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Fatigue is the most common side effect of cancer treatment with chemotherapy, radiation therapy, or selected biologic response modifiers. Cancer treatment-related fatigue generally improves after therapy is completed, but some level of fatigue may persist for months or years following treatment. Research indicates that for at least a subset of patients, fatigue may be a significant issue long into survivorship.[2,3] Fatigue is also seen as a presenting symptom in cancers that produce problems such as anemia, endocrine changes, and respiratory obstruction and is common in people with advanced cancer who are not undergoing active cancer treatment. Cancer treatment-related fatigue is reported in 14% to 96% of patients undergoing cancer treatment [4,5,6,7,8,9,10] and in 19% to 82% of patients posttreatment.[1,2]
Several studies have documented significantly worse fatigue in cancer survivors compared with noncancer populations, as described in one review article. For example, a Norwegian cross-sectional study  compared the prevalence of fatigue in long-term survivors of testicular cancer (n = 1,431) at an average of 11 years posttreatment with the prevalence of fatigue in age-matched men in the general Norwegian population (n = 1,080). The prevalence of chronic cancer-related fatigue (CRF) was 17.1% (95% confidence interval [CI], 15.2-19.1%) among testicular cancer survivors, compared with 9.7% (95% CI, 8.0-11.5%) in the general population. Chronic CRF was also associated with multiple psychosocial problems, somatic complaints, and poor quality of life.
Fatigue, like pain, is viewed as a self-perceived state. Patients may describe fatigue as feeling:
Health professionals have included fatigue within concepts such as:
Research on fatigue in people with cancer has included primarily self-reports of fatigue, with fewer but increasing data exploring biologic or physiologic correlates. Such correlates have included measures of muscle weakness, maximal oxygen uptake, cytokines, and cortisol.
Fatigue experienced as a side effect of cancer treatment is differentiated from fatigue experienced by healthy people in their daily lives. Healthy fatigue is frequently described as acute fatigue that is eventually relieved by sleep and rest; cancer treatment-related fatigue is categorized as chronic fatigue because it is present over a long period of time, interferes with functioning, and is not completely relieved by sleep and rest. Also, the level of CRF is often disproportionate to the level of activity or energy exerted. Although the label chronic fatigue is accurate, using this label does not mean that people with cancer who experience fatigue have chronic fatigue syndrome. Using the phrase chronic fatigue can be confusing to both patients and health professionals. Terms such as cancer fatigue, cancer-related fatigue, and cancer treatment-related fatigue have all been used in the clinical literature, research literature, and educational materials for patients and the public.
Fatigue has a negative impact on all areas of function, including the following:[14,15,16,17]
The pattern of fatigue associated with cancer treatment varies according to type and schedule of treatment. For example, people treated with cyclic chemotherapy regimens generally exhibit peak fatigue in the days following treatment, then report lower levels of fatigue until the next treatment; however, those undergoing external-beam radiation therapy report gradually increasing fatigue over the course of therapy of the largest treatment field. Few studies of people undergoing cancer treatment have addressed the issue of fatigue as a result of the emotional distress associated with undergoing a diagnostic evaluation for cancer and the effects of medical and surgical procedures used for that evaluation and for initial treatment. Because most adults enter the cancer care system following at least one surgical procedure and because surgery and emotional distress are both associated with fatigue, it is likely that most people beginning nonsurgical treatment are experiencing fatigue at the beginning of treatment.[19,20]
Recommendations for fatigue management focus on identifying factors that may be contributing to fatigue. Because the only definitive causal mechanism demonstrated through research to date is chemotherapy-induced anemia, most clinical recommendations for managing fatigue caused by something other than chemotherapy-induced anemia rely on careful development of clinical hypotheses, as outlined in the National Comprehensive Cancer Network guidelines on fatigue. The only level 1 intervention for CRF at this time is exercise. (Refer to the Exercise section of this summary for more information.) Much more research is needed to better define fatigue and its trajectory, understand its physiology, and determine the best ways to prevent and treat it.
In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.
Except for chemotherapy-induced anemia, the mechanisms responsible for fatigue in people with cancer are not known. Understanding the causes of fatigue in people with cancer is especially challenging because each individual may experience multiple possible causes of fatigue simultaneously. This multifactorial etiologic hypothesis is apparent in the various models that have been proposed for the study of fatigue.[1,2] Energy balance, stress, life demands, sleep, neurophysiologic changes, disruption of circadian rhythms, cardiac issues, and neuroimmunologic changes are generally incorporated in these models, based on the rationale that these factors are associated with fatigue in contexts other than cancer. The cancer literature supports some of these variables.
There is a burgeoning amount of evidence, particularly in women with breast cancer and men with prostate cancer, that fatigue is associated with markers of increased immune inflammatory activity. When fatigued individuals with a history of breast cancer are compared with breast cancer survivors without fatigue, different patterns emerge with respect to interleukin-6, interleukin-1 receptor antagonist, C-reactive protein, neopterin, and soluble tumor necrosis factor receptor-II.[4,5,6] Although the precise relationships-and the clinical meaning of those relationships-are not yet known, increased cytokines likely contribute to the symptoms of asthenia, fatigue, and lethargy, as supported in animal models of cytokine-induced sickness behavior [7,8] and in humans. There have not yet been large, well-controlled studies that have evaluated the effects of general anti-inflammatory agents on fatigue or cytokine biomarkers.
Other studies demonstrate a change in the regulation of cortisol by the hypothalamic pituitary adrenal axis. One key study put fatigued and nonfatigued breast cancer survivors through a stress battery in a laboratory setting. Nonfatigued survivors mounted a significant cortisol increase in response to acute stress, while fatigued survivors had a very blunted response. Another study has shown fatigued breast cancer survivors have flattened cortisol slopes, having higher levels of cortisol at the end of the day than do nonfatigued survivors. It is the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis that may account for the prolonged inflammatory cytokine milieu; understanding the body's response to numerous chronic stressors in cancer may help in managing fatigue.
