Cancer-related fatigue refers to the subjective sense of physical, emotional and or cognitive tiredness, related to cancer or cancer treatment. The fatigue is not proportional to recent activity and interferes with usual functioning. It is a severe fatigue (1), chronic (2), leading to disability (3) and not explained by somatic illness or a psychiatric disorder (4).

Cancer-related fatigue negatively influences quality of life (1), functioning (2), work ability (3) and mental health (4). About a quarter of the patients experience fatigue after treatment.

The risk factors for cancer-related fatigue appear to not explain the persistence of fatigue over time. Higher levels of cancer-related fatigue are associated with:

• Depressive symptoms (positive).
• Anxiety (positive)
• Distress (positive)
• Sleep disturbances (positive)
• Catastrophizing about fatigue (positive)
• Worries about future health (positive)
• Sleep quality (negative)
• Physical activity (negative)
• Hours of exercise (negative)
• Body image (negative)

The cognitive behavioural model of cancer-related fatigue states that fatigue is triggered by cancer but the fatigue is perpetuated by psychological factors. There are several perpetuating factors for cancer-related fatigue:

• Excessive fear of cancer recurrence
  This can lead to a permanent increase in stress levels, which can lead to cancer-related fatigue. This is treated by changing cognitions and coping methods regarding the fear.
• Poor coping with cancer and cancer treatment
  This is treated by reactivation of the events in a supportive environment.
• Dysfunctional fatigue cognitions
  This includes a perceived lack of control about fatigue and focusing on the fatigue (e.g. catastrophizing). This can be treated by focusing on more functional ways to think about the fatigue.
• Dysregulation of sleep-wake cycle
  This can be treated by improving the sleep-wake cycle.
• Dysregulation of activity
  This can be treated by encouraging people to remain active and become more active again.
• Low social support
  This can be treated through CBT or by strengthening the person’s social support network.

Cognitive behavioural therapy (CBT) appears to be effective in the treatment for cancer-related fatigue but the availability is limited. An online version of this treatment is expected to be less demanding for patients (1), more broadly available (2) and more time-efficient for therapists (3).

The cytokine hypothesis of cancer-related fatigue states that activation of pro-inflammatory cytokines in the periphery signals the brain, leading to fatigue and other behavioural changes. This could occur because tumours can produce pro-inflammatory cytokines (1), as a result of cancer treatment-related tissue damage (2) and psychological factors (3). Cancer may maintain or exacerbate inflammatory signalling after tumour removal.

Childhood trauma is a strong predictor of fatigue and is associated with inflammation and neurologic and neuroendocrine processes relevant to fatigue. It is associated with low-grade inflammation and an exaggerated inflammatory response to challenge. This could influence a patient’s baseline fatigue level.

Loneliness could influence fatigue through immune dysregulation. Individual differences in peripheral immune status can influence inflammatory and behavioural responses to subsequent challenge. Cancer treatment could lead to an increased production of pro-inflammatory cytokines. It also influences the integrity of the blood-brain barrier and thus the trafficking of peripheral immune cells to the brain. Dysregulation in diurnal cortisol secretion could be an indicator of circadian rhythm disturbance.

An increase in self-efficacy is associated with a decrease in fatigue. Treatment is associated with an increase in self-efficacy and an increase in physical activity. However, physical activity does not mediate the effect of graded activity on fatigue.

TKI treatment for cancer is associated with an increase in fatigue.

The treatment of advanced cancer has become more effective and this leads to an increased life expectancy. There is a major improvement in their quality of life. The prevalence of cancer-related fatigue is very high (i.e. >70) in patients with advanced cancer.

Graded exercise therapy (GET) states that fatigue is maintained by deconditioning and loss of muscle function caused by a low level of physical activity. Cognitive behaviour therapy (CBT) states that fatigue is maintained by beliefs and behaviour.