Fatigue, one of the most common symptoms experienced by cancer patients, is multidimensional and is associated with significant impairment in functioning and overall quality of life. Although the precise pathophysiology of cancer-related fatigue (CRF) is not well understood, a number of metabolic, cytokine, neurophysiologic, and endocrine changes have been described in these patients. A better understanding of these abnormalities is likely to lead to novel therapeutic interventions. Clinically, all patients presenting with significant fatigue should be evaluated for treatable conditions that might contribute to this symptom. Exercise and treatment of anemia are the two most established interventions for CRF. Psychostimulants seem promising based on early studies. Several complementary medicine treatments that showed efficacy in preliminary studies merit further testing.
Keywords: Fatigue, Multidimensional approach, Oncology
The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as "a persistent, subjective sense of tiredness related to cancer or cancer treatment that interferes with usual functioning."  These symptoms are persistent, disproportionate to the level of exertion, and typically not relieved by rest. The criteria of NCCN for the diagnosis of CRF have been accepted by the International Classification of Diseases (ICD, 10 th revision, clinical modification).  CRF is underrecognized and undertreated, partly because of limited understanding of its pathophysiology and lack of effective treatments. With better treatments available for cancer-related pain, nausea, and vomiting, increasing attention is being paid to CRF. In this review, we present the current understanding of the clinical significance, pathophysiology, and management of CRF.
Fatigue is one of the most common symptoms experienced by cancer patients. The prevalence of self-reported fatigue in these patients ranges from 17% to 95% in different studies. ,, This wide range partly reflects heterogeneity in different studies in terms of the definition of fatigue, stage of tumor, and use of adjuvant therapy. The prevalence of fatigue was only 17% when the most stringent diagnostic criteria were used.  Most patients with advanced-stage tumor have significant fatigue. A higher proportion of patients receiving chemotherapy, radiotherapy, biologic response modifiers, or autologous transplantation develop fatigue compared with patients who do not receive these treatments. ,,
Impact on quality of life
Fatigue has a significant impact on the overall quality of life. In the Fatigue-1 study, of the 419 patients with cancer who participated in a telephone interview, 78% experienced fatigue during the course of their treatment.  Fatigue adversely affected patients in their daily lives more than did pain (61% vs. 19%). Specific treatment for fatigue was recommended by oncologists for only 23% of the patients. The Fatigue-2 study involved a telephone survey of 379 patients with cancer who had previously received chemotherapy.  Seventy-six percent of the patients reported experiencing significant fatigue at least a few days each month during their most recent chemotherapy cycle, with 30% experiencing daily fatigue. Most patients noted that when they experienced fatigue, they were unable to lead a "normal" life (91%) or had alteration in their daily routine (88%) because of fatigue. The treatment that patients said was most often recommended to them by their physicians was bed rest/relaxation (37%). However, data collected in both these studies were retrospective and, thus, increased the possibility of recall bias. Presence of ongoing fatigue is associated with greater symptom distress and worse performance status and is a prognostic factor associated with overall survival in univariate but not multivariate models. ,
Fatigue symptoms fluctuate over the course of the cancer. In patients receiving chemotherapy, fatigue is generally worst 4-5 days after receiving chemotherapy or at the nadir of cell counts in patients who develop significant myelosuppression. , With radiotherapy, the severity of fatigue usually peaks at the end of treatment and improves over the next 3-6 months. , However, fatigue may persist for years after completing treatment, even while patients are in complete remission. 
The precise pathophysiology of CRF is not well understood. Subjectivity in fatigue assessment, the multidimensional component of fatigue, and the lack of an animal model contribute to this limitation. Several metabolic, cytokine, neurophysiologic, and endocrine changes associated with fatigue have been described.
Medical conditions contributing to fatigue
A number of treatable conditions that are common in cancer patients can contribute to fatigue [Table 1].  Psychosocial conditions that predispose to fatigue include the presence of anxiety and depression, inadequate coping skills, and a lack of social support. Other associations of significant fatigue include female gender, higher cancer stage, smaller size of household, higher education level, and full-time employment status. 
Cancer is associated with the release of several cytokines. These include interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Injection of these cytokines in laboratory animals has been shown to induce anorexia, weight loss, and social withdrawal.  In an observational study of 40 patients with breast cancer, including 20 who reported fatigue and 20 without fatigue, significantly higher levels of proinflammatory cytokines were demonstrated in patients who reported fatigue.  The elevated cytokines included IL-1 receptor antagonist, soluble TNF receptor type II, and neopterin.
