Clinical Characteristics
The pathophysiology of CRF is not well understood even today. Since the late 1800s, basic scientists and clinicians have been attempting to explain the causes of CRF. Given the similar constructs of the models, Mitchell organized them into 4 themes: energy balance/energy analysis, fatigue as a stress response, neuroendocrine-based regulatory fatigue, and hybrid models. Energy balance/energy analysis posits an imbalance of energy intake, metabolism, and expenditure, thus facilitating the development of fatigue. Fatigue as a stress response suggests that there is a continued adaptation along a continuum that is differentiated in both behavioral and symptom characteristics. Neuroendocrine-based regulatory fatigue theorizes that the multidimensionality of fatigue is due to a dysregulation of the neuroimmunoendocrine system, which is interrelated both anatomically and functionally and includes the hypothalamic-pituitary-adrenal axis, cytokines, circadian rhythms, and neurotransmitters. Hybrid models include those that suggest that stressors caused by cancer and cancer treatments generate a decline in 4 particular areas (cognitive function, nutrition, muscle endurance, and quality of sleep), which impedes ability to adapt, as well as those that propose that biological, psychological, and functional variables induce CRF.
Fatigue can be peripheral or central. Peripheral fatigue can be referred to as muscle fatigability caused by muscle and neuromuscular disorders. It occurs when there is a lack of neuromuscular system response after central stimulation. Central fatigue results when transmission of motor impulses has failed or there is an inability to perform voluntary activities. It affects not only the physical body but also cognition such that patients find it difficult to concentrate mentally.
Contributing factors to fatigue, sometimes referred to as secondary fatigue, include age, physical symptoms, psychological symptoms, comorbidities, advanced disease, treatment side effects, and abnormal laboratory values ( Table 1 ). With advanced cancer, the impact of each factor contributing to fatigue will vary throughout the disease trajectory.