Although fatigue is a common symptom in the cancer population,[1-5] it has been poorly recognized by oncologists and is seldom assessed or treated systematically. Few studies of fatigue have been conducted, and both the lack of empiric research and the complexity of the condition have contributed to a sense of therapeutic nihilism. This nihilism may also relate to the reluctance of patients to complain about fatigue, which may be considered a symptom to be "endured" or an inevitable side effect of the disease or its treatment.
The historical neglect of fatigue as a clinical problem is slowly changing. New methods for the measurement of fatigue have yielded survey data that demonstrate its high prevalence and adverse impact. These data have begun to improve both professional and public awareness of the need for better care. Obstacles to progress, including a confusing nomenclature and the lack of accepted practice guidelines, are gradually being addressed.
Fatigue is an inherently subjective and multidimensional condition. Like other symptoms, it may be described in terms of a variety of characteristics (eg, severity, distress, or temporal features). It also may be described in terms of specific impairments or qualities (eg, lack of energy, muscle weakness, somnolence, mood disturbance, or cognitive impairment). These varied qualities of fatigue suggest the possibility of subtypes that may be amenable to different primary or symptomatic therapies.
Various definitions of pathologic fatigue have been proposed.[2,6,7] In 1998, the International Classification of Diseases 10th Revision-Clinical Modification accepted cancer-related fatigue as a diagnosis (Table 1). The most important diagnostic criteria in this definition are chronicity; the presence of various symptoms (eg, diminished energy, diminished motivation or attention, a feeling of exhaustion or generalized weakness, difficulty in completing daily tasks); a level of distress associated with these symptoms; and a relationship between the symptoms and the cancer or its therapy. A final criterion distinguishes cancer-related fatigue from other comorbid psychiatric disorders, such as major depression.
Fatigue can have an enormous impact on all dimensions of quality of life.[3,8] In a study in 419 cancer patients, fatigue was reported to significantly impair the ability to work and enjoy life (60%), experience emotional well-being (51%), care for family (42%), and sustain relationships with family and friends (38%). One-third of patients noted that fatigue increased their concerns about mortality and survival (33%).
Regardless of the context, unremitting fatigue may limit physical functioning and undermine psychological well-being by distorting role functioning and by contributing to anxiety, depression, or a sense of helplessness. Social well-being may be compromised by the inability to maintain employment or continue routine relationships with family and friends. Spiritual well-being may be challenged because of increased feelings of uncertainty or hopelessness and interference with the ability to perform activities and roles that give meaning and value to life.
Cancer-related fatigue is extremely prevalent. Among patients with metastatic disease, the overall prevalence of diminished energy or fatigue has been reported to exceed 75%,[10-12] with a range from 60% to more than 90%. Fatigue commonly occurs after surgery,[13,14] chemotherapy,[15,16] radiotherapy,[17,18] and immunotherapy.[19-21] Prevalence rates as high as 96% have been reported with chemotherapy and radiotherapy, and fatigue has been described as an almost constant phenomenon with the use of biological response modifiers.[19-21] All these disease-related factors presumably increase the base rate for chronic fatigue, which appears to be as high as 20% among patients attending general medical clinics.
Fatigue related to treatment has a temporal relationship to the intervention. When associated with chemotherapy, it often peaks within a few days and declines until the next treatment cycle.[23,24] With fractionated radiation therapy, it peaks after a period of weeks. In some cases, fatigue lingers beyond the end of chemotherapy or radiation therapy.
Cancer fatigue may also be associated with major organ dysfunction and metabolic disturbances. The connection between fatigue and anemia has been well documented,[25,26] and there is some evidence that hemoglobin levels of 11 to 12 g/dL reflect an important transition point, below which fatigue is more likely to be a problem. Although the incidence of fatigue related to cardiac or pulmonary disease, renal failure, hepatic failure, hypothyroidism, adrenal insufficiency, and neuromuscular disorders has been poorly documented, it frequently develops in association with these disorders. Similarly, metabolic derangements, such as dehydration, poor nutrition, and the changes associated with systemic infection, appear to predispose a patient to fatigue.
Fatigue has also been associated with psychological conditions, particularly depression. Based on anecdotal observations, it seems likely that anxiety and stress can induce or exacerbate fatigue. In addition, a primary sleep disorder can cause excessive daytime somnolence and fatigue. To some extent, the occurrence of fatigue in patients with depressed or anxious mood may relate to concurrent insomnia.
Fatigue is a common adverse effect of the use of multiple centrally acting drugs for the treatment of cancer and other chronic illnesses. Such agents include the opioids, antidepressants, and antihypertensives.
Finally, clinical observations suggest that a variety of miscellaneous factors may be relevant etiologies. For example, immobility can rapidly lead to deconditioning, which may contribute to fatigue. Other symptoms, such as pain or dyspnea, may exacerbate fatigue through mechanisms that may be psychologically mediated or related directly to the underlying pathophysiology or to specific treatments.
Pathogenesis of Cancer-Related Fatigue
The pathogenesis of fatigue is unknown and is probably multifactorial. The diversity of potential etiologies and associated factors, as well as the complex phenomenology of this entity, suggest that fatigue represents a "final common pathway" to which many mechanisms may potentially contribute.[2,29-31] The most studied mechanisms associated with cancer fatigue involve cytokines, such as tumor necrosis factor, interferon, and interleukin. These compounds may play a role in the asthenia-cachexia of AIDS and cancer patients. Further research is needed to elucidate the mechanisms by which these cytokines produce fatigue.
Some fatigue may be caused by abnormalities in energy metabolism related to increased need, decreased substrate, or abnormal production of substances that may impair muscle functioning. Direct neuromuscular dysfunction may be responsible for fatigue associated with neurologic diseases or deconditioning. Fatigue associated with sleep disorders and depression suggests that dysfunction of the neurobiological substrates of arousal and mood, respectively, may be pathogenic in some cases.