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Cancer-related fatigue (CRF) is a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.[
Cancer treatment–related fatigue is a commonly reported symptom, with 80% of patients reporting fatigue while receiving chemotherapy or radiation therapy.[
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.[
Fatigue, like pain, is a self-perceived state and patient-reported outcome. Patients may describe fatigue as feeling:[
Health professionals have included fatigue within concepts such as:
Studies of women with breast cancer have attempted to define specific fatigue trajectories. For example, some patients experience a high degree of fatigue during treatment and recovery, while others deteriorate over time. In contrast, some patients suffer from little fatigue throughout treatment. Suggested fatigue trajectories include the following:[
Research on fatigue in people with cancer has included primarily self-reports of fatigue, with increasing data exploring biological or physiological correlates. Such correlates have included measures of muscle weakness, maximal oxygen uptake, cytokines, cortisol, and genetic biomarkers.[
Fatigue has a negative impact on all areas of function, including the following:[
The pattern of fatigue associated with cancer treatment varies according to the type and schedule of treatment. For example, people treated with cyclic chemotherapy regimens generally exhibit peak fatigue in the days following treatment, then lower levels of fatigue until the next treatment. However, patients 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 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.[
Fatigue management focuses on identifying and treating the underlying factors that may be contributing to fatigue. Most clinical recommendations for managing the symptoms of fatigue caused by something other than chemotherapy-induced anemia rely on careful development of clinical hypotheses, as outlined in the National Comprehensive Cancer Network (NCCN) guidelines on fatigue.[
For more information, see the Interventions section.
Although much progress has been made, further 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.
References:
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. Multiple underlying etiological factors beyond the type and treatment of cancer have been proposed, including psychological distress, life demands, sleep disturbance, neurophysiological changes, disruption of circadian rhythms, cardiac issues, neuroimmunological changes, and genetic variations.[
Growing evidence, particularly for women with breast cancer and men with prostate cancer, suggests 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.[
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.[
Finally, another theory is that chronic exposure to proinflammatory cytokines negatively impacts serotonin levels. 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.[
References:
Although fatigue is clearly prevalent in patients with cancer, it has been difficult to identify consistent correlates of fatigue in this population. The factors most often implicated include the following:[
Fatigue has also been identified as a common symptom in symptom clusters associated with cancer, e.g., fatigue-pain and fatigue-cognitive clusters. For more information, see Symptom Clusters in Cancer.
Cancer Treatment
The association of fatigue with the major cancer treatment modalities of surgery, chemotherapy, radiation therapy, endocrine 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 after cancer treatment.[
Many people with cancer undergo surgery for diagnosis or treatment. Despite the high incidence of postoperative fatigue observed in these patients in clinical practice, few investigators have examined its causes and correlates. It is clear, however, that fatigue postsurgery improves with time and is compounded by fatigue caused by other cancer treatments.[
Fatigue has long been associated with radiation exposure and is reportedly one of the most common and activity-limiting side effects of radiation therapy for cancer.[
Fatigue increases throughout radiation therapy, peaking around mid-course and remaining at this level until radiation therapy is completed. It then improves somewhat during the 2 months after treatment ends. A study that investigated the trajectory of fatigue in men who were undergoing radiation therapy for prostate cancer (N = 82) found significant interindividual variability.[
A second study of 73 women who were undergoing adjuvant radiation therapy for breast cancer found similar differences in the patterns and predictors of morning versus evening fatigue.[
Morning fatigue was higher for those who:
Advanced disease and comorbidities also added to the severity of morning fatigue.[
Several research studies document a fatigue syndrome that is not specific to disease type or radiation site and that demonstrates a gradual decline in fatigue in the patient after treatment is completed.[