Finally, another theory is that serotonin is negatively impacted through chronic exposure to proinflammatory cytokines. One hypothesis is that the relationship between central nervous system concentrations of serotonin and fatigue have a U-shaped relationship, suggesting that very high and very low levels of serotonin may be associated with cancer-related fatigue. However, studies that have evaluated serotonergic agents have not demonstrated a benefit for fatigue. The role and relationship of many important neurotransmitters such as dopamine, norepinephrine, and serotonin with HPA axis functioning and cytokine expression have yet to be fully understood.
Although fatigue is clearly prevalent in patients with cancer, it has been difficult to identify consistent correlates of fatigue in this patient population. The factors most often implicated have been the following:[1,2,3,4,5,6,7,8,9]
The association of fatigue with the major cancer treatment modalities of surgery, chemotherapy, radiation therapy, and biologic response modifier therapy caused speculation that fatigue resulted from tissue damage or accumulation of the products of cell death. Interest in the effects of cancer treatment on the production of proinflammatory cytokines is based on recognition of the strong fatigue-inducing effect of some biologic response modifiers such as interferon-alpha and the finding of elevated levels of proinflammatory cytokines in people experiencing persistent fatigue following cancer treatment.[10,11]
Many people with cancer undergo surgery for diagnosis or treatment. Despite the high incidence of postoperative fatigue observed in clinical practice, little research exists that examines causes and correlates of postoperative fatigue in people with cancer. It is clear, however, that fatigue is a problem postsurgery that improves with time and is compounded by fatigue experienced from other cancer treatments.
Fatigue has long been associated with radiation exposure and is reported as being one of the most common and activity-limiting side effect of radiation therapy for cancer.[4,13] Most of the research describing the fatigue trajectory during radiation therapy has been conducted with women who have breast cancer and men who have prostate cancer.[13,14] Fatigue increases throughout radiation therapy, peaking around mid course; it remains at this level until radiation therapy is completed, improving somewhat during the 2 months after completion of treatment.[13,14,15] A study that investigated the trajectory of fatigue in men (n = 82) who were undergoing radiation therapy for prostate cancer found significant interindividual variability. The authors used hierarchical linear modeling, a highly sophisticated analytical method, to identify predictors for prolonged fatigue trajectories. Younger men with a high level of fatigue at radiation therapy initiation were at increased risk of higher levels of morning and evening fatigue during the course of radiation therapy. Additionally, level of depression at radiation therapy initiation predicted the level of morning fatigue during the course of radiation therapy.
A second study that included 73 women who were undergoing adjuvant radiation therapy for breast cancer found similar differences in the patterns and predictors of morning versus evening fatigue. Participants were recruited to the study at the time of their simulation visit and completed baseline questionnaires. Data were then collected on 2 subsequent days, in the morning and at bedtime, each week during radiation therapy; every 2 weeks for 2 months after radiation therapy; and once a month for 2 additional months thereafter. Fatigue was measured with the Lee Fatigue Scale. For the group as a whole, over the 25 weeks of data collection, morning fatigue decreased slightly during radiation therapy and was constant for 4 months afterwards, while evening fatigue increased through radiation therapy and then declined slightly after treatment. Evening fatigue was higher for those who:
Morning fatigue was higher for those who:
Advanced disease and comorbidities also added to the severity of morning fatigue.[Level of evidence: III]
A number of research studies document the existence of a fatigue syndrome that is not specific to the disease type or radiation site and that demonstrates a gradual decline in fatigue in the patient after treatment is completed.[15,17,18,19,20] Some of these studies suggest, however, that not all patients return to pretreatment energy levels. Specific etiologic factors and correlates of fatigue associated with radiation therapy have not been identified. Risk factors for persistent low energy in cancer patients include older age, advanced disease, and combination-modality therapy.
Fatigue is a dose-limiting toxicity of treatment with a variety of biotherapeutic agents. Biotherapy exposes patients with cancer to exogenous and endogenous cytokines. Biotherapy-related fatigue usually occurs as part of a constellation of symptoms called flulike syndrome. This syndrome includes:
Mental fatigue and cognitive deficits have also been identified as biotherapy side effects. The type of biotherapeutic agent used may influence the type and pattern of fatigue experienced.
Treatment with chemotherapy is a predictor of fatigue and can be exacerbated by the coexistence of pain, depression, and/or anxiety.[Level of evidence: II] A longitudinal, descriptive study reported highest levels of fatigue at the midpoint of a patient's chemotherapy cycles, with fatigue improving after treatment but not quite returning to baseline levels 30 days after the last treatment. In another longitudinal study of women with stage 0 to stage II breast cancer who received chemotherapy with or without radiation therapy (N = 103) versus radiation therapy alone (N = 102) versus a control group (N = 193), increases in fatigue were demonstrated 3 years posttreatment for the group that received chemotherapy with or without radiation therapy, compared with the two other groups. Mean scores for fatigue severity as measured by the Fatigue Symptom Inventory (range, 0-10) increased over the 3 years as follows:
There were statistically significant group-by-time effects for the group that received chemotherapy with or without radiation therapy. This increase in fatigue was not explained by hormone therapy and approached clinically meaningful values. It is not currently known what specific patient characteristics are associated with risk for long-term increased fatigue or more severe fatigue and who will experience fatigue resolution.
