INTRODUCTION — Fatigue is the most common symptom in palliative care patients who have advanced cancer or other serious and/or life-threatening illnesses. It is also one of the most underreported and undertreated symptoms in such patients as well as in other palliative care populations, including those with end-stage heart failure. Fatigue has substantial adverse physical, psychosocial, and economic consequences for both patients and caregivers. However, due to its subjective nature and multidimensional causes, assessment and treatment of fatigue in the palliative settings can be complex.
This topic review will provide an overview of the clinical evaluation and treatment of fatigue in palliative care. Although the focus is on fatigue in cancer patients receiving palliative care, the principles of assessment and management are similar in other end-stage disease states. A more extensive discussion of fatigue in patients with cancer and of the assessment and management of chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), are presented elsewhere. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment" and "Cancer-related fatigue: Treatment" and "Clinical features and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome" and "Treatment of myalgic encephalomyelitis/chronic fatigue syndrome".)
DEFINITION — It is important to distinguish fatigue from other common presentations in palliative care, including depression, delirium, drowsiness, demoralization [1], psychomotor retardation, and weakness. Demoralization is a frequent syndrome of existential distress in patients with cancer (13 to 18 percent). Early identification of this syndrome using a demoralization scale would be helpful to distinguish it from fatigue [1,2]. Psychomotor retardation involves a slowing down of thought and a reduction of physical movements in an individual, while weakness is a term commonly used to describe a state of lack of physical, muscle, or motor strength.
Fatigue in palliative care settings can be broadly defined as “a subjective state characterized by feelings of tiredness and a perception of decreased capacity for physical or mental work” [3]. The National Comprehensive Cancer Network [4] defines cancer related fatigue as 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 activity and that interferes with usual functioning.” (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Definition'.)
In the past, the terms “asthenia” and “weakness” were used to describe a subjective sensation of tiredness, while the specific term “fatigue” was used to describe a symptom of tiredness precipitated by effort. However, the terms are now often used in the same context. The term “fatigue” has gained widespread acceptance in the medical literature and is preferentially used in the National Cancer Institute toxicity grading scale that covers generalized weakness (table 1).
PREVALENCE — Fatigue is the most common symptom in palliative care patients who have advanced cancer or other serious and/or life-threatening illnesses [5]. It is also one of the most underreported and undertreated symptoms in such patients [6,7]. The prevalence of fatigue in patients with cancer ranges from 48 to 75 percent [8]. The prevalence increases to 85 percent in patients with serious and/or life-threatening illnesses at the end of life (table 2) [9,10]. Fatigue is especially prevalent at the end of life in patients with end-stage heart failure and in those with nonmalignant chronic lung disease, such as chronic obstructive pulmonary disease (COPD). (See "Palliative care for patients with advanced heart failure: Decision support and management of symptoms", section on 'Fatigue' and "Palliative care for adults with nonmalignant chronic lung disease", section on 'Other symptoms in chronic lung disease'.)
CAUSES AND PATHOPHYSIOLOGY — Among patients with serious and/or life-threatening illness, fatigue can be distinguished as acute and caused by an acute illness, such as infection or cardiac decompensation, or more chronic, as in most of the cancer-related causes. Possible contributors to fatigue in patients with advanced cancer are outlined in the table (table 3).
In palliative care patients, fatigue is most often a multidimensional symptom, often with multiple causes. Correlative studies have shown an association of fatigue with pain, dyspnea, anorexia, psychological symptoms, gastroparesis symptoms (such as upper abdominal discomfort, bloating, and abdominal distension), and constipation [11-14]. The intensity of the individual symptom in a given patient may determine the ultimate contribution of that symptom to causation of fatigue. Other major contributors are anemia and medications. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Main contributory factors'.)
Anemia — Anemia is a particularly important contributor to fatigue, especially in patients undergoing cancer treatment. In a study of 4382 anemic cancer patients receiving chemotherapy, there was a positive correlation between hemoglobin levels and fatigue and quality of life across the range of clinically relevant hemoglobin levels of 8 to 14 g/dL [15]. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Anemia' and "Cancer-related fatigue: Treatment", section on 'Anemic patients'.)
However, towards the end of life, the importance of anemia as a contributor to fatigue is diminished. In such patients, fatigue is typically multidimensional and the main contributors are psychological symptoms such as anxiety and depression, pain, cachexia, medications, physical inactivity, infection, and hypogonadism. As the severity of these factors increases progressively at the end of life, the relative contribution of anemia to the causation of fatigue diminishes [11,16].