Fatigue is a dose-limiting toxicity of treatment with a variety of biotherapeutic agents. Biotherapy exposes patients with cancer to exogenous and endogenous cytokines.[
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.[
Treatment with chemotherapy is a predictor of fatigue and can be exacerbated by the coexistence of pain, depression, and/or anxiety.[
A longitudinal, descriptive study of 78 women with gynecological cancer examined the daily and intraday changes and interrelationships among fatigue, depression, and disruptions in sleep and activity, before and after each individual chemotherapy treatment, for three treatments. Significant changes in symptoms were noted over time. Before infusions, fatigue was associated with depression; after infusions, fatigue was significantly associated with increased depression and sleep/wake irregularities (increases in minutes awake at night and decreases in daytime activity and sleep/wake activity).[
Aromatase inhibitors—the recommended first-line adjuvant endocrine therapy in postmenopausal women with hormone receptor–positive breast cancer—have been linked to cancer-related fatigue (CRF). In one study of survivors of stage 0 to III breast cancer who were receiving adjuvant aromatase inhibitor therapy at an outpatient breast oncology clinic, 616 of 1,103 participants (55.8%) had moderate to severe CRF.[
Treatment with immune checkpoint inhibitors has been associated with clinically significant fatigue. Reviews of outcomes data demonstrated that fatigue is the most common adverse event incorporating anti–programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) agents. In the first phase I studies of nivolumab, 16% to 24% of patients had treatment-related fatigue, and 1% to 2% had grade 3 or 4 severity. Single-agent immune checkpoint studies have reported an incidence of 16% to 37% with anti–PD-1 agents, and 12% to 24% with anti–PD-L1 agents. Clinical studies that combined anti–PD-1/PD-L1 agents with other immune checkpoint inhibitors reported even higher rates of fatigue, in up to 71% of patients. The specific mechanism by which immune checkpoint inhibitors cause fatigue is not known; however, when fatigue symptoms occur during treatment, clinicians should be vigilant in assessing for early symptoms of endocrine dysfunction, such as hypothyroidism.[
Anemia
Evidence suggests that anemia may be a major factor in CRF and quality of life in cancer patients.[
A retrospective review was conducted to understand anemia in patients undergoing radiation therapy. Anemia was found in 48% of the patients initially and increased to 57% during therapy. It was more common in women than in men (64% vs. 51%); however, men with prostate cancer experienced the greatest increase in anemia during radiation therapy.[
Nutrition Factors
Fatigue often occurs when the body's energy requirements exceed the supply of energy sources. In people with cancer, three major mechanisms may be involved:
Causes of nutritional alterations are listed in Table 1.
| Mechanisms | Causes |
|---|---|
| Altered ability to process nutrients | Impaired glucose, lipid, and protein metabolism |
| Increased energy requirements | Tumor consumption of and competition for nutrients |
| Hypermetabolic state due to tumor growth | |
| Infection/fever | |
| Dyspnea | |
| Decreased intake of energy sources | Anorexia |
| Nausea/vomiting | |
| Diarrhea | |
| Bowel obstruction |
A randomized controlled trial compared a plant-based, high-protein diet to usual care in 103 patients with newly diagnosed breast cancer who were undergoing adjuvant chemotherapy.[
Psychological Factors
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.[
Depression can be a comorbid, disabling syndrome that affects approximately 15% to 25% of people with cancer.[
The anxiety and fear associated with a cancer diagnosis—and the impact of that diagnosis on a person's physical, psychosocial, and financial well-being—are sources of emotional stress. Distress associated with the cancer diagnosis 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% of participants 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 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 above levels seen in the general population.[
Psychological and symptom distress have also been found to be significant predictors of fatigue.[
Cognitive Factors
Impairment in cognitive functioning, including decreased attention span and impaired perception and thinking, is commonly associated with fatigue.[
Sleep Disorders and Inactivity
Causative or contributing factors in CRF may be:
Patients with less daytime activity, restless sleep, and obesity were noted to have consistently higher levels of CRF.[
Sleep disorders clearly contribute to fatigue [
Other Medications That Contribute to Fatigue
Medications other than chemotherapy drugs may contribute to fatigue. Opioids used to treat cancer-related pain are often associated with sedation, though the degree varies among individuals. Opioids are known to alter the normal function of the hypothalamic secretion of gonadotropin-releasing hormone.[
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.