Evidence suggests that anemia may be a major factor in cancer-related fatigue (CRF) and quality of life in cancer patients.[28,29,30] Anemia can be related to the disease itself or caused by the therapy. Occasionally, anemia is simply a co-occurring medical finding that is related to neither the disease nor the therapy. Anemia is often a significant contributor to symptoms in persons with cancer. For individual patients, it can be difficult to discern the actual impact of anemia because there are often other problems that confound the ability to weigh the specific impact of anemia. The impact of anemia varies depending on factors such as:
A retrospective review was conducted to understand the problem of anemia in patients undergoing radiation therapy. Anemia was prevalent in 48% of the patients initially, and increased to 57% of the patients during therapy. It was more common in women than men (64% vs. 51%); however, men with prostate cancer experienced the greatest increase in anemia during radiation therapy. In certain cancers, such as cancer of the cervix and cancer of the head and neck, anemia has been found to be a predictor of poor survival and diminished quality of life in patients undergoing radiation therapy.[33,34,35,36]
Fatigue often occurs when the energy requirements of the body exceed the supply of energy sources.[37,38] In people with cancer, three major mechanisms may be involved:
Causes of nutritional alterations are listed in Table 1.
Numerous factors related to the moods, beliefs, attitudes, and reactions to stressors of people with cancer can also contribute to the development of chronic fatigue. Anxiety and depression are the most common comorbid psychiatric disorders of CRF. Often, fatigue is the final common pathway for a range of physical and emotional etiologies.
Depression can be a comorbid, disabling syndrome that affects approximately 15% to 25% of persons with cancer. The presence of depression, as manifested by loss of interest, difficulty concentrating, lethargy, and feelings of hopelessness, can compound the physical causes for fatigue in these individuals and persist long past the time when physical causes have resolved.
Anxiety and fear associated with a cancer diagnosis, as well as its impact on the person's physical, psychosocial, and financial well-being, are sources of emotional stress. Distress associated with the diagnosis of cancer alone may trigger fatigue. A study of 74 early-stage breast cancer patients with no history of affective disorder assessed various symptoms of adjustment approximately 2 weeks after diagnosis; about 45% noted moderate or high levels of fatigue. This fatigue may have been secondary to the increased cognitive strain of dealing with the diagnosis or to insomnia, reported as moderate to severe by about 60% of the patients. Therefore, fatigue may begin before treatment as a result of worry or other cognitive factors, both primary and secondary to insomnia. Various forms of treatment may compound this fatigue.
In cancer survivors, fatigue may also be increased above levels seen in the general population.[43,44] In testicular cancer survivors, anxiety and depression were predictive of fatigue, suggesting a possible role for psychiatric intervention in fatigue management. (Refer to the PDQ summaries on Depression and Adjustment to Cancer: Anxiety and Distress for more information.)
Psychologic and symptom distress have also been found to be significant predictors of fatigue.[46,47] In a study of 101 women about to undergo surgery for breast cancer, younger age, presurgery distress, and expectations about fatigue significantly predicted fatigue levels 1 week after surgery. In the regression model, age, distress and expectancy each uniquely contributed to fatigue, with distress and expectancy accounting for 25% of the variance.[Level of evidence: III] In a longitudinal study with women who had gynecologic cancer, symptom and psychologic distress significantly predicted fatigue before, during, and after treatment with chemotherapy, explaining up to 80% of the variance in fatigue scores after chemotherapy treatment.
Impairment in cognitive functioning, including decreased attention span and impaired perception and thinking, is commonly associated with fatigue.[48,49] Although fatigue and cognitive impairments are linked, the mechanism underlying this association is unclear. Mental demands inherent in the diagnosis and treatment of cancer have been well documented, but little is known about the concomitant problem of attention fatigue in people with cancer. Attention problems are common during and after cancer treatment. Some of the reported attention problems may be caused by the fatigue of directed attention.[50,51] Attention fatigue may be relieved by activities that promote rest and recovery of directed attention. Although sleep is necessary for relieving attention fatigue and restoring attention, it is insufficient when attention demands are high. Empirical literature suggests that the natural environment contains the properties for restoring directed attention and relieving attention fatigue.
Sleep Disorders and Inactivity
Causative or contributing factors in CRF may be:
Patients with less daytime activity and more nighttime awakenings were noted to consistently report higher levels of CRF. Those with lower peak-activity scores, as measured by wristwatch activity monitors, experienced higher levels of fatigue.
Sleep disorders clearly contribute to fatigue  and may differentially affect fatigue ratings, depending on the time of the rating. A study that evaluated fatigue in women undergoing radiation therapy for breast cancer found that sleep had a greater influence on morning fatigue values than on evening fatigue scores. In a similar study of men undergoing radiation therapy for prostate cancer, sleep contributed to both morning and evening fatigue levels. However, fatigue and sleep can also be distinct problems. One study that resulted in significant improvement in sleep with the use of cognitive behavioral therapy did not significantly affect fatigue.
Refer to the PDQ summary on Sleep Disorders for more information.
Medications other than chemotherapy may contribute to fatigue. Opioids used in the treatment of cancer-related pain are often associated with sedation, though the degree of sedation varies among individuals. Opioids are known to alter the normal function of the hypothalamic secretion of gonadotropin-releasing hormone.
Hypogonadism may be found in patients with advanced cancer and can contribute to fatigue during cancer treatment. One case-control study examined the effects of chronic oral opioid administration in survivors of cancer and, consistent with the research on intrathecal administration, found marked central hypogonadism among the opioid users with significant symptoms of sexual dysfunction, depression, and fatigue. One trial (NCT00965341) has studied whether testosterone replacement therapy affects fatigue in men with advanced cancer and low testosterone levels; results are pending.
Other medications-including tricyclic antidepressants, neuroleptics, beta blockers, benzodiazepines, and antihistamines-may produce side effects of sedation. In addition, concurrent medications such as analgesics, hypnotics, antidepressants, antiemetics, steroids, or anticonvulsants-many of which act on the central nervous system-can significantly compound the problem of fatigue. The coadministration of multiple drugs with varying side effects may compound fatigue symptoms.
