Bower (2019). The role of neuro-immune interactions in cancer-related fatigue: Biobehavioural risk factors and mechanisms – Article summary

Cancer-related fatigue refers to a distressing, persistent, subjective sense of physical, emotional and cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning. Fatigue may be elevated before treatment onset and typically increases over the course of treatment. 20% of cancer survivors report persistent fatigue after treatment.

The cytokine hypothesis of cancer-related fatigue states that the activation of pro-inflammatory cytokines in the periphery signals the brain, leading to fatigue and other behavioural changes (i.e. sickness behaviour). Inflammation can occur because tumours can produce pro-inflammatory cytokines (1), it can occur as a result of tissue damage related to cancer treatment (2) and it can occur because of psychological factors, such as stress (3). Cancer and the treatment of cancer can lead to the release of pro-inflammatory cytokines which act on the brain to provoke sickness behaviour, including fatigue.

However, inflammation does not occur in isolation and is regulated by psychological, neural, neuroendocrine and immune processes. The state of these systems before cancer may influence a patient’s baseline inflammatory state as well as the inflammatory response to diagnosis and treatment. The systems may also be indirectly influenced by cancer and its treatment. This means that cancer may exacerbate or maintain inflammatory signalling after tumour removal.

There are a lot of individual differences in response to tumour development (1), diagnosis (2) and treatment (3). Predisposing factors are enduring traits that increase an individual’s general vulnerability to develop symptoms. Precipitating factors are situational conditions that trigger the onset of symptoms. Perpetuating factors are factors that contribute to the maintenance of symptoms over time.

The effects of cancer and its treatment on the body and brain are believed to be the precipitating factors of cancer-related fatigue. Predisposing factors may increase the risk for fatigue by influencing more proximal responses to diagnosis and treatment.

Individuals with predisposing factors may be fatigued before cancer and may influence the response to cancer and its treatment (1), the regulation of the response (2) and how the response is experienced and expressed (3).

Childhood adversity predicts poor mental health and fatigue. It is linked to inflammation and other neurologic and neuroendocrine processes relevant for fatigue. Childhood trauma is the strongest and most consistent predictor of fatigue. Exposure to childhood maltreatment is also associated with higher levels of fatigue. Childhood adversity is associated with low-grade inflammation and an exaggerated inflammatory response to challenge. This could influence a patient’s baseline state as well as the inflammatory response to cancer diagnosis and treatment. Childhood adversity may also influence neuroendocrine systems relevant for fatigue (e.g. HPA axis) and it affects neural development. Neonatal stress leads to long-term alterations in neuro-immune function. It also influences affective, cognitive and behavioural processes linked to inflammation.

A history of major depressive disorder is a risk factor for poor psychological adjustment to stress. It may influence fatigue. It is linked with elevated fatigue before treatment. It increases the risk for fatigue early in the cancer trajectory and especially emotional fatigue. It is associated with alterations in neural, neuroendocrine, psychological, behavioural and immune processes relevant for fatigue.

Trait anxiety refers to a general tendency to experience anxiety and is associated with fatigue. It is believed to be stable over time and thus less influenced by cancer diagnosis and treatment. It is associated with elevated morning fatigue.

Loneliness (i.e. perceived social isolation) is associated with inflammation. It is associated with higher levels of fatigue. It is also associated with cytomegalovirus antibody titers which is associated with fatigue. This means that loneliness could influence fatigue through immune dysregulation.

Illness perceptions and coping strategies play a role in fatigue among cancer patients. Catastrophizing refers to a cognitive process characterized by a lack of confidence and an expectation of negative outcomes. This is associated with fatigue. It may play a causal role in the persistence of fatigue. Perceptions of low control over fatigue and intrusive thoughts about cancer and associated symptoms are related to catastrophizing.

Lower levels of physical activity is associated with fatigue. Reductions in physical activity after a cancer diagnosis predict higher levels of post-treatment fatigue. Patients who reduce activity after diagnosis and treatment may experience physical deconditioning and may feel less confident about their ability to exercise. This could contribute to fatigue. Physical inactivity can also lead to elevated inflammation which could influence fatigue. Fatigue may then, in turn, lead to reductions in physical activity, leading to a vicious cycle. Increased energy expenditure with decreased energy availability may lead to persistent fatigue in cancer survivors.

Sleep disturbance is related to fatigue. Pre-treatment sleep disturbance is associated with elevated fatigue during treatment. Sleep disturbance predicts elevations in fatigue which, in turn, predicts elevations in depressed mood. It can also influence fatigue through its influence on inflammatory activity.

Alterations in cellular immune system may drive inflammatory biology before cancer and may influence the inflammatory response to cancer and its treatment. Individual differences in peripheral immune status can influence inflammatory and behavioural responses to subsequent challenge. Polymorphisms in cytokine genes are associated with fatigue in patients with cancer and survivors and may be a predisposing risk factor.

Cancer treatment can also lead to increased production of pro-inflammatory cytokines and chemokines. Tumours and cancer treatment influence neuro-immune and neuroinflammatory processes (e.g. alterations in brain pro-inflammatory cytokines). Cancer treatments can also influence the integrity of the blood-brain barrier and thus the trafficking of peripheral immune cells to the brain. Stress can also influence trafficking of peripheral immune cells to the brain. Psychological and physical challenges of cancer and its treatment may lead to neuro-immune alterations that influence behaviour.

Neuroendocrine systems (e.g. HPA axis; autonomic nervous system) are linked to fatigue outside of the cancer context. There appears to be an association between alterations in cortisol and fatigue for patients undergoing treatment. Dysregulation in diurnal cortisol secretion may be an indicator of circadian rhythm disturbance. There also is an association between autonomic dysregulation and post-treatment fatigue in cancer survivors.

There is an association between task-related prefrontal activation and fatigue in patients before treatment onset. There also appears to be an association between alterations in resting-brain connectivity and persistent fatigue. Neural inefficiency in the executive control network at pre-treatment was associated with post-treatment fatigue. Alterations in neural processes may be a predisposing risk factor for fatigue. The dopamine and reward pathways in the brain appear to be relevant for fatigue. Hypervigilance as seen in amygdala activity might also play a role.