Fatigue is associated with several abnormalities in skeletal muscle structure and function. In patients with advanced gastric cancer, an increase in skeletal muscle protein breakdown was shown without a significant change in total body protein turnover.  Some of the other reported abnormalities include increased resting energy consumption, impaired muscle protein synthesis, abnormalities in adenosine triphosphate (ATP) generation, and intracellular calcium flux. Neurologic changes described with CRF include an overall diminished activation from the central nervous system and reduced neuromuscular efficiency. 
Some chemotherapeutic agents, such as vincristine, cisplatin, and paclitaxel, are also directly neurotoxic and thus might cause fatigue through this mechanism.
Several endocrine changes are described in patients with CRF. The search for a central endocrine abnormality leading to CRF is enticing because a representative model might lead to a direct and simple therapeutic intervention. However, the present models lack specificity and, although the abnormalities related to fatigue are reasonably well described, it is not clear whether the changes observed are causative for CRF or mere associations. Dysfunctions of the hypothalamic-pituitary-adrenal axis (HPA) are described in patients with CRF and in chronic fatigue syndrome. These include decreased steroid output, lower levels of gonadotropins and androgens, and reduced HPA function on neuroendocrine challenge tests.  An elevation in proinflammatory cytokines (in turn stimulated by interferon-α and IL-2) affects the HPA function, leading to a reduction in cortisol output. Another intriguing model relates to the importance of disruption of the circadian rhythms in CRF. Most biologic functions of humans have a circadian rhythm. These include endogenous steroid production, melatonin secretion, sleep-wake cycle, and temperature regulation, among others. A disruption of circadian rhythms is reported to cause sleep disturbance, depression, anorexia, and, possibly, fatigue. However, the current evidence behind the circadian rhythms being the central abnormality leading to fatigue is not conclusive. In attempts to find a common underlying mechanism for the development of CRF, several disease models have been developed. , Four such hypotheses are described in a recent review: the anemia hypothesis, the ATP hypothesis, the vagal afferent hypothesis, and the HPA-pituitary axis, cytokine, and 5HT (serotonin dysregulation) hypothesis.  However, none of these models fully describes all the dimensions of fatigue. Thus, much work remains to be done in this field.
Because patients may not self-report fatigue, they should be actively screened for symptoms consistent with CRF. Most patients with CRF should be appropriately evaluated. This evaluation should include assessment of fatigue symptoms (severity, duration, time course, and exacerbating and relieving factors), evaluation of potentially reversible conditions [Table 1], assessment of the effect of fatigue on quality of life and performance status, and evaluation of symptoms commonly associated with fatigue. A number of validated scales have been developed to measure fatigue severity.  The Brief Fatigue Inventory (BFI) is one of the most simple instruments that can be used in clinical and research settings.  Fatigue severity is scored from 0 to 10, with mild fatigue being 1 to 3, moderate 4 to 6, and severe 7 to 10.
The NCCN and the Fatigue Coalition have developed guidelines and algorithms for the management of patients with CRF. , The focus is to identify and treat underlying reversible conditions with a broad array of pharmacologic and non-pharmacologic treatments, recognizing the multidimensional aspects of fatigue. In general, patients with mild fatigue (BFI 1-3) should continue to be closely observed with an effort at anticipating and preventing the development of more severe fatigue. For patients with moderate or severe fatigue, further evaluation and management is recommended.
Treatment of fatigue
Few interventions have demonstrated a benefit for the treatment of fatigue in the absence of a reversible condition. Individual interventions and the levels of evidence behind their use are discussed in the following paragraphs.
Treatment of anemia
Anemia is a common reversible cause of fatigue in patients with cancer. Several causes of anemia are recognized in these patients, including hemorrhage, hemolysis, nutritional deficiencies, bone marrow infiltration, cytokine-mediated problems, anemia related to chemotherapy or radiotherapy, and anemia of chronic disease. Once specific deficiencies and other reversible causes are excluded, treatment of anemia with erythropoietin-α or darbepoetin-α was shown to improve fatigue in four well-designed randomized double-blind clinical trials. ,,, In general, maximal benefit is observed at a target hemoglobin range of 11-13 g/dL.
Most exercise programs have been shown to improve fatigue and other symptoms, including functional capacity and overall quality of life. Forms of exercise that have been tested and found efficacious in randomized controlled trials include cycle ergometers, , walking, ,,,,, resistance training,  and exercise of choice. ,, Exercise is also reported to have a beneficial effect on functional capacity following anticancer therapy.  Exercise should ideally be prescribed to prevent the development of fatigue because patients with moderate to severe fatigue are likely to find it difficult to start an exercise program. Most studies testing exercise were designed as preventive trials. ,,,,,, Furthermore, the evidence for the efficacy of exercise in patients with advanced disease is limited. 
Several types of psychosocial intervention have been found to be beneficial in CRF. A 6-week program of structured psychiatric intervention (health education, enhancement of problem-solving skills, stress management, and psychological support) improved depression, fatigue, confusion, and total mood disturbance at 6 months in patients with malignant melanoma. , Similar improvement was seen in a follow-up study that was designed as a randomized trial.  In another randomized trial, in patients about to start chemotherapy, self-administered stress management training was reported to be superior to professional training or no intervention.  Group support was reported to improve mood states and coping response in a randomized trial in patients with metastatic breast cancer.  A comprehensive coping strategy program comprised of preparatory information, cognitive restructuring, and relaxation with guided imagery improved nausea and fatigue in a randomized trial in women with breast cancer undergoing autologous stem cell transplantation.  Other interventions reported to be efficacious for improving fatigue symptom severity include psychotherapy and tailored behavioral intervention. 
Pharmacologic agents tested for CRF include psychostimulants, progestational agents, and corticosteroids [Table 2]. Two open-label clinical trials reported on the effect of methylphenidate for CRF. In the larger study involving 31 patients, methylphenidate use was reported to be efficacious in improving fatigue in patients with advanced cancer.  Patients' fatigue improved significantly from a Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F) score of 7.2 ± 1.6 to 3.0 ± 1.9 after 7 days of treatment. In the other open-label study, which involved 11 patients with advanced cancer, methylphenidate intake was associated with improved fatigue from moderate to severe, to mild in nine patients within 3 days.  Methylphenidate also improved fatigue measured by the Edmonton Symptom Assessment System (ESAS) in a more rigorously designed randomized trial in patients with human immunodeficiency virus infection.  Results of a more definitive study of methylphenidate for CRF in a double-blind randomized controlled trial are awaited. Two additional psychostimulants have been tested for the treatment of fatigue in chronically ill patients. Modafinil was considered to be efficacious in improving fatigue in a single-arm study in patients with multiple sclerosis. , Many other pharmacologic treatments have been examined for CRF. Corticosteroids were shown to cause decreased depression and analgesic consumption and increased appetite and daily activity in a small, randomized placebo-controlled trial of a 14-day course of oral methylprednisolone in terminally ill cancer patients. However, no larger trials involving longer courses of corticosteroids in other populations have been carried out. Trials have also failed to show any benefit of dextroamphetamine,  multivitamins,  or antidepressants.  In a meta-analysis, neither progestational steroids nor paroxetine were found to be better than placebo in the treatment of CRF.  Finally, in a Cochrane systematic review published in 2008 and updated in 2010, no clinically meaningful benefit was found for agents other than psychostimulants in the pharmacologic treatment of CRF. 
Complementary and alternative medicine
A reductionistic approach to treatment of CRF may not work for most patients. Fatigue has an effect on the physical, social, psychological, and spiritual aspects of patients' lives, and therapeutic models encompassing all these realms are more likely to address this symptom effectively. Several alternative treatment programs, particularly the mind-body interventions, are built on such a biopsycho-socio-spiritual model. Cancer patients commonly use complementary and alternative (CAM) interventions, often without the knowledge of their treating physicians. Several CAM interventions have been tested for CRF. CAM interventions with preliminary evidence of efficacy include acupuncture,  energy conservation and activity management,  healing touch,  hypnosis,  lectin-standardized mistletoe extract,  levo-carnitine,  massage,  sleep promotion,  support groups,  and Tibetan yoga.  However, the results from these studies are not conclusive because of small sample size, methodologic limitations, and use of fatigue as a secondary endpoint.
Because the treatment of established fatigue is difficult, anticipation and prevention of the development of significant fatigue is a prudent approach. Patient education is the single most important component at this stage of management. It is important to help patients understand that the development of fatigue does not necessarily imply a spread of their cancer.  Furthermore, it is hoped that maintenance of an optimal level of physical activity, anticipation and treatment of psychiatric disorders, and optimal management of pain and anemia will minimize the development of significant fatigue.
Fatigue is the most common symptom experienced by patients with cancer and is associated with worsening of functioning and overall quality of life. Fatigue is significantly underreported by patients and undertreated by physicians. The precise pathophysiology of CRF is not well understood, but it is likely to involve several related medical, neuroendocrine, cytokine, and muscular changes. All patients with significant fatigue should be evaluated for reversible medical conditions and educated about the prevalence, prevention, and management of CRF. Exercise and treatment of anemia are the two most effective interventions for CRF. Several psychosocial interventions may also be beneficial. Psychostimulants seem promising in preliminary clinical studies, but more definitive studies are needed. A number of CAM interventions have shown promise in preliminary studies and merit further testing. Clearly, more research is needed using well-designed, prospective clinical trials for better management of patients with CRF.
[Table 1], [Table 2]