Assessment of fatigue is multidimensional in nature, and a number of tools originally developed for fatigue research have also been used in clinical practice. Most of these tools include symptom dimensions other than fatigue intensity, such as the impact or consequences of fatigue, timing of fatigue, related symptoms, and self-care actions.[2,3,4,5,6,7,8,9,10] Research has also contributed a validated 10-item measure for children.
However, much of the time in clinical practice, because of perceived provider/patient burden, screening most often relies on a single-item fatigue intensity rating.[12,13,14,15] According to National Comprehensive Cancer Network (NCCN) guidelines, ratings of fatigue of 4 or higher on a scale of 0 to 10 (where 10 is very severe fatigue) are further evaluated for known contributing factors such as pain, emotional distress, anemia, sleep, nutrition, and level of activity. These comorbidities are then treated. One study of ambulatory outpatients with solid tumors (N = 148) evaluated the usefulness of single-item screening for symptoms such as fatigue and pain. Investigators found that the single-item assessment can assist as a first screening step to identify patients requiring comprehensive assessment of symptoms. Patients identified by using single-item screening tools undergo comprehensive assessments to detect clinically relevant symptomatology.[12,13]
Ambiguous literature and a previous lack of specific tools to measure fatigue have created difficulties in establishing assessment and management guidelines. Comprehensive assessment of the fatigued patient starts with obtaining a careful history to characterize the individual's fatigue pattern and to identify all factors that contribute to its development. The following may be included in the initial assessment:
Specific attention is paid to underlying factors that contribute to fatigue and may be correctable, including the following:[17,18]
Proposed criteria for cancer-related fatigue (CRF) are listed below. These criteria have been adopted for inclusion in the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Clinical Modification (ICD-10-CM).
Defining CRF as a diagnostic syndrome has some potential advantages and disadvantages. One of the possible advantages is that it would enable clinicians to document the presence or absence of fatigue in a reproducible fashion. It may also be useful in establishing appropriate reimbursement for management of this finding. The potential disadvantage of this approach is that it may deter management of fatigue that does not reach the threshold for ICD-10 diagnosis. The alternative to the syndrome-based approach (commonly used for depression) is a symptom-based approach, which is commonly used for phenomena such as pain and nausea. The utility of the following ICD-10 criteria for CRF has not been validated.
ICD-10 Criteria for Cancer-related Fatigue
The following symptoms have been present every day or nearly every day during the same 2-week period in the past month:
As with other self-reported symptoms such as pain, it may be necessary to encourage the patient and other family members to report symptoms of fatigue to the medical staff. Information regarding the potential for fatigue due to the underlying disease or treatments, possible options for management, and the importance of reporting these symptoms is given to patients at the initiation of treatment. Patients may not mention the fatigue they experience unless they are prompted by a health professional.
Several barriers hamper appropriate management of CRF. Some of these barriers were identified in phase 1 of an ongoing three-phase project related to the implementation of evidence-based (NCCN) guidelines for fatigue management. The most commonly identified barriers were the following:[21,22]
Although there is no universally accepted standard for the measurement of fatigue, there are a variety of instruments that have been developed to assess fatigue and related sequelae.[2,3,4,5,6][Level of evidence: II];[7,8,9,10] Fatigue is also commonly assessed in multidimensional quality-of-life instruments. Selected instruments for assessing fatigue are listed below.
Evaluation of Anemia
The proper evaluation of anemia in cancer patients includes the following:
In combination, the information from these investigations is often diagnostic.
One commonly used method for classifying anemia is to categorize the anemia by the size of the red blood cell as measured by the mean corpuscular volume (MCV). Microcytic anemias are associated with an MCV of 79 fL or lower and include iron-deficiency anemia, thalassemia, and anemia of chronic disease. Macrocytic anemias are associated with an MCV higher than 101 fL and include anemias related to vitamin B12 or folate deficiency, myelodysplasia, and liver disease. Most anemias are normocytic, meaning that the MCV is in the normal range. This category includes the following:
However, a mixed red blood cell population consisting of both microcytic and macrocytic cells (anisocytosis) may indicate a combined etiology, for example, chronic blood loss (microcytic) with resultant reticulocytosis (macrocytic). In this situation, the MCV may be in the normal range, but the red blood cell size distribution width would be elevated.
The peripheral blood smear examination, though often overlooked, remains an important step in the evaluation of anemia. For example, nucleated blood cells and teardrop-shaped red blood cells suggest myelophthisic anemia. Macro-ovalocytes and hypersegmented neutrophils often indicate megaloblastic anemia. Small target cells and basophilic stippling are associated with thalassemia.
Additional studies that are sometimes required to characterize anemia in a given patient include testing of vitamin B12 or folate levels; serum iron, transferrin, and ferritin levels; erythropoietin level, the direct and indirect Coombs test, and/or examination of a bone marrow aspirate and biopsy. In cancer patients, the underlying etiology is often multifactorial.
Much of the information regarding interventions for fatigue relates either to healthy subjects or to persons in whom muscle fatigue is the primary etiology of the problem or fatigue is secondary to treatment-related anemia.[1,2][Level of evidence: II];[3,4] Without a determination of the causative mechanisms of fatigue in oncology patients, interventions must be directed to symptom management and emotional support. Although some recommendations for the management of fatigue in oncology patients have been made, these are theoretical or anecdotal in nature and in general have not been the focus of scientific evaluation.
Published in 2013, a study conducted in patients with advanced cancer (N = 152) demonstrated that managing symptoms (e.g., pain, nausea, and decreased appetite) can have a significant positive impact on fatigue. In this 12-week study, patients were randomly assigned to receive either monitoring and protocolized treatment of physical symptoms coordinated by a nurse or care as usual (symptom management included in the standard oncologic care). Patients in the intervention group received tailored treatment for any of the identified troublesome symptoms. Fatigue levels, as measured by the Multidimensional Fatigue Inventory, showed significant improvement in the intervention group compared with the group receiving care as usual. The intervention group also showed improvements in the following:
Similar studies are needed to investigate whether treatment of specific physical and psychological symptoms can alleviate fatigue and to identify patient populations that might benefit from such management. One message of this study may be that fatigue can be a primary symptom or a secondary symptom (a result of other bothersome problems). Therefore, assessing patients for the appropriate target symptom for intervention is probably the most efficient way to help patients improve health-related quality of life.
