Most of the causes of fatigue in patients with cancer are poorly understood, and patients are likely to be coping with many possible causes of fatigue at the same time. Fatigue commonly is an indicator of disease progression and is frequently one of the first symptoms of cancer in both children and adults. For example, parents of a child diagnosed with acute lymphocytic leukemia or non-Hodgkin lymphoma frequently seek medical care because of the child's extreme fatigue. Tumors can cause fatigue directly or indirectly by spreading to the bone marrow, causing anemia, and by forming toxic substances in the body that interfere with normal cell functions. People who are having problems breathing, another symptom of some cancers, may also experience fatigue.

Fatigue can occur for many reasons. The extreme stress that people with cancer experience over a long period of time can cause them to use more energy, leading to fatigue. However, there may be other reasons that patients with cancer suffer from fatigue. The central nervous system (the brain and spinal cord) may be affected by the cancer or the cancer therapy (especially biological therapy) and cause fatigue. Medication to treat pain, depression, vomiting, seizures, and other problems related to cancer may also cause fatigue. Tumor necrosis factor (TNF), a protein made mainly by white blood cells, can cause necrosis (death) of some types of tumor cells and may be given to a patient as a cancer treatment. TNF may cause the loss of protein stores in muscles, making the body work harder to perform normal functions and causing fatigue. There are many chemical, physical, and behavioral factors that are thought to cause fatigue.