Behavioral symptoms, including fatigue, depression, sleep disturbance, and cognitive alterations, are prevalent among patients with cancer and may be induced by both cancer and its treatment. Fatigue is the most prevalent and distressing of these behavioral symptoms. Cancer-related fatigue (CRF) and associated behavioral disturbances cause profound functional impairments that can persist for years after treatment ends. Nevertheless, the pathogenic mechanisms that mediate CRF remain poorly understood, and current therapies are only partially effective in reducing symptom burden. Progress has been seriously hindered by the lack of appropriate animal models.

Recent evidence suggests that CRF may be conceptualized as a “sickness behavior” that is mediated in part by the central effects of inflammatory cytokines. Sickness behaviors reflect the activity of a central perceptual-affective-motivational system that reorganizes behavior to promote survival. However, under conditions of chronic activation these inflammatory signals are maladaptive and may contribute to the development of persistent fatigue and associated behavioral disturbances in patients with cancer. The constructs of fatigue and sickness contain multiple psychological components that appear to be mediated by distinct molecular, cellular, and neural systems. Advancing our understanding of the neural basis of CRF will require the development of translational measures that parse fatigue and sickness into their specific psychological components using well-validated animal models. Although other biological mechanisms are likely to contribute to the development of CRF (see Chapter 10), the cytokine hypothesis will be used to illustrate how animal models can help researchers evaluate potential mechanisms.