Because the etiology and mechanisms regarding fatigue/asthenia in cancer patients are indeterminate, there is considerable variation in practice patterns regarding the management of this symptom. The focus of medical management is often directed at identifying specific and potentially reversible correlated symptoms, as in the following examples:
It is often helpful to consider discontinuation of drugs that may be safely withheld. There is no agreed-upon approach for the evaluation and treatment of fatigue, but an increasing number of clinical trials are designed to address this issue in cancer patients.
Treatment of Anemia
Anemia in patients with cancer is best managed by treatment of the underlying cause. When the cause is obscure or there is no specific remedy, then treatment is supportive. Nutritional interventions, including the intake of nutrient-rich foods and supplements, are considered in addition to other treatment modalities. Transfusion of packed red blood cells is the most widely used and most rapid way to alleviate symptoms in cancer patients with symptomatic anemia. The likelihood of success in raising the level of hemoglobin is very high with transfusion, and the risks of complications are low. Nevertheless, repeated transfusions can be cumbersome, and the risks of blood-borne infection can be worrisome for patients. Other risks include an acute transfusion reaction, transfusion-associated graft-versus-host disease, subtle immune modulation that occurs with transfusion, and iron overload in patients who receive repeated transfusions.
Several large, community-based studies have examined the effectiveness of epoetin alfa and darbepoetin alfa [Level of evidence: I];[Level of evidence: I] in the treatment of cancer-related anemia in patients receiving chemotherapy.[Level of evidence: II];[Level of evidence: III];[Level of evidence: I] A few of the studies of epoetin alfa employed an open-label, nonrandomized design and included objective endpoints (hemoglobin response, transfusion requirements) and subjective evaluation of fatigue and quality of life. In this setting, epoetin alfa has been effective at increasing hemoglobin levels and decreasing transfusion requirements. In addition, epoetin alfa has been associated with improved functional status and quality of life, independent of tumor response. Several studies of epoetin alfa and darbepoetin alfa employed a randomized, controlled design. These studies varied in terms of medication dosage and frequency of administration. A review and meta-analysis of randomized and open-label studies concluded that these agents are effective in the management of CRF  but also raised serious concerns about safety data and adverse outcomes associated with these agents. The authors concluded that the risks associated with these agents outweigh their benefits for the treatment of CRF and therefore are not to be used.
The FDA has conducted a comprehensive review of safety information from studies of these agents. The review showed that in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers, erythropoiesis-stimulating agents (ESAs) shortened overall survival and/or increased the risk of tumor progression or recurrence. The review also showed that ESAs increase the risk of serious cardiovascular and thromboembolic events when they are administered to target higher hemoglobin levels (13.5-14 g/dL).
On the basis of these findings, the FDA mandated revised ESA labeling to include an updated warning, a new boxed warning, and modifications to the indications and dosing instructions. The boxed warning includes information on the higher mortality risks caused by cardiovascular/thromboembolic events and tumor progression or recurrence. The 2010 American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) guidelines recommend the following:
A Cochrane review concluded that ESAs provide a clinically significant reduction in fatigue for anemic patients receiving chemotherapy. However, on the basis of safety concerns raised by the FDA and in view of identified side effects, this review further concluded that ESAs should not be used in clinical practice for fatigue. Clinicians initiate discussions with patients and family members about the risks and benefits of ESAs.
In February 2010, the FDA approved and mandated a risk management program to inform health care providers and their patients about the risk of ESAs.[12,17] This program includes a specific medication guide for patients that, along with the FDA public health advisory, states that ESAs are not approved or indicated for the treatment of fatigue in patients with cancer.
One of the most popular categories of pharmacologic interventions evaluated for cancer-related fatigue (CRF) is psychostimulants (see Table 2). Psychostimulants are drugs that interact with neurotransmitters and receptors in the brain to increase cortical function. Different types of psychostimulants work through various mechanisms to produce activity in the brain consistent with short-term improvement in energy level and psychomotor activity. These medications may also improve mood, attention, and concentration in some populations. Psychostimulants on the market include the following:
Initial support for the hypothesis that psychostimulants may improve CRF arises largely from clinical anecdotal experiences. These medications are not approved by the U.S. Food and Drug Administration (FDA) for the treatment of CRF. However, preliminary evidence from randomized controlled studies [19,20,21] suggests that these medications might be helpful in a subpopulation of patients experiencing more severe fatigue. There are at least seven published randomized clinical trials evaluating psychostimulants for CRF: six with methylphenidate and one with modafinil. Only one of these randomized trials  has shown significant differences between the placebo group and methylphenidate group with respect to the outcome of fatigue.
The one study that demonstrated significant improvements over placebo for CRF used a mean dose of 27.7 mg of the D-isomer of methylphenidate as a study intervention. The population that benefited was women who had completed chemotherapy for breast or ovarian cancer. The study design incorporated a titration to effect, so some patients who may have benefited may have received more than 27.7 mg of the drug. Furthermore, 11% of participants on this trial withdrew because of adverse events, compared with 1% in the placebo arm. Conversely, an equally large randomized controlled trial randomly assigned patients with early and advanced disease, both on and off treatment, to receive 54 mg of a long-acting methylphenidate preparation equaling 27 mg of the D-isomer or a placebo; this trial found no differences between the two groups in any of the fatigue outcomes.[Level of evidence: I] There were significant differences between groups for nervousness and appetite loss, with the methylphenidate arm scoring worse on both of those side effects.