Polypharmacy — Medications (side effects, cumulative effects of multiple drugs, and drug-drug interactions) are an often-overlooked contributor to fatigue. As examples, coadministration of opioids with other sedating medications, or drug-drug interactions between classes of medications such as anticholinergics, antihistamines, anticonvulsants, neuroleptics, opioids, central antagonists, beta blockers, diuretics, antidepressants, muscle relaxants, and benzodiazepines may contribute to drowsiness and fatigue. Statins cause fatigue [17] and can be safely stopped without increasing mortality for those at the end of life, with an improvement in quality of life [18]. In some cases, altering the dose or dosing interval of a medication may substantially improve fatigue. Detailed information on drug interactions can be found in the Lexicomp drug interaction program within UpToDate. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Somnolence and mental clouding' and "Palliative care: The last hours and days of life", section on 'Eliminating non-essential medications' and "Deprescribing".)
Autonomic dysfunction — Autonomic dysfunction is a common complication of advanced cancer [19]. This syndrome includes postural hypotension, occasional syncope, fixed heart rate, and gastroparesis and is associated with gastrointestinal symptoms such as nausea, anorexia, diarrhea or constipation, and generalized weakness. While an association between fatigue and autonomic dysfunction has been established in neurological dysautonomic syndromes and chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the relationship between autonomic dysfunction and fatigue in patients with advanced cancer remains unclear [14,20,21]. (See "Mechanisms, causes, and evaluation of orthostatic hypotension", section on 'Symptoms' and "Clinical features and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome".)
Male hypogonadism — Hypogonadism affects at least two-thirds of men with advanced cancer. Low testosterone levels in men with cancer are associated with fatigue, anorexia, depression, and insomnia [22,23]. Chronic inflammation, cachexia, chemotherapy, and medications such as opioids, megestrol acetate, and glucocorticoids [24] can all contribute to hypogonadism.
Guidelines from the Endocrine Society recommend measuring testosterone levels in men requiring long-term opioid therapy [25]. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Neuroendocrine effects' and "Clinical features and diagnosis of male hypogonadism" and "Causes of secondary hypogonadism in males".)
Role of inflammatory cytokines — Inflammatory cytokines may have a role in the pathophysiology of fatigue, based upon several lines of evidence:
●Increased levels in non-oncologic conditions that are characterized by fatigue, such as CFS [26,27]. (See "Clinical features and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome", section on 'Immune system differences'.)
●The occurrence of fatigue as a major side effect of therapeutic cytokines, including interleukins, tumor necrosis factor (TNF) alpha, and interferon [28-30].
●Up-regulation of pro-inflammatory cytokines and their correlation with fatigue in cancer patients [31-34]. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment" and "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Main contributory factors'.)
Proinflammatory cytokines can act on mood, muscle mass, cognition, and metabolic status to induce fatigue [35,36]. The inflammatory cytokines may also induce disturbance in the hypothalamic pituitary axis, affecting the levels of corticotrophin-stimulating hormone and adrenocorticotropic hormone (ACTH). These hormones, in turn, may influence adrenocorticoid hormone secretion by the adrenals [36].
CLINICAL ASSESSMENT — The assessment of fatigue in palliative care patients can be complex, given its multidimensional nature. In general, in cases of acute onset of fatigue in patients with a serious life-threatening illness, identification of the cause (eg, infection, cardiac decompensation) and treatment for the specific underlying condition may successfully reverse fatigue. In more chronic causes of fatigue such as that seen in patients with advanced cancer, fatigue is often multifactorial, so a multidimensional interdisciplinary approach is preferable.
A comprehensive history and physical examination should be undertaken to ascertain the various organ systems affected by the underlying disease and the impact of fatigue on activities of daily living and quality of life, to search for potentially reversible or treatable contributory factors, and to direct the diagnostic workup. Review of all medications (both prescribed and over the counter, including complementary/alternative therapies) is important and may reveal potential side effects, cumulative effect of multiple drugs, or drug-drug interactions that may be contributing to fatigue. If a medication is identified as being a potential contributor to fatigue, simply altering the dose or dosing interval may substantially improve fatigue. (See 'Polypharmacy' above.)
In patients with cancer, accurate assessment of the patient’s current disease status, type of treatment, and response to treatment is an important component of the initial evaluation. Factors that are often causally related to cancer-related fatigue should be specifically assessed, including anemia, uncontrolled pain, emotional distress, sleep disturbance, nutrition and electrolyte disturbances (table 4), and the presence of other comorbidities. Comorbidities that are unrelated to the cancer or its treatment (eg, infection, cardiopulmonary, renal, hepatic, neurologic, or endocrine dysfunction) may contribute significantly to symptoms of fatigue. Optimizing treatment for conditions that have been previously unrecognized (eg, hypothyroidism in a patient who previously had neck irradiation or who is receiving therapy with certain tyrosine kinase inhibitors targeting vascular endothelial growth factor such as sunitinib or sorafenib) or suboptimally treated (eg, recurrent heart failure because of doxorubicin-induced cardiomyopathy) may improve fatigue.
