 The methods used for screening patients for fatigue and the characteristics of the patient groups may account for this variability.
The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of multiple mechanisms contributing to fatigue in an individual patient.
CENTRAL NERVOUS SYSTEM DISTURBANCES
The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores.4 Increased levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF.5 However, there is not enough evidence at this time to support central nervous system disturbance as the main factor contributing to fatigue in cancer patients.
CIRCADIAN RHYTHM DYSREGULATION
Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways.2 Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors.6 These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.
INHIBITION OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis.6 Inhibition of the HPA axis may occur with higher levels of serotonin as well.7 The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue.8 Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue.2
SKELETAL MUSCLE EFFECT
Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction.9 ATP infusion improved muscle strength in 1 trial, but this was not confirmed in another trial.10,11 Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls.12 This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles.13,14
Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom of fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Levels of interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma.15 IL-6 was also associated with increased fatigue in breast cancer survivors.16 Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy.17 Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients.18,19 Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients.20 Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF.21