The newer so-called wake-promoting agents, modafinil and armodafinil, are just beginning to be studied for CRF. Modafinil is a centrally acting, nonamphetamine, central nervous system stimulant. Armodafinil is the R-enantiomer of modafinil and an alpha-1 adrenoceptor agonist. Modafinil and armodafinil are approved by the FDA for narcolepsy, obstructive sleep apnea, and shift-work disorders. Neither of these agents is approved by the FDA for the treatment of CRF. These agents are also not indicated for use in children and adolescents. The mechanism of action of modafinil and armodafinil is different from that of amphetamines, but the exact mechanisms by which these agents improve wakefulness are not known. On the basis of a couple of promising open-label pilot trials,[25,26] a large randomized controlled trial evaluated modafinil for CRF using 200 mg versus placebo in more than 850 patients receiving chemotherapy. Patients had to have fatigue ratings of at least 2 out of 10 to be eligible for this study. During four cycles of chemotherapy, this study failed to show significant differences between arms. Because armodafinil is newer to the marketplace, research on its possible role in CRF has not yet been published. More research is needed to identify whether modafinil and armodafinil can ameliorate fatigue and which populations of cancer survivors can benefit most from them.
With both methylphenidate and modafinil, there have been exploratory data suggesting that patients with more severe fatigue or more advanced disease may receive more benefit from these drugs.[21,22] A small (n = 13), randomized, placebo-controlled study  using methylphenidate (titrated up to 30 mg/day) as an intervention failed to show statistical difference on the primary outcome measure, the Brief Fatigue Inventory (BFI) total score, or activity interference subscale. However, the methylphenidate group showed significant reductions in the BFI severity subscale scores compared with the reductions seen in the placebo group. The mean severity score at baseline was 6.5 for the methylphenidate group and 5.7 for the placebo group, placing these patients in a more severe fatigue category. A secondary analysis of the phase III trial that evaluated modafinil versus placebo for CRF also revealed that patients with more severe fatigue may have benefited from modafinil. More research is needed to further evaluate whether psychostimulants are beneficial for patients experiencing more severe CRF.
The side effects most commonly described with psychostimulants include the following:[19,21,22,27,28]
High doses and long-term use may produce:
Patients with cancer carry a higher risk of cardiovascular complications, depending on the type of cancer and cancer treatment (e.g., cardiotoxic chemotherapy regimens). Cardiovascular complications with psychostimulants can arise even in patients without any significant risk factors. In the study using methylphenidate as an intervention for the treatment of CRF in patients with prostate cancer, 6 of 16 subjects (27%) in the methylphenidate group were discontinued because of increased blood pressure and tachycardia. It is important to note that none of these subjects were being treated with known cardiotoxic chemotherapeutic regimens such as anthracyclines. Careful and continuous monitoring of certain cardiovascular parameters (mainly blood pressure and heart rate) is critical when psychostimulants are used to treat CRF. In certain complex cases, consulting with cardiology services may be considered. Cardiovascular issues are thought to be less of a risk with modafinil and armodafinil. Risk-benefit ratio may be considered and patients may be evaluated for response and side effects when these agents are used to treat CRF.
The package inserts for all Schedule IV stimulant medications carry boxed warnings indicating risk of abuse potential and/or risk of psychological dependence. Additionally, boxed warnings for certain stimulant medications (methylphenidate and dexmethylphenidate products) indicate risk of psychotic episodes. Other stimulant medications (amphetamine, dextroamphetamine, lisdexamfetamine dimesylate, methamphetamine, and mixed salts of amphetamine products) carry boxed warnings alerting clinicians that misuse of these medications may cause serious cardiovascular adverse events, including sudden death.
On the basis of limited clinical experience and acknowledging a lack of evidence in randomized controlled trials, it might be reasonable to consider a psychostimulant such as methylphenidate or modafinil for the treatment of severe fatigue, particularly for short periods of time (a couple of weeks) in patients with advanced disease. When the use of these medications is being considered, it is important to obtain informed consent, with careful discussion of risks, benefits, and alternatives. Continuous monitoring of cardiovascular parameters is crucial when these medications are used, especially in patients with preexisting cardiovascular issues and in patients being treated with known cardiotoxic chemotherapeutic regimens (e.g., anthracyclines). In certain cases, consulting with cardiology services might be necessary. Longer-term psychostimulant therapy is not advisable at this time because there is limited information about its potential negative effects and longer-term benefits.
Other Pharmacologic Interventions
Bupropion is a stimulating antidepressant with a primarily dopaminergic and noradrenergic mechanism of action. Preliminary evidence from a small open-label study (N = 21) suggests that the sustained-release (SR) form of bupropion has potential as an effective therapeutic agent for treating CRF with or without comorbid depressive symptoms.[Level of evidence: II] Seizure, a rare but serious side effect of this agent, did not occur in this study (the maximum dose of bupropion SR used in this study was 300 mg).
Dexamethasone is a potent anti-inflammatory agent that has recently been evaluated for the treatment of fatigue in patients with advanced cancer. Eighty-four patients were randomly assigned to receive either dexamethasone 4 mg twice per day or a placebo for 14 days. The primary endpoint was improvement in fatigue from baseline to day 15, as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale. Investigators also evaluated depression, anxiety, and symptom distress. In the group who received dexamethasone, mean scores on the FACIT-F scale were significantly improved by day 8 (P = .005) and at day 15 (P = .008). Physical well-being and physical distress were also significantly better in the group who received dexamethasone. Emotional scores and overall symptom distress were not significantly different. Adverse events, as measured by the Common Terminology Criteria for Adverse Events, version 3.0, did not differ between groups.