For patients with a non-cancer diagnosis, in addition to a thorough assessment of comorbidities, medications, and other potentially contributory causes, as with patients with cancer, diagnostic testing such as blood tests and radiographic imaging may be needed and should be based upon clinical suspicion. For patients with obvious findings due to end organ failure (eg, cardiac, respiratory, hepatic, or renal disease), the diagnostic workup for fatigue should focus on assessment of the specific underlying cause. For cases where there are no obvious findings, clinicians may evaluate for anemia, metabolic abnormalities, malnutrition, and infections.
A more in-depth discussion of clinical assessment of fatigue in patients with cancer is provided elsewhere. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Clinical assessment'.)
Fatigue can be quantified by using the 0 to 10 visual analog scale and instruments, such as the Brief Fatigue Inventory, which measure not only intensity of fatigue but also functional impact (table 5). However, scales such as these are not useful to sort out causality. From a clinical perspective, a patient presenting with a fatigue score of “9 out of 10” on a 0 to 10 scale may have anemia and cachexia as the main cause, while another patient with the same intensity of fatigue may have depression as the main cause. Use of the simple revised Edmonton Symptom Assessment Scale (table 6) [37] or other multidimensional tools may be helpful for a more comprehensive assessment of fatigue in both clinical and research settings (table 7) [38].
MANAGEMENT — Optimal management of fatigue involves aggressive treatment of reversible causes, if any are identified during the initial assessment. If a cause is not reversible or apparent, symptomatic treatment is appropriate (table 8).
The treatment of fatigue should ideally involve an interdisciplinary team approach with active participation by the clinician, nurse, psychiatric counselor, social worker, chaplain, physical therapist, and occupational therapist.
Multimodal interventions for refractory fatigue — Symptomatic treatment should be considered in all cases in which fatigue is not effectively managed by treatment of reversible causes. In these cases, due to the complex, multidimensional nature of fatigue, it is unlikely that fatigue can be effectively mitigated using a single pharmacologic or nonpharmacologic intervention. Patients are likely to benefit from a combination of pharmacologic and nonpharmacologic interventions such as cognitive-behavioral therapy, increased physical activity, and pharmacologic therapy aimed at countering inflammation, changes in body composition, or brain function. In these cases, therapy must be individualized.
It is important to address fatigue as a subjective symptom and not as a physical syndrome; treatment should not focus solely on strategies to increase function/physical function. Lastly, patients suffer considerable distress if there is a gap between the patient’s expectation for improved physical function through intervention and the reality of actual decline in function over time; ultimately, most patients who are terminally ill will become bedridden. Measures that help adjust a patient’s expectation may include changing the focus from physical functioning to other enjoyable, non-physical activities [39].
Further studies are needed to investigate the efficacy of the multimodal intervention in patients with fatigue, particularly those with advanced cancer [40].
Treatment of anemia — Optimal management of symptomatic anemia requires an accurate diagnosis to identify potentially remediable causes (eg, ongoing blood loss, hemolysis, or deficiency of iron, folic acid, or vitamin B12). If a potentially treatable cause cannot be identified, treatment options include red blood cell (RBC) transfusion or, for selected patients, an erythropoiesis-stimulating agent (ESA).
Transfusions of packed red blood cells can improve fatigue that is due to anemia, at least in the short term. In a prospective study of 61 patients receiving treatment in the palliative care unit, blood transfusions in patients with hemoglobin of 8 ±0.5 g/dL improved fatigue, dyspnea, and well-being for a short term (approximately 15 days) [41]. However, higher-quality studies are needed to determine which patients are most likely to respond, which are not, and the duration of any response [42]. Furthermore, for those patients requiring repeated transfusions, there are potential harms, including blood-borne infection, acute transfusion reaction, transfusion-associated graft-versus-host disease, subtle immune modulation, and iron overload. (See "Hemolytic transfusion reactions" and "Immunologic transfusion reactions" and "Transfusion-associated circulatory overload (TACO)" and "Transfusion-transmitted bacterial infection" and "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload'.)
It is also important to realize that, while some hospice providers may think of transfusions as “aggressive care,” patients and families or other loved ones generally do not [43].
Treatment with ESAs can be beneficial in relieving fatigue and improving quality of life in patients with chronic anemia that is related to cