Cancer-Related Fatigue-Complex, Multidimensional, and Challenging to Treat

Katherine Yeager, PhD, RN

Research Assistant Professor

Fatigue is a very distressing symptom experienced by most individuals with cancer.

This symptom has deleterious effects on many aspects of quality of life including physical, psychological, and social well-being. When an individual has fatigue, it can limit his or her ability to function at home and at work, to socialize, and to participate in previously enjoyable activities.¹

In comparison to the fatigue experienced by healthy individuals, fatigue experienced by cancer patients is different in that it is often not alleviated by rest or sleep.² Despite the negative impact of cancer-related fatigue, in general it is underreported by patients and underestimated by providers. One challenge in the assessment and treatment of this symptom is the lack of knowledge about fatigue, specifically the mechanism underlying fatigue.³

The cause of cancer-related fatigue is complex and multidimensional, involving many potentially contributing elements. These include tumor-related factors and comorbid medical/ psychological conditions and also side effects associated with cancer treatment and other medications.² Some of the biologic mechanisms that have been investigated include anemia, cytokine dysregulation, hypothalamic—pituitary–adrenal axis dysregulation, 5-hydroxytryptophan neurotransmitter dysregulation, and alterations in adenosine triphosphate and muscle metabolism. The process that has received the most attention is the dysregulation of cytokines, with a focus on proinflammatory cytokines.³

Inflammation and Fatigue

The connection between inflammation and fatigue comes from animal studies where inflammatory cytokines can signal central nervous system (CNS) changes and produce fatigue and other symptoms. Investigators have proposed that tumors and the treatments used to treat them can activate the proinflammatory cytokine network, leading to symptoms of fatigue via cytokine signaling in the CNS.

The inflammatory response can persist long after treatment completion. Studies conducted with cancer patients before treatment, during treatment, and after treatment have shown associations between fatigue and inflammatory markers, although results have not been consistent.³ In order to learn more about this important association, longitudinal studies are needed.

Canhua Xiao, PhD, RN, a research assistant professor at Nell Hodgson Woodruff School of Nursing at Emory University is currently studying the link between fatigue and inflammation in patients with head and neck cancer receiving radiotherapy. Patients with head and neck cancer typically receive radiation treatment and have particularly high rates of fatigue which often lasts after therapy is complete. Her study seeks to clarify and broaden the understanding of the association of fatigue with pro- and anti-inflammatory signaling. In addition, this study investigates genetic mechanisms with a longitudinal descriptive design. Patients receiving radiation for head and neck cancer are followed from before radiation therapy begins to 1 year post radiation therapy. Xiao’s work is motivated by the hope that understanding the biologic mechanisms of fatigue will be the key to its successful management and perhaps also will benefit other related symptoms.

Assessment and Treatment of Fatigue

Until the mechanisms of fatigue are better understood, clinicians should concentrate on available resources. The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology recommend that all cancer patients be screened for fatigue at their initial clinical visit, and then regularly during and after their cancer treatment has been completed.⁴ One unique challenge in the assessment of fatigue is that a patient’s perception of fatigue can change before, during, and after treatment, meaning that fatigue scores cannot be compared throughout the treatment continuum.

Once it has been determined that a patient is experiencing fatigue, the next step is to determine if there are any potentially treatable factors that could have contributed to the development of cancer-related fatigue, such as anemia, pain, emotional distress, sleep disturbance, malnutrition, medication side effects, and comorbidities.

However, even after treating these conditions, a significant proportion of cancer patients will continue to experience fatigue. For these individuals, intervention with additional therapeutic modalities may be required.²

Pharmaceutical agents to treat fatigue have been studied but none have proved to reliably prevent or treat this symptom.⁵ A variety of nonpharmacologic interventions have shown potentially beneficial effects including physical activity, psychosocial support, and mind—body treatments.

Specific interventions such as cognitive-behavior approaches, acupuncture, mindfulness-based yoga, and biofield therapies have shown promise but need further investigation.3 Because fatigue is such a distressing symptom, clinicians and researchers must continue to work to understand the mechanisms behind this challenging symptom and determine the most effective treatments.

References

• Koornstra RH, Peters M, Donofrio S, et al. Management of fatigue in patients with cancer—a practical overview. Cancer Treat Rev. 2014;40(6):791- 799.
• Mustian KM, Morrow GR, Carroll JK, et al. Integrative nonpharmacologic behavioral interventions for the management of cancer-related fatigue. Oncologist. 2007;12(suppl 1):52-67.
• Bower JE. Cancer-related fatigue-mechanisms, risk factors, and treatments [published online August 12, 2014]. Nat Rev Clin Oncol.
• Mock V, Atkinson A, Barsevick A, et al. NCCN Practice Guidelines for Cancer-Related Fatigue. Oncology (Williston Park). 2000;14(11A):151-161.
• Minton O, Richardson A, Sharpe M, et al. Drug therapy for the management of cancer-related fatigue. Cochrane Database Syst Rev. 2010;7(7):CD006704.