One limitation of this study was that it was only 2 weeks long, and longer-term use of dexamethasone is well known to be associated with unwanted side effects. Therefore, the risk versus benefit of treating fatigue with dexamethasone for more than 2 weeks requires investigation. Because fatigue has been associated with high levels of inflammation, this study is noteworthy in its evaluation of dexamethasone as an anti-inflammatory agent to alleviate fatigue. The investigators did not assess inflammatory biomarkers; therefore, the proof of concept that modifying inflammation can reduce fatigue needs replication.
Dietary supplements comprise other, often popular, pharmacologic interventions for CRF.
L-carnitine is a widely used dietary supplement believed to be helpful for the treatment of CRF because of its role in cellular energy metabolism and carnitine's ability to decrease pro-inflammatory cytokines. Promising pilot data led to the development and completion of a large (N = 376) phase III study in a multisite cooperative group setting. Participants with moderate to severe fatigue were randomly assigned to receive either 10 g levocarnitine or a placebo for 4 weeks. The primary endpoint was change in average fatigue. Despite increases in mean levels of L-carnitine, there was not a statistically significant difference in fatigue between arms, with both arms reporting improved fatigue during the study.
Ginseng, another popular supplement used to treat fatigue, has also been the subject of evaluation in large, multisite clinical trials. On the basis of a promising phase II dose-finding study, a phase III, randomized, placebo-controlled trial was completed involving 364 patients with cancer who either were undergoing anticancer treatment or had completed treatment. Participants were randomly assigned to receive either 2,000 mg of American ginseng (specifically, Wisconsin ginseng) in the form of ground root in a capsule or a matching placebo. The primary endpoint was change in fatigue scores as measured by the Multidimensional Fatigue Symptom Inventory-Short Form. At 4 weeks, the group receiving ginseng showed a trend toward significant improvement, while at 8 weeks, there was a significant and clinically meaningful difference favoring the ginseng group. There were no discernible side effects during the course of the trial, either within or between groups.
Preliminary studies [35,36,37][Level of evidence: I];[Level of evidence: II];[39,40][Level of evidence: III];[41,42][Level of evidence: IV] suggest that exercise (including light- to moderate-intensity walking programs) has potential benefits for people with cancer. The benefits shown in these studies and observed in clinical settings include improved physical energy, appetite stimulation, and/or enhanced functional capacity, with improvements in quality of life and in many aspects of psychologic state (e.g., improved outlook and sense of well-being, enhanced sense of commitment, and the ability to meet the challenges of cancer and cancer treatment).
Several reviews and National Comprehensive Cancer Network guidelines outline numerous studies that support the beneficial effects of exercise on fatigue.[43,44] Reductions in fatigue of about 35% and improvements in vitality of 30% have been shown in randomized trials, with stronger effects being shown during cancer therapy in some studies and after therapy in other studies.[43,45] Many initial trials of exercise programs focused on women with breast cancer, but later studies included men with prostate cancer, multiple myeloma, and colorectal cancer. Some studies have had methodologic weaknesses, including the following:[Level of evidence: I]
Some examples of the breadth of trials evaluating exercise are discussed in the following paragraphs. One study of patients undergoing peripheral blood stem cell transplantation found symptomatic benefits and improvements in mood in patients who participated in the interval-training program versus the control group.[48,49][Level of evidence: I] Supervised aerobic group exercise provided functional and quality-of-life benefits for women during treatment for breast cancer.[Level of evidence: I] Exercise improved function in patients treated for breast cancer.[51,52][Level of evidence: I]
In a study of 545 breast cancer survivors who were, on average, 6 months postdiagnosis, increased physical activity was consistently related to both improved physical functioning and reduced fatigue and bodily pain. Prediagnosis physical activity was associated with better physical functioning at 39 months but generally unrelated to symptoms. Increased physical activity after cancer was related to less fatigue and pain and better physical functioning. Significant positive associations were found with moderate to vigorous recreational physical activity but not household activity. This study suggests that breast cancer survivors may be able to decrease fatigue and bodily pain and be better able to pursue daily activities by increasing their recreational physical activities after cancer.[Level of evidence: II]
Exercise for patients with advanced or terminal disease is difficult to study but may yield similar benefits. The ability of patients with advanced cancer who are in hospice care and on a physical therapy regimen to carry out activities of daily living has been reported to improve in one study.[Level of evidence: III] Improved satisfaction with the physical therapy regimen was reported when family involvement in the program increased. A randomized study suggested that exercise improved fatigue during breast cancer treatment.[Level of evidence: I]
When educating patients about activity with respect to CRF, one important goal to consider is inclusion of 3 to 5 hours per week of moderate activity. It is critical that:
Beginning with lighter activity for shorter periods of time and building in intensity and length of time may be required. Studies have confirmed this can be safely done both during active treatment and after treatment is completed.
Variations of exercise that have a mind-body component include complementary modalities such as qigong, tai chi, and yoga, popular interventions that are being studied for their effects on CRF. These modalities are unique in that they incorporate cognitive and spiritual elements with movement, stretching, and balance. One fairly large study evaluated medical qigong for CRF in a heterogeneous group of 162 patients either undergoing cancer treatment or having finished cancer treatment. This study reported significant improvements in fatigue and several other aspects of quality of life for the intervention group versus usual care.
The qigong intervention was delivered in 90-minute group sessions twice a week for 10 weeks, for 1,800 minutes of treatment. The usual-care group did not receive any group meetings or additional provider interaction. It is therefore difficult to say what qigong uniquely provided over and above nonspecific or group-interaction effects. It is also not known how much survivors would need to continue performing qigong to maintain benefits. There were no adverse events in this study, so other than time and resource expenditure, it is difficult to pinpoint a downside to encouraging patients to adopt such an activity. One important strength of the study evaluating qigong was the collection of serum to measure markers of inflammation. At the end of 10 weeks, the C-reactive protein of patients in the medical qigong group decreased 3.6 mg/L, while patients in the usual-care group experienced an increase in this marker of 19.57 mg/L. This was a statistically significant difference.
