Fatigue randomized controlled trials—how tired is “too tired” in patients undergoing glioma treatment?

The prevalence of fatigue in the primary brain tumor population ranges between 25% and 90% and occurs at all stages of care. Like sadness and major depressive disorder (MDD), frequency depends on the definition used. In MDD, there is a requirement for it to be pervasive, persistent, and interfering with the ability to work, sleep, study, eat, and enjoy life. For research purposes, fatigue has sometimes been defined as “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning” (http://oralcancerfoundation.org/treatment/pdf/fatigue.pdf). Fatigue is one of the top 10 priority research areas identified by the brain tumor community.1 High-quality research in this area is therefore very important, but challenging. Theoretical models separate fatigue into primary fatigue, directly related to disease mechanisms, and secondary fatigue, related to non-disease-specific factors. Primary fatigue in any condition affecting the brain, whether it be brain tumor, irradiation, demyelination, stroke, or post–head injury, may be the result of centrally mediated processes: neuronal damage, inflammation, demyelination, or axonal loss leading to physical and cognitive impairment or disability. Suggested mechanisms in CNS diseases have been functional cortical reorganization that may result in a higher energy demand in certain brain areas, although mechanistic research is still in its infancy.2 Secondary causes of fatigue may include psychological factors (anxiety or depression), co-occurring symptoms (sleep disturbance and pain), comorbid conditions (hormone dysfunction, infection, and malnutrition), or medication.3