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 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.
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