A second, smaller study (N = 96) that compared a qigong group to a wait-list control group evaluated fatigue using the BFI as a secondary outcome and also assessed a biologic measure, salivary cortisol. This study did not find any significant difference in fatigue or cortisol between groups. The intervention dose in this study, comprising five 40-minute sessions over 6 weeks of radiation therapy in women diagnosed with breast cancer, was much lower than the intervention dose in the larger study described above.
The major weakness limiting interpretation and integration of both of these studies, despite differing results, is that there was no attempt to control for attention or any of the social aspects of the intervention.
Cognitive Behavior Therapy
Cognitive behavior therapy (CBT) has long been used to treat a variety of psychophysiological problems, with therapy focusing on the thoughts (cognitions) and functional behaviors relevant to the presenting problems. In a randomized clinical trial, 98 mixed-type cancer survivors (intervention group = 50, wait-list control = 48) experiencing severe fatigue not attributable to a specific somatic cause were provided individual CBT.[Level of evidence: I] The CBT focused on each participant's unique pattern of the following six possible factors that might serve to perpetuate their post-cancer treatment fatigue:
The number of therapy sessions varied according to the number of perpetuating factors (range: 5-26 1-hour sessions; mean: 12.5 sessions); results showed a clinically significant decrease in fatigue severity and functional impairment.
Activity and Rest
Health professionals can work with patients with cancer to develop an activity/rest program based on an assessment of the patient's fatigue patterns that allows the best use of the individual's energy. Any changes in daily routine require additional energy expenditure. Individuals with cancer are advised about setting priorities and maintaining a reasonable schedule. Health professionals may assist patients by providing information on support services that are available to help with daily activities and responsibilities. An occupational therapy consultation can be of assistance in evaluating energy conservation methods. Sleep hygiene, including avoidance of lying in bed at times other than sleep, shortening naps to no more than 1 hour, avoiding distracting noise (e.g., television, radio) during sleep hours, and other measures may improve sleep and activity cycles.
Much of the management of chronic fatigue in people with cancer involves promoting adaptation and adjustment to the condition. The possibility that fatigue may be a chronic disability may be discussed. Although fatigue is frequently an expected, temporary side effect of treatment, the problem may persist if other factors continue to be present.
An important goal of management is to facilitate self-care for the person with cancer. Since fatigue is documented as the most commonly reported symptom in individuals receiving outpatient chemotherapy (81% of cancer patients report fatigue), a shift in responsibility for control of side effects from the health care professional to the individual is important. It is imperative that individuals with cancer are educated about fatigue before it occurs and are taught about self-care strategies necessary to manage fatigue.
Specific techniques for the management of fatigue include the following:
In a controlled trial of patients who reported the symptom cluster of pain and fatigue while receiving chemotherapy, a nursing behavioral intervention produced improvements in quality of life and decreased symptom burden relative to usual care.[62,63][Level of evidence: I] These intriguing results need to be further explored in patient populations other than women with breast or gynecologic malignancies.
As researchers and practitioners learned with pain, misconceptions and a lack of knowledge may prove to be patient- and provider-related barriers to successful assessment and management. A quasi-experimental study tested a multisystem educational approach to improving both pain and fatigue management. The approach consisted of the following:
Over a 3-month period, the educational intervention resulted in increases in knowledge and a decrease in barriers related to management of pain and fatigue. Of note, important patient barriers related to fatigue management included the following beliefs:[Level of evidence: II]
Current Clinical Trials
Check the list of NCI-supported cancer clinical trials for supportive and palliative care trials about fatigue and anemia that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI website.
This posttreatment section has been especially prepared for those individuals with cancer who have been off all antineoplastic therapy for at least 6 months. The rationale for creating a separate section is twofold. First, the etiology of problems is different for individuals undergoing treatment versus those who are no longer undergoing therapy. Second, intervention strategies and information can be better tailored so that there will be a greater likelihood of meeting the needs of these two distinct populations.
Fatigue is a separate and distinct problem for individuals after treatment is completed. Many theories have been proposed to explain the etiology of fatigue in the patient undergoing treatment and to explain the impact of that treatment on quality of life. Many of these theories, however, do not apply to the posttreatment population. Nonetheless, fatigue continues to be a major issue for individuals who are no longer undergoing therapy and who are considered to be disease free.
There is evidence that fatigue significantly affects the quality of life of cancer survivors. The experience of fatigue in cancer survivors is quite similar to the experience of patients with chronic fatigue syndrome in the general medical setting. Few studies have been done that indicate the impact of fatigue on quality of life, but some examples follow:
Although many studies document the incidence of fatigue in those who are no longer undergoing cancer treatment, the specific mechanism of fatigue remains unknown. Because fatigue is a multifaceted problem, determining its etiology is difficult.
The information available regarding fatigue in survivors of childhood cancer is from the literature describing the physiologic and cognitive effects following treatment. In one study, cognitive outcomes were evaluated in children 3 to 4 years after diagnosis of brain tumors. Fatigue was a factor in poor school performance.
In another study, survivors of acute lymphoblastic leukemia who were evaluated for cognitive deficits after treatment were noted to have a typical fatigue effect. This was thought to be a factor in the variability of their test scores. Anecdotally, individuals who have received chest and total-body irradiation complain of fatigue, with an increased sleep requirement.
People who are successfully treated for cancer are at risk for a variety of organ-specific complications that are secondary to their treatment. Fatigue in the posttreatment population underscores the importance of follow-up care. The persistence of fatigue following cancer treatment requires a thorough evaluation to rule out contributing physiologic conditions.
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of fatigue. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
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PDQ® Supportive and Palliative Care Editorial Board. PDQ Fatigue. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/side-effects/fatigue/fatigue-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389484]
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Last Revised: 2017-01-13
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Last modified on: 8 September 2017