References:
The first step in the assessment of fatigue is screening.[
Patients with moderate-to-severe levels of fatigue require further evaluation. One study of ambulatory outpatients with solid tumors (n = 148) evaluated the usefulness of single-item screening for symptoms such as fatigue and pain.[
Cancer-related fatigue (CRF) is multifactorial. The purpose of an in-depth evaluation is to assess diverse factors that can cause or contribute to fatigue.[
A comprehensive assessment of a fatigued patient starts with carefully obtaining a history to fully characterize the patient's fatigue pattern and to identify all factors that contribute to its development. An in-depth evaluation of fatigue includes the following:
An in-depth fatigue evaluation also includes an assessment of specific aspects of fatigue based on patient self-report:
Although there is no universally accepted standard for the measurement of fatigue, a variety of instruments can assess fatigue and related sequelae.[
Table 2 delineates several instruments that are commonly used (in research and clinical practice) and have known psychometric properties. The use of a specific instrument in clinical practice is informed by what the instrument assesses and the objective of fatigue assessment at a specific time. For example, the VAS is used to screen for the presence or absence of fatigue in an expedited manner and to get a quick assessment of its severity. Multi-item but unidimensional assessments such as the BFI can be used to conduct an in-depth fatigue assessment, including fatigue severity, patterns, and impact on functioning. The multidimensional instruments can be used to conduct a comprehensive evaluation of fatigue in patients with complex fatigue patterns. These instruments assess fatigue severity, patterns, and impact on functioning, similar to the unidimensional assessments. Additionally, these instruments can be used in multiple fatigue domains (e.g., physical, affective, and cognitive).
| Instrument | Description | Reference |
|---|---|---|
| NCCN = National Comprehensive Cancer Network; QOL = quality of life. | ||
| Single-item screening instruments | ||
| Visual analog scale (VAS) for fatigue | Uses a 10-cm, 0- to 100-mm line; assesses severity only | Glaus, 1993[ |
| NCCN intensity tool | 0–10 scale; assesses severity only | Mock et al., 2007[ |
| Multi-item, unidimensional instruments | ||
| Brief Fatigue Inventory (BFI) | 9 items; 0–10 numeric scale; measures severity of fatigue in past 24 h | Mendoza et al., 1999[ |
| Fatigue Symptom Inventory (FSI) | 13 items; 0–10 numeric scale; measures fatigue severity, duration, and impact on QOL in past 7 d | Hann et al., 1998[ |
| Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) | 13 items; 5-point, 0–4 scale; measures fatigue severity, duration, and impact on QOL in past 7 d | Yellen et al., 1997[ |
| Multi-item, multidimensional instruments | ||
| Multidimensional Fatigue Inventory (MFI) | 20 items; 7-point Likert scale; measures general, mental, and physical dimensions and activity level in past 24 h | Smets et al., 1995[ |
| FACIT-F | 40 items; 5-point, 0–4 scale; includes 13-item FACIT-F scale; also measures physical, social/family, emotional, and functional dimensions | Yellen et al., 1997[ |
| European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Fatigue Module (EORTC QLQ-FA13) | 13 items; measures physical, emotional, and cognitive aspects of fatigue, fatigue interference, and its sequelae | Weis et al., 2013[ |
| Revised Piper Fatigue Scale (PFS-R) | 22 items; 11-point scale; measures behavioral, affective, sensory, and cognitive dimensions of fatigue | Piper et al., 1998[ |
Proposed criteria for 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 potential advantages and disadvantages.[
ICD-10 Criteria for CRF
CRF exists when 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.[
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 guidelines for fatigue management from NCCN.[
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).
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 tests for the following:
In cancer patients, the underlying etiology is often multifactorial.
References:
Much of the information regarding interventions for fatigue relates to healthy subjects, people in whom muscle fatigue is the primary etiology of the problem, or people in whom fatigue is secondary to treatment-related anemia.[
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.[
Assessing patients for the appropriate target symptom for intervention is probably the most efficient way to help them improve their health-related quality of life and manage their fatigue symptoms.
