Supportive Care in Cancer

, Volume 26, Issue 10, pp 3353–3364 | Cite as

The pathophysiology of cancer-related fatigue: current controversies

  • C. M. O’Higgins
  • B. Brady
  • B. O’Connor
  • Declan WalshEmail author
  • R. B. Reilly
Review Article


Fatigue is one of the most common and debilitating cancer symptoms, and is associated with impaired quality of life. The exact pathophysiology of cancer-related fatigue (CRF) is poorly understood, but in any individual, it is likely multifactorial and involves inter-related cytokine, muscular, neurotransmitter, and neuroendocrine changes. Underlying CRF mechanisms proposed include central and peripheral hypotheses. Central mechanisms include hypotheses about cytokine dysregulation, hypothalamic-pituitary-adrenal-axis disruption, circadian rhythm disruption, serotonin, and vagal afferent nerve function while peripheral mechanisms include hypotheses about adenosine triphosphate and muscle contractile properties. Currently, these hypotheses are largely based on evidence from other conditions in which fatigue is characteristic. The purpose of this article is to provide a narrative review of the literature and present the current controversies in the pathophysiology of CRF, particularly in relation to central and peripheral hypotheses for CRF. An understanding of pathophysiology may facilitate direct and simple therapeutic interventions for those with cancer.


Cancer-related fatigue Pathophysiology Proinflammatory cytokines Hypothalamic-pituitary-adrenal axis Neuromuscular abnormalities Serotonin 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of MedicineTrinity College DublinDublinIreland
  2. 2.Trinity Centre for BioengineeringTrinity College DublinDublinIreland
  3. 3.Academic Department of Palliative MedicineOur Lady’s Hospice and Care ServicesDublinIreland
  4. 4.School of Medicine and Medical SciencesUniversity College DublinDublinIreland
  5. 5.Department of Supportive Oncology, Levine Cancer Institute, Carolinas HealthCare System, School of MedicineUniversity of North Carolina at Chapel HillCharlotteUSA
  6. 6.School of EngineeringTrinity College DublinDublinIreland

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