The exact mechanism that causes or promotes fatigue in patients with cancer is not known. It is likely that many different mechanisms play a role.[1,2] Various models have been proposed for the study of fatigue. Prolonged stress that produces a stress response may be used as a model for fatigue.[3] People with cancer frequently suffer from extreme stress over a long period of time, causing them to expend energy and experience a high level of fatigue. In contrast, one study demonstrated that energy requirements vary in people with cancer.[4] This suggests that factors other than energy requirements contribute to fatigue.

A neurophysiologic model has been proposed to study fatigue. This model has both central and peripheral components. The central component consists of the psyche/brain and spinal cord. The peripheral system consists of peripheral nerves, muscle sarcolemma, transverse tubular system, calcium release, actin/myosin interaction, cross-bridge tension and heat, and force/power output. Impairment of the central component causes lack of motivation, impaired spinal cord transmission, and exhaustion or malfunction of brain cells in the hypothalamic region. Damage to the peripheral component can cause impaired peripheral nerve function in transmission at the neuromuscular junction, thereby affecting fiber activation. Both types of damage may play a role in chronic fatigue. The central mechanism may be the key to explaining the extreme fatigue of biotherapy-treated patients.[5] It remains to be established whether potentially neurotoxic chemotherapeutic regimens cause fatigue through this mechanism. Additionally, many individuals with cancer may be concurrently receiving analgesics, hypnotics, antidepressants, antiemetics, or anticonvulsants. Because many of these drugs exert their effect on the central nervous system, they can significantly compound the problem of fatigue.

Another perspective in the study of fatigue focuses on the reduction in skeletal muscle protein stores that may result from endogenous tumor necrosis factor (TNF) or from TNF administered as antineoplastic therapy. This muscle wasting would require individuals to exert an unusually high amount of energy to generate adequate contractile force during exercise performance or during extended periods of sitting or standing.[6]

Last, a fatigue framework has been proposed that encompasses biochemical, physiologic, and behavioral factors that cause manifestations of fatigue. These factors are modified by the perception of fatigue. Thirteen patterns are thought to influence fatigue:[7]

• Accumulation of metabolites.
• Changes in energy and energy substrate.
• Activity/rest.
• Sleep/wake.
• Disease/treatment.
• Symptoms.
• Psychologic.
• Oxygenation.
• Changes in regulation/transmission.
• Environmental.
• Life events.
• Social.
• Unique circadian rhythm.

References

1. Miaskowski C, Portenoy RK: Update on the assessment and management of cancer-related fatigue. Principles and Practice of Supportive Oncology Updates 1 (2): 1-10, 1998. 
   
   
2. Morrow GR, Andrews PL, Hickok JT, et al.: Fatigue associated with cancer and its treatment. Support Care Cancer 10 (5): 389-98, 2002.  [PUBMED Abstract]
   
   
3. Aistars J: Fatigue in the cancer patient: a conceptual approach to a clinical problem. Oncol Nurs Forum 14 (6): 25-30, 1987 Nov-Dec.  [PUBMED Abstract]
   
   
4. Kaempfer SH, Lindsey AM: Energy expenditure in cancer: a review. Cancer Nurs 9 (4): 194-199, 1986. 
   
   
5. Funk SG, Tornquist EM, Champagne MT, et al., eds.: Key Aspects of Comfort: Management of Pain, Fatigue and Nausea. New York: Springer Publishing, 1989. 
   
   
6. St Pierre BA, Kasper CE, Lindsey AM: Fatigue mechanisms in patients with cancer: effects of tumor necrosis factor and exercise on skeletal muscle. Oncol Nurs Forum 19 (3): 419-25, 1992.  [PUBMED Abstract]
   
   
7. Piper BF, Lindsey AM, Dodd MJ: Fatigue mechanisms in cancer patients: developing nursing theory. Oncol Nurs Forum 14 (6): 17-23, 1987 Nov-Dec.  [PUBMED Abstract]