Because the etiology and mechanisms regarding fatigue in cancer patients are varied, there is considerable need to personalize symptom management to provide goal-concordant care. Medical management is often directed at identifying specific and potentially reversible correlated symptoms, as in the following examples:
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.
The transfusion of packed RBCs is the most widely used and most rapid way to alleviate symptoms in cancer patients with symptomatic anemia. The likelihood of raising a patient's hemoglobin level is very high with transfusion, and the risks of complications are low. Nevertheless, repeated transfusions can be cumbersome, and the risk of blood-borne infection can be worrisome. 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.[
The management of cancer-associated anemia using erythropoiesis-stimulating agents (ESAs) was established in the 2019 American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) guidelines, which recommended the following:[
Psychostimulants
Psychostimulants are a common pharmacological intervention for cancer-related fatigue (CRF); however, the evidence for their efficacy is mixed. 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. Psychostimulant clinical trials for the management of fatigue include the following therapies (for information about levels of evidence and dosing used in the clinical trials, see Table 3):
Psychostimulants are not approved by the U.S. Food and Drug Administration (FDA) for the treatment of CRF. However, preliminary evidence from randomized controlled studies [
| Drug | Dosage | Outcome | Comments/Primary Side Effects |
|---|---|---|---|
| AUC = area under the curve; bid = twice daily; CAD = coronary artery disease; CRF = cancer-related fatigue; LHRH = luteinizing hormone-releasing hormone; MAOI = monoamine oxidase inhibitor; PO = by mouth; prn = as needed; q2h = every 2 hours; qd = every day; SR = sustained release; SSRI = selective serotonin reuptake inhibitor. | |||
| a As defined by the U.S. Controlled Substances Act. | |||
| Dextroamphetamine (Dexedrine) | 10 mg PO bid x8 d | No significant difference in fatigue.[ |
Schedule II.a Major potential interactions with citalopram and venlafaxine. Avoid in patients with uncontrolled hypertension, underlying CAD, and tachyarrhythmias.[ |
| Methylphenidate (Ritalin) | Titrate up to 54 mg/d PO (27 mg D-isomer) over 4 w | Did not improve CRF compared with placebo.[ |
Schedule II.a High-fat meals may increase AUC. Peak concentration 102 h postingestion. Do not use with MAOIs as it can precipitate hypertensive crisis. Antidepressants that increase norepinephrine can increase amphetamine side effects. Concomitant use with SSRI can increase SSRI concentrations. Avoid in patients with uncontrolled hypertension, underlying CAD, and tachyarrhythmias.[ |
| 5 mg PO bid titrated every 3 d based on response | Dose-dependent improvement in CRF compared with placebo.[ |
||
| 5 mg PO q2h prn, up to 20 mg/d | CRF improved at day 15 with or without nursing telephone call.[ |
||
| 18 mg SR PO daily x2 w | Did not improve CRF.[ |
||
| 10 mg PO qd | CRF improved at 10 w among men receiving LHRH agonists.[ |
||
| 5 mg PO bid x3 d each cycle | Did not improve CRF.[ |
||
| 5 mg PO prn titrated every 2–3 d to maximum 30 mg | CRF improved among men with prostate cancer.[ |
||
| Modafinil (Provigil) | 200 mg PO qd | CRF improved in patients receiving chemotherapy with severe fatigue, but not mild/moderate fatigue.[ |
Schedule IV.a Avoid driving or operating machinery until effects are known. Do not take at bedtime. Peak concentration in 2–4 h. Food slows absorption by about 1 h but does not affect bioavailability. Decreases efficacy of birth control pills. |
| 100 mg PO bid (up to 400 mg/d) x6 w | Did not improve CRF over placebo in patients with primary brain tumors.[ |
||
| 200 mg PO qd x15 d | Did not improve CRF over placebo in patients receiving docetaxel.[ |
||
| 100 mg PO qd on days 1–14 and 200 mg qd on days 15–28 | Did not improve CRF over placebo in patients with lung cancer.[ |
||
