Fatigue is a symptom of many diseases, and it is one of the most common complaints of patients with cancer. Due to the magnitude of the cancer diagnosis, however, the symptom is given the unique distinction of cancer-related fatigue (CRF) when it manifests in patients with cancer. Although CRF is difficult to define as it varies among cancer patients, the National Comprehensive Cancer Network (NCCN) guidelines define cancer-related fatigue as “a distressing persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”1 Cancer-related fatigue, whatever its cause, is the focus of many supportive care interventions that address patient needs associated with cancer.2,3
MECHANISMS OF FATIGUE
CRF varies among patients with cancer, and its causes are also extremely diverse. The etiology of fatigue is categorized as central or peripheral. Central fatigue refers to central nervous system (CNS)-associated mechanisms; peripheral fatigue, however, does not necessarily refer to the peripheral nervous system but to peripheral muscle activity as being the fatigue mechanism.3,4
Central fatigue involves pathophysiology within the cerebral hemispheres or the cerebrum of the brain. This is not to imply that the fatigue is psychological but that various contributors—chemotherapy, poor nutrition, and possibly, the cancer itself—affect the neurons in the central nervous system.5 Chemotherapy agents affect the CNS and cause fatigue based on the agent’s penetration through the blood-brain barrier. Nutritional deficiencies such as inadequate protein intake can also affect neurologic function. Many cancers affect higher-level neurologic function directly via metastasis or indirectly by way of paraneoplastic processes.2,4 Changes in motor neuron activity in patients with cancer are similar to changes in motor neuron activity seen in patients with noncancer illnesses that manifest with symptoms of fatigue.
Peripheral fatigue involves peripheral muscle activity or a lack thereof. Neuromuscular physiology studies have demonstrated electroactivity and chemical changes in patients with illness-related fatigue. Both the loss of electrical stimuli and calcium synaptic activity correlates with increased fatigue. Although magnetic resonance spectrometry has been used to document altered peripheral muscle activity in patients with noncancer illnesses, its effectiveness in measuring the extent of peripheral fatigue in cancer patients with CRF has yet to be studied. These two basic mechanisms of fatigue typically do not manifest exclusively; instead both play a varying role in each case of cancer-related fatigue.6,7
MECHANISMS SPECIFIC TO CANCER
In addition to these mechanisms, causes of fatigue that are specific to patients with cancer need to be elucidated. Precipitating maladies that can cause cancer-related fatigue include cachexia, anemia, hypogonadism, hypothyroidism, infection, chemo- or radiotherapy, dehydration, pain, and psychological distress.8,9
Cachexia, defined as a 5% or greater loss of lean body weight, is often precipitated by both the cancer and its treatment and results in altered muscle physiology and dysfunction. Anemia, for obvious reasons, results in decreased tissue oxygenation and expectant fatigue. An often overlooked cause of CRF is hypogonadism, as gonadal dysfunction, and decreased or altered hormone levels often explain the mechanism of fatigue. Pain control and hydration status can be assessed with an adequate history and a complete physical examination, and correction improves CRF. Mental fatigue is associated with depression and often overlooked as a cause of CRF. Psychological and pharmacologic interventions are used to manage mental fatigue.8,9
Radiation therapy can cause cancer-related fatigue in some patients. Cancer-related fatigue can occur in patients who receive radiation therapy to the brain; however, evidence indicates that CRF also occurs when the radiation is focused on areas outside of the cerebrum, often referred to as an abscopal effect. Recently, the event was studied in more detail in women undergoing pelvic radiotherapy for anal or uterine cancer.
Radiation therapy-related CRF has multiple causes, including the release of inflammatory mediators such as various cytokines in the gastrointestinal (GI) tract. A clinical investigation demonstrated an inverse relationship between serum citrulline (an amino acid produced by GI epithelial cell glutamine degradation) levels and fatigue scores.10 Reduced plasma citrulline levels also correlated with reduced epithelial cell mass. In addition, a reduction in citrulline level was proposed to be a biomarker for CRF in patients receiving pelvic radiation.11,12
Targeted therapy is a novel approach to cancer treatment. One targeted approach uses small molecule inhibitors to disrupt tyrosine kinase signaling, which initiates the molecular cascade for cell growth in malignant, as well as normal, tissues.13 Asthenia and/or chronic fatiguelike side effects are associated with small molecule inhibitors. An important note to remember, CRF may be due to thyroid hormone suppression in some patients.
APPROACHES TO TREATMENT
Once cancer-related fatigue is diagnosed in a patient, easily reversed causes should be addressed immediately. Figure 1 illustrates an algorithm for diagnosis and treatment of CRF. Anemia should be corrected with transfusions or recombinant erythropoietin-type agents, when appropriate. Nutritional counseling and support, especially if mechanical issues are the result of poor nutrition, should also be provided. Rehydration should be achieved in patients with clinically evident dehydration. Hormonal insufficiencies determined through androgen, estrogen, and thyroid level measurements can often be corrected easily. However, this may be contraindicated in patients with hormone-dependent tumors such as prostate and breast cancer. Identifying and treating infectious disease processes is based on clinical as well as objective parameters using various culturing techniques. Pharmacologic agents and both individual and group therapy can be instituted to address depression and other psychological issues related to CRF.2,8,9