SUMMARY OF KEY POINTS
Etiology of Complications
Evaluation of the Patient
Grading of the Complication
Fatigue in patients with cancer, often referred to as cancer-related fatigue (CRF), has been defined by the National Comprehensive Cancer Network as a “distressing persistent, subjective sense of tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”
Fatigue is a universal human experience that, in healthy individuals, is regarded as a basic protective mechanism against the depletion of body reserves of adenosine triphosphate and resulting exhaustion and possible tissue damage. Compared with the fatigue of healthy individuals, which resolves with adequate rest and sleep, the fatigue of patients with cancer often remains after a period of rest or sleep, is of greater magnitude and persistence, is more disruptive to activities of daily living, and has a more negative affective impact. When patients with cancer were asked to describe their fatigue, responses revealed three major characteristics: physical sensations (59% of responses) such as weakness and decreased physical performance, affective sensations (29% of responses) such as sadness and diminished motivation, and cognitive effects such as difficulty concentrating and decreased problem-solving ability (12% of responses).
CRF has been accepted as a diagnosis in the International Statistical Classification of Diseases, 10th Revision—Clinical Modification with the required criterion of “significant fatigue, diminished energy, or increased need to rest, disproportionate to any recent change in activity level” plus five or more criteria related to the impact of fatigue and present every day or nearly every day during 2 weeks of the previous month. Although these criteria are promising in the diagnosis of CRF, they have been tested in only one study of cancer survivors, in which the prevalence of CRF was determined to be 17%.
CRF is the most prevalent unmanaged symptom reported by patients being treated for cancer, and it affects 70% to 100% of patients receiving cytotoxic chemotherapy, radiation therapy, stem cell or marrow transplantation, or treatment with biologic response modifiers.      Fatigue is a persistent, distressing symptom in 17% to 40% of patients who have completed treatment     and is a significant symptom in more than 75% of patients with metastatic disease.    The increasing prominence of CRF is related to both the increase in intensive multimodal cancer treatments, characterized by increased dose density and dose intensity, and better management of formerly predominant symptoms of pain, nausea, and vomiting. Patients report fatigue to be the most distressing symptom associated with cancer and its treatment, more distressing even than pain.  
Management of CRF is important for several reasons beyond its prevalence and the discomfort and distress that it causes. First, high levels of fatigue affect functional status and the ability to tolerate cancer treatment. Research reports indicate that fatigue can have a profound effect on functional status,   and it is uncertain whether patients regain full functioning when treatment is over. If fatigued patients cannot tolerate their cancer treatment or must choose between treatment and quality of life, control of their malignancy may be compromised. In addition, high levels of fatigue affect patients’ quality of life and interfere with their ability to engage in valued roles and activities.
DESCRIPTION OF FATIGUE
Fatigue in patients with cancer is a complex and multifactorial phenomenon that may have a variety of causes and contributing factors. The exact mechanisms that are involved in its pathophysiology are unknown.  
Fatigue may be caused by the malignancy itself or by cancer treatment and treatment-related anemia.   Physiologic factors that are known to contribute to CRF are cachexia, deconditioning, and high levels of certain cytokines, such as interleukin-1, interleukin-6, and tumor necrosis factor-a. Psychosocial factors that contribute to fatigue include anxiety, depression, and insomnia. Fatigue is also associated with high levels of other symptoms. In fact, fatigue commonly occurs in the context of multiple symptoms and, in this context, is highly correlated with decreased functional status.
Patterns of Fatigue
Patients with cancer frequently state that fatigue begins with cancer treatment or during the stressful diagnostic process. They report that fatigue continues during the course of active cancer treatment and declines when treatment is over. The fatigue may persist after treatment at a higher-than-baseline level, and a significant percentage of disease-free survivors report disruptive levels of fatigue for years after treatment. For example, in a survey of 1957 survivors of breast cancer, one-third reported severe and persistent fatigue 3 years after diagnosis.
Patterns of fatigue during the course of cancer treatments vary according to the type of treatment. Fatigue typically rises sharply after intravenous cytotoxic chemotherapy to a peak 48 to 72 hours later and drops to near-normal levels 3 weeks later, with a smaller peak occurring on days 10 to 14 with some regimens.   Studies have not shown substantial increases in fatigue during successive infusions.
During radiation therapy for breast cancer, fatigue levels typically increase linearly over time to a maximum intensity during the fourth week of treatment and then plateau. Levels of fatigue after radiation therapy return to normal in most patients within 3 weeks to 3 months but are more likely to persist at high levels after chemotherapy. In a study of 322 patients with breast cancer in remission, post-treatment fatigue levels were highest in women who received chemotherapy in addition to radiation therapy and lowest in those who received radiation therapy only.
The National Comprehensive Cancer Network has developed guidelines for the evaluation and treatment of CRF on the basis of available research findings and clinical experience (see www.nccn.org for the most recent guidelines). This multidisciplinary panel of experts in CRF developed an algorithm in which patients are screened regularly for fatigue by means of a brief screening instrument and are treated according to their level of fatigue and clinical status. The algorithm includes phases of screening, primary evaluation, intervention according to three levels of clinical status, and reevaluation ( Fig. 43-1 ).
Figure 43-1 Evaluation and management of cancer-related fatigue. (Adapted with permission from the National Comprehensive Cancer Network, Inc. Mock V, Atkinson A, Barsevick A, et al. NCCN [v.1.2003]. Cancer-related fatigue clinical practice guidelines in oncology. J Natl Comp Cancer Network 2003;1:308–331.)
Progress in the management of CRF has been limited by several factors relating to screening. Patients are reluctant to report fatigue to health care professionals because they fear that their cancer therapy may be modified, doses may be reduced, or treatment may be stopped. Another reason patients give for not reporting CRF is that they believe that it is a symptom to be endured (like sleep problems or emotional distress), which they should be able to manage themselves. Many health care professionals are reluctant to screen for CRF because they are unaware of evidence-based treatments or because they are unaware of the distress and interference with function that accompany fatigue. The result is that fatigue in patients with cancer is underreported, underdiagnosed, and undertreated.
The guidelines recommend that screening for the presence and severity of fatigue occur at the patient's initial contact with an oncology care provider, at appropriate intervals (including the follow-up period after treatment ends), and as clinically indicated. If the patient reports the presence of fatigue during screening, the fatigue should be quantified for future comparison. Although a variety of valid and reliable research instruments are available to measure the multiple dimensions of fatigue, many are lengthy and burdensome for patients with CRF. The guidelines recommend measuring the intensity of fatigue by using a brief clinical instrument such as the 0 to 10 rating scale commonly used to measure pain. On the 0 to 10 scale, 1 to 3 is generally considered to be a mild level of fatigue; 4 to 6 is moderate; and 7 to 10 is severe. Although moderate levels of fatigue may cause distress and a reduction in activity level, severe fatigue levels are accompanied by a marked decrease in the ability to work and perform other activities of daily living.  
If the patient reports no fatigue or a mild level of fatigue, education should be provided regarding fatigue as a possible or common side effect of treatment, especially if the patient is embarking on a treatment regimen that is known to cause fatigue. A plan to reevaluate the fatigue level as cancer treatment proceeds is appropriate because fatigue levels commonly rise in later stages of treatment. Patients and family members who do not receive this information often interpret decreased energy as a lack of treatment effectiveness or even a progression of disease, and the fatigue becomes a major source of worry.
If the screening process reveals a moderate or severe level of fatigue (4 to 10 on the 0 to 10 scale), the clinician should perform a focused history and physical examination as part of the primary evaluation phase. This evaluation includes an assessment of the patient's current disease status to rule out recurrence or progression and a review of current medications. Many of the medications that are used during cancer treatment, such as antiemetics and narcotics, may interact to produce lethargy and fatigue. Other medications the patient may be taking for comorbidities, such as β-blockers for cardiac conditions, may contribute to worsening of fatigue. The focused history should also include an in-depth fatigue assessment that evaluates the intensity and pattern of fatigue, the duration and changes over time, the exacerbating or alleviating factors, and interference with daily activities.
An essential component of the focused history is an assessment of treatable factors that are known to commonly contribute to fatigue. The factors that have been identified by the National Comprehensive Cancer Network practice guidelines panel are pain, emotional distress, sleep disturbance, anemia, nutritional status, activity level, and comorbidities. The guidelines recommend that these factors be assessed and treated as a first step in managing fatigue. Although these seven factors might not be the primary cause of the patient's fatigue, because they are known to increase the intensity as well as the distress of fatigue, treating these factors—if they are present—as an initial approach often reduces the fatigue to a tolerable level.
Numerous studies have shown that fatigue commonly clusters with pain, emotional distress, or sleep disturbance.    Depression, in particular, has been associated with fatigue.   Preliminary evidence suggests that the relationship between fatigue and depressive symptoms is mediated by functional status. Anemia commonly occurs in patients with cancer as a result of the neoplastic process or myelosuppressive therapies. Hemoglobin levels below 9 g/dL are often accompanied by severe fatigue, and improvements in energy are measurable with anemia correction to hemoglobin levels of 12 to 13 g/dL.
Nutritional deficits related to anorexia, nausea, vomiting, diarrhea, or mucositis can lead to impaired protein synthesis, weight loss, muscle wasting, cachexia, weakness, and fatigue in patients with cancer.  Appropriate treatment with supplementation and correction of fluid and electrolyte imbalances provides nutrients that are necessary for energy. Consultation with a nutrition expert may be appropriate.
Patients with moderate to severe fatigue should be assessed for changes in their ability to tolerate exercise and other daily activities. A decrease in regular activity frequently accompanies cancer diagnosis and treatment. The resulting deconditioning can be ameliorated by a progressive increase in activity, which could decrease fatigue.
Noncancer comorbidities are important potential contributors to CRF. The status and current management of identified comorbidities should be evaluated, and more effective treatment should be instituted if the comorbidity is not optimally managed. Comorbidities that require evaluation include infections; cardiac, pulmonary, renal, hepatic, neurologic, and endocrine dysfunction; and hypothyroidism.
If any of the seven contributing factors that are known to be associated with CRF are identified, they should be treated, and the fatigue should be reevaluated. If the patient continues to have moderate to severe levels of fatigue, treatment with nonpharmacologic and pharmacologic clinical interventions should be instituted in accordance with the patient's clinical status (e.g., receiving active cancer treatment, receiving disease-free long-term follow-up, or receiving palliative care at end of life). In many instances, a combination of approaches must be used to successfully reduce the fatigue and restore optimum functioning.
Interventions for the clinical management of CRF include both specific and general approaches. When an etiologic or contributing factor for CRF, such as anemia or insomnia, can be identified, it should be treated by using clinical practice guidelines as an initial approach to fatigue management. Guidelines provide “best care” information based on current evidence to support treatment. However, in many patients with cancer, no cause for fatigue can be readily identified beyond the disease and cancer therapies. In this situation, the approach to management is a general one.
Pharmacologic interventions include administration of erythropoietin alfa for chemotherapy-induced anemia, administration of medications for cause-specific treatments, such as antidepressants for depression, and thyroid hormone replacement for hypothyroidism. Corticosteroids have been shown to increase feelings of well-being and energy levels in some patients with advanced cancer, and psychostimulants have been used on a limited basis to increase energy and decrease fatigue.
Anemia is a common cause of CRF; it occurs in a majority of patients receiving myelosuppressive chemotherapy. Three community-based, nonrandomized, open-label studies    and two double-blind randomized trials comparing erythropoietin alfa   with placebo have shown a beneficial effect on CRF, transfusion requirements, and quality of life. Erythropoietin alfa is effective in subcutaneous doses of 10,000 U three times a week or 40,000 U weekly. Crawford and colleagues demonstrated that the incremental increase in the patient's quality of life was highest when the hemoglobin level rose from 11 to 12 g/dL. Research reports confirm the relationship between increases in hemoglobin during erythropoietin alfa treatment and quality-of-life improvements in patients with chemotherapy-related anemia.    These studies provide good clinical evidence for reduction of CRF by returning the hemoglobin level in the patient with cancer and anemia to a more normal value. Published guidelines support treatment with erythropoietin alfa.   It is important to note that although most patients with anemia report significant fatigue and there is good evidence of fatigue reduction with anemia correction, the causes of CRF are multifactorial, and many cancer patients with cancer and fatigue are not anemic.
Aside from the treatment with erythropoietin alfa, there have been few controlled studies that have investigated pharmacologic therapy for CRF, although a few clinical reports have been published. Psychostimulants have been found to relieve fatigue in other chronic conditions such as human immunodeficiency virus infection, but the data are limited regarding efficacy in CRF.
Methylphenidate has been found to be effective in reducing opiate-induced somnolence, acute depression, and cognitive dysfunction in the palliative care setting, but a randomized trial in cancer patients found no difference between methylphenidate and placebo in reducing fatigue levels.
Pemoline, a central nervous system stimulant similar to methylphenidate, has shown some effectiveness in relief of fatigue in patients with multiple sclerosis (46% response) but has not been tested in patients with cancer. In addition, serious liver problems have been reported in some patients receiving this drug. Modafinil has been used to treat narcolepsy, and some reports suggest that it might be helpful in managing CRF, but no clinical trials have been reported.
In summary, the evidence is strong for pharmacologic treatment for CRF in the case of erythropoietin alfa for correction of anemia, but evidence is insufficient to support the use of psychostimulants. More research is needed before recommendations can be made regarding the use of psychostimulants to manage CRF.
Nonpharmacologic interventions for CRF are notable in that they are effective, safe, and usually inexpensive; however, they have not been widely recognized for their efficacy, nor are they commonly included as standard of care for fatigue management. Nonpharmacologic treatments include alterations in activity and rest—including exercise, sleep therapy, and energy conservation—and psychosocial support programs and coping strategies to reduce stress.
Strong evidence from clinical trials supports the efficacy of exercise to manage fatigue in patients with cancer. The theory that supports exercise as a treatment for CRF suggests that the combined effects of cytotoxic treatments and reductions in physical activity during lengthy, often debilitating treatments lead to a decreased capacity for physical performance. Thus, even ordinary activities are perceived as fatiguing. Regular exercise, even at a moderate level, can maintain and increase functional capacity and result in greater exercise tolerance as evidenced by increased cardiac output, reduced heart rate, and less fatigue as less energy is required to perform equivalent work ( Box 43-1 ). If the patient has severe deconditioning, advanced disease, or significant comorbidities, referral to a rehabilitation program supervised by a physical therapist or specialist in physical medicine or rehabilitation is indicated.
EXERCISE PRESCRIPTION FOR CANCER-RELATED FATIGUE
At the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, we have evaluated a moderate symptom-limited walking exercise program to manage cancer-related fatigue in patients with solid tumors who are beginning outpatient treatment with adjuvant chemotherapy or radiation therapy. After initial testing with more than 100 patients with breast cancer, we have extended the program to include patients with prostate and colorectal cancer.
On screening during the cancer therapy planning visits, we identify patients who do not have metastatic disease or comorbidities that would contraindicate a regular walking program. In consultation with the patient's oncologist and an exercise physiologist, our oncology nurses teach the walking exercise program to consenting patients. Patients are given an individually tailored exercise prescription to follow throughout their cancer treatment. The initial prescription is to walk briskly for 15 to 20 minutes per day on 5 to 6 days of the week at a moderate intensity (with a target heart rate range of 60% to 80% of maximum heart rate), but the regimen is modified according to the patient's age, physical condition, and planned cancer therapy. Each walking session begins and ends with 3 to 5 minutes at a slow pace as “warm-up” and “cool-down” periods to protect the heart. Patients progress, as tolerated, to a maximum of 30 minutes of walking on 5 to 6 days per week. Very debilitated or sedentary patients might need to begin by walking for 5- to 10-minute sessions twice daily until they can tolerate longer periods. We contact patients every 2 weeks to discuss their progress with the program and the side effects of cancer treatment. The exercise program is adjusted as indicated. Patients are taught how to exercise safely—including how to monitor pulse rate—and when to contact the oncology care team to report signs and symptoms (e.g., dizziness, chest pain). Patients are encouraged to walk with a family member or friend at a convenient location, such as in their neighborhood, at a shopping mall, or at a community exercise facility. The program is well accepted by patients, the cost is low, and walking is beneficial and safe. Our patients have experienced no adverse events that could be attributed to the exercise program.
The cumulative evidence from studies of exercise in patients with cancer who are receiving active cancer treatment, as well as in long-term survivors, demonstrates that this health-promoting activity hasmany positive benefits and few risks for patients with cancer. Furthermore, a few cohort studies report significant improvements in survival related to increased levels of physical activity after cancer diagnosis.   
Four meta-analyses     and a number of systematic reviews       have addressed exercise as an intervention for cancer patients and survivors. The number of studies in the meta-analyses ranged from 14 to 35 depending on whether all types of trials or only randomized controlled trials were included. The reviewed studies examined the effects of various forms of aerobic exercise, resistance exercise, and combinations. They included supervised laboratory programs and home-based programs, both during cancer treatment and initiated after treatment. The majority of interventions consisted of aerobic exercise of moderate intensity (60% to 85%) of estimated maximal oxygen uptake (VO2 max) 3 to 5 days per week for 20 to 30 minutes each day for less than 3 months’ duration. All of the studies showed positive results for physical functioning, psychological well-being, and symptoms—including fatigue, difficulty sleeping, and nausea—as well as for health-related quality of life. Fatigue levels were found to be 40% to 50% lower in exercising subjects. Although no adverse events were reported in any of the studies, high-risk patients with serious comorbidities were excluded from participation. Adherence to exercise programs is a challenge for both healthy and chronically ill populations. In the studies of patients with cancer, adherence ranged from 60% to 80% in the home-based programs to 100% in laboratory studies, a marked contrast to the 50% dropout rate for healthy individuals who begin an exercise program. Apparently, patients with cancer are sensitized to the potential beneficial effects of health-promoting activities.
The published exercise studies of patients with cancer have notable limitations. The majority of the studies were samples of female patients with breast cancer, and ethnic diversity and age ranges were limited. Thus, the study results have limited generalizability to other cancer diagnoses, older individuals or children, and varied ethnic groups. Another limitation of the studies is that the exercise interventions were begun at a specific point in patients’ cancer therapy—either the beginning or the end—regardless of their level of fatigue. There is limited information about the effectiveness and feasibility of initiating an exercise program for patients who already have high levels of fatigue and have difficulty performing activities of daily living. Current evidence indicates preventing CRF by initiating regular exercise early in the course of cancer treatment may be more effective than managing high levels of fatigue after it develops.
Rest and Sleep
Oncology care providers commonly recommend additional rest and sleep to patients with cancer who report distressing levels of CRF. Patients who use additional rest and sleep to manage fatigue report that it helps but does not relieve the symptom. Several studies, in which actigraphy was used to measure activity and sleep, indicate that patients with cancer spend increased time resting and sleeping but that their pattern of sleep may be severely disrupted, with awakenings nearly every hour.   Frequent night awakenings were accompanied by lower levels of daytime activity, more daytime napping, and high levels of fatigue. The potential for deconditioning resulting from reductions in activity during lengthy cancer treatments may be an important contributing factor to CRF. Although sleep disturbances have been identified as a neglected problem in oncology, the relationship between sleep problems and CRF has been inadequately explored. Few studies in which a sleep intervention was tested in cancer patients have been published.
Energy conservation is an intervention that utilizes planned management of personal energy resources to prevent their depletion. Strategies include priority setting, use of labor-saving devices, balancing periods of rest and activity, and delegating activities of lesser importance. Energy conservation may be a particularly useful intervention for patients with advanced disease or those with significant weakness or debilitating fatigue. Although research is limited, results of a pilot study testing an energy conservation intervention has been published and indicates beneficial effects.
Studies of psychosocial interventions aimed at stress reduction and improved coping have also demonstrated reductions in fatigue. Since both depression and anxiety may be characterized by fatigue, it has been proposed that CRF is a response to the stress of cancer diagnosis and treatment through activation of the hypothalamic-pituitary-adrenal axis. Since it is also evident that high levels of fatigue may lead to emotional distress when valued roles and activities are affected, the precise relationship between emotional distress and fatigue is not clearly understood.
Psychosocial interventions tested include cognitive behavior therapy, psychoeducational counseling,   a comprehensive coping strategy, and stress management training. The investigations were randomized controlled clinical trials with adequate sample sizes and included a variety of cancer populations. All studies demonstrated significant effects of the intervention on fatigue levels. A limitation of several of the studies was that fatigue was a secondary endpoint that was measured by either a single item or a subscale of an instrument used to measure emotional distress.
Fatigue is the most prevalent symptom reported by patients with cancer and the source of much distress for them. Fatigue may have profound effects on functional status and quality of life. However, clinical evaluation and management of this disturbing side effect of cancer and cancer treatment have been limited as a function of both patient and care provider barriers. Patients have been hesitant to report fatigue, and clinicians have been unaware of effective treatments.
Effective management of CRF begins with informed and supportive oncology care providers who perform initial and regular screening for fatigue and provide treatment as indicated by the patient's fatigue level. When the patient's fatigue levels are mild, education about fatigue is indicated. When fatigue levels are moderate or severe, the initial screening is expanded to include a focused evaluation of current disease and treatment status, review of body systems, and an in-depth fatigue assessment. The patient should be assessed for the presence of treatable contributing factors such as pain, emotional distress, sleep disturbance, anemia, nutritional deficits, decreased activity level, and unmanaged comorbidities. If any of these conditions are present, they should be treated as an initial step, and the fatigue should be reevaluated. If none of these factors are present or if fatigue levels remain moderate or severe, fatigue management strategies should be considered as appropriate for the patient's clinical status.
Evidence-based interventions for managing CRF include correction of anemia, moderate exercise regimens, and psychosocial support programs. A combination approach might be needed, and referral to other members of the multidisciplinary team should be considered. Although CRF is common and expected, it can be managed and does not need to be distressful and disruptive to quality of life.
Several important gaps exist in our knowledge of fatigue and fatigue management. These are reflected in the recommendations for future research presented in Box 43-2 . However, evidence-based practice guidelines are available to guide clinical care of patients with CRF, and health care professionals are increasingly aware of the importance of addressing this distressing symptom.
RECOMMENDATIONS FOR FUTURE CANCER-RELATED FATIGUE RESEARCH