| Armodafinil (Nuvigil) | 50 mg PO bid | Did not improve daytime fatigue over placebo in cancer survivors with insomnia.[ |
Schedule IV.a Avoid driving or operating machinery until effects are known. Do not take at bedtime. Peak concentration in 2 h if fasting, slowed to as many as 4 h if fed; food does not affect bioavailability. Decreases efficacy of birth control pills. |
| 150 mg PO qd x56 d | Did not improve CRF over placebo in patients with multiple myeloma.[ |
||
Methylphenidate
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.[
Conversely, an equally large randomized controlled trial assigned patients with early and advanced disease, who were either receiving treatment or not receiving 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.[
Modafinil and armodafinil
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.[
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 two promising open-label pilot trials,[
A randomized placebo-controlled trial (four-arm factorial study) comparing cognitive behavioral therapy (CBT) for insomnia (CBT-I) versus armodafinil (50 mg by mouth twice a day) found that CBT-I with and without armodafinil resulted in a clinically and statistically significant reduction of subjective daytime fatigue in cancer survivors with chronic insomnia.[
For both methylphenidate and modafinil, exploratory data have suggested that patients with more severe fatigue or more advanced disease may benefit from these drugs.[
Clinical considerations
The side effects most commonly described with the use of psychostimulants include the following:[
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 (i.e., cardiotoxic chemotherapy regimens). Cardiovascular complications with psychostimulants can arise even in patients without any significant risk factors.[
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, consultation with cardiology services may be considered. Cardiovascular issues are thought to be less of a risk with modafinil and armodafinil. The 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 (as defined by the U.S. Controlled Substances Act) carry boxed warnings that indicate the risk of abuse potential and/or risk of psychological dependence. In addition, boxed warnings for certain stimulant medications (methylphenidate and dexmethylphenidate products) indicate the risk of psychotic episodes.[
On the basis of limited clinical experience and 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, clinicians should obtain informed consent, with a 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).
Longer-term psychostimulant therapy is not advisable at this time because there is limited information about its potential negative effects and longer-term benefits. Further research is needed in the form of CRF studies using psychostimulants in patients with depression or with drowsiness and sleep disturbance. In the design of these studies, it is important to consider patients with moderate to severe fatigue. These studies should also be performed for a longer period (>4 weeks) to account for the placebo wash-in period.[
Other Pharmacological Interventions
Bupropion
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.[
A small, double-blind, placebo-controlled trial of bupropion SR 150 mg daily versus placebo in a heterogeneous group of patients with cancer (N = 40) [
Corticosteroids
Corticosteroids are by far one of the most commonly used medications for symptom control in patients with advanced cancer. These agents have potent anti-inflammatory effects and act by binding to cytoplasmic steroid hormone receptor and modulation of inflammatory gene transcription.[
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.[
Dietary supplements
Dietary supplements comprise other, often popular, pharmacological interventions for CRF.
American ginseng
Ginseng, a popular supplement used to treat fatigue, has been evaluated in large, multisite clinical trials. On the basis of a promising phase II dose-finding study,[
Other supplements
Two additional supplements, coenzyme Q10 and levocarnitine (L-carnitine), have been tested in large, randomized trials for the treatment of fatigue; however, they have failed to yield positive effects.
L-carnitine, a widely used dietary supplement, is 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.[
Similarly, 300 mg of coenzyme Q10 was tested against placebo in a double-blind randomized controlled trial of 236 breast cancer patients. Although supplementation led to sustained increases in plasma coenzyme Q10, there were no significant differences between the groups over the 24-week study.[
Exercise
Studies suggest that exercise or physical activity has a beneficial effect on fatigue in patients during and after cancer treatment. The National Comprehensive Cancer Network (NCCN) guidelines [
Initial trials of exercise programs focused on women with breast cancer, but subsequent studies included men with prostate cancer and patients with multiple myeloma, lung cancer, nasopharyngeal cancer, non-Hodgkin lymphoma, colorectal cancer, and advanced cancers.[
Some studies had methodological weaknesses, including the following:[
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 to better pursue daily activities by increasing their recreational physical activities after cancer.[
A similar study of breast cancer survivors (N = 222) who were randomly assigned to a 3-month, multicomponent physical activity and behavior change intervention (Better Exercise Adherence after Treatment for Cancer [BEAT Cancer]) demonstrated reduced fatigue, depression, and anxiety symptomatology.[
A study of 1,033 patients with breast, gynecological, gastrointestinal, or lung cancer who had received chemotherapy in the past 2 weeks identified associations between level of exercise and fatigue and co-occurring sleep disturbance.[
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 reportedly improved in one study.[
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.[
Aerobic exercise
Two randomized controlled trials demonstrated the benefit of exercise in reducing fatigue during breast cancer treatment. A trial of a 12-week aerobic exercise program compared with usual care showed a nonsignificant improvement in fatigue 3 and 6 months later.[
Limitations of both studies included the lack of a placebo control group and low participation rates. Low participation is a common finding in exercise studies of cancer patients, suggesting the need for tailored approaches to overcome barriers. The benefits shown in these studies are buttressed by a Cochrane review of 56 studies (including 4,068 participants), which concluded that aerobic exercise significantly reduced fatigue during or after cancer treatment.[
Anaerobic (resistance-training) exercise
Studies have also examined the use of resistance training to improve fatigue. In one large randomized controlled trial, 160 breast cancer patients (stages 0–III) were randomly assigned to a progressive resistance training intervention or a relaxation control intervention, twice weekly for 12 weeks. The primary endpoint was perceived fatigue, and the secondary endpoint was evaluated quality of life.[
Adherence to this group-based intervention program was as high as 97%. Significant improvements were noted between groups, favoring the resistance-training group for general fatigue (P = .044), especially for the physical fatigue subscale (mean difference = –0.8; 95% confidence interval, –1.5 to –0.2, P = .013), but not for affective fatigue (P = .91) or cognitive fatigue (P = .65). For quality of life, significantly larger improvements regarding role function (P = .035) and pain (P = .040) were noted among exercisers compared with controls. This study demonstrated that resistance training was a feasible and efficacious strategy for improving fatigue and other components of quality of life.
Meta-analyses of aerobic, anaerobic, and combined exercise studies
Several literature reviews and meta-analyses have explored, with mixed results, the effect of exercise on fatigue. They have begun to examine which type of exercise—aerobic (cardio), anaerobic (resistance training), or a combination of the two—is most beneficial in ameliorating fatigue.
One large meta-analysis of breast cancer survivors identified 25 randomized controlled trials (including 3,418 patients) and examined the efficacy of exercise interventions for fatigue and physical functioning during and after treatment and at a 6-month follow-up.[
A 2018 systematic review and meta-analysis identified 245 studies of all cancer types, explored nonpharmaceutical interventions for fatigue during and after treatment, and conducted an indirect-comparisons meta-analysis among intervention types.[
A study of pooled baseline data from three studies (n = 436) investigated reallocating sedentary time to an equal amount of light or moderate-to-vigorous engagement in physical activity in patients with breast cancer. The study showed that fatigue improved in these patients.[
Limitations remain regarding the need to identify a more exacting exercise prescription, including the need to identify the type, intensity, frequency, and resting intervals to fully incorporate into cancer practice and survivorship care plans.[
Other exercise modalities
Variations of exercises that have a mind-body component are being studied for their effects on CRF; popular interventions include complementary modalities such as yoga, qigong, and tai chi.[
Yoga
Yoga is an ancient system of practices used to balance the mind and body through exercise, meditation (focusing thoughts), and control of breathing and emotions. Yoga has been shown to improve fatigue in cancer survivors in several pilot and larger randomized controlled trials (NCCN category 1 intervention).[
In one pilot study, 12 weeks of yoga was compared with a health education intervention in a control group in 31 breast cancer survivors.[
Similarly, in a larger randomized controlled trial, investigators examined the effect of two 90-minute hatha yoga sessions per week for 12 weeks delivered in a group setting, compared with a wait-list control in 181 breast cancer survivors.[
In one large, multicenter phase III randomized controlled trial, investigators examined the effect of a standardized 4-week yoga therapy program (Yoga for Cancer Survivors [YOCAS]) on fatigue compared with standard survivorship care in 410 cancer survivors.[
A meta-analysis (including 10 studies of cancer survivors) examining yoga for fatigue found that yoga demonstrated a significant improvement in fatigue over usual care, with a moderate effect size (SMD, –0.68; 95% CrI, –0.93 to –0.43).[
The limitations of these studies include study designs that varied in the type of yoga and its duration, frequency, and number of weeks; failed to include attention control comparisons; and varied in fatigue assessment measures.
Qigong
Qigong is a traditional Chinese mind/body exercise and meditation that uses slow and precise body movements with controlled breathing and mental focusing to improve balance, flexibility, muscle strength, and overall health. One fairly large study evaluated medical qigong for CRF in a heterogeneous group of 162 patients during or after cancer treatment.[
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 was the collection of serum to measure markers of inflammation. At the end of 10 weeks, the C-reactive protein level of patients in the medical qigong group decreased by 3.6 mg/L, while patients in the usual-care group experienced an increase of 19.57 mg/L, 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; it also assessed a biological measure, salivary cortisol.[
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.
In a third small study (N = 76), men with prostate cancer undergoing radiation therapy were randomly assigned to qigong/tai chi, light exercise, or a waiting list.[
Tai chi
Tai chi is a Chinese martial arts activity that involves deep breathing, exercise, and slow movement with a meditative aspect, connecting the individual's physical, mental, and emotional states. Tai chi has been examined for its effect on cancer symptoms, including CRF.
Investigators conducted a randomized controlled trial to compare the effect of tai chi versus low-impact exercise on CRF during treatment for 91 lung cancer patients.[
In a subsequent meta-analysis, including six studies and more than 370 cancer patients, researchers noted significant and positive improvement in short-term CRF in patients with breast and lung cancer, but not in patients with prostate cancer.[
CBT
CBT has long been used to treat a variety of psycho-physiological problems, with therapy focusing on the thoughts (cognition) and functional behaviors relevant to the presenting problems. While most of the CBT research for CRF has focused on the survivor period, CBT and CBT variants (e.g., CBT-I and mindfulness-based cognitive therapy) have been shown to be useful during both active treatment and the survivor period.[
In the context of active treatment (e.g., chemotherapy, radiation therapy, surgery), CBT plus hypnosis may be effective for patients struggling with CRF.[
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.[
The number of therapy sessions varied according to the number of perpetuating factors (range, 5–26 one-hour sessions; mean: 12.5 sessions). Results showed a clinically significant decrease in fatigue severity and functional impairment.
Fatigue-related improvements that occur during CBT for CRF can be maintained for extremely long periods of time, even without periodic, long-term follow-up (booster) sessions that are usually a component of CBT. In a 10-year follow-up of 81 individuals who completed a CRF CBT protocol,[
While CBT and medication therapy may often work hand in hand, some studies show that CBT alone has a more powerful impact on fatigue than medication alone. In a 7-week, double-blind treatment study,[
The study found a significant reduction of fatigue with CBT alone or with CBT plus armodafinil (though the drug provided limited additive benefit compared with CBT alone), and no improvement with armodafinil alone.[
Patient Education
Informing patients about the risk of fatigue and educating them about strategies to reduce fatigue are valuable adjuncts to other management strategies. However, a Cochrane review of educational interventions for CRF in adults cautions that educational interventions should be part of a more-comprehensive approach to managing 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.[
As researchers and practitioners have 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.[
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:[
Providing patient education about strategies to reduce fatigue may help eliminate the barriers related to managing fatigue.
Current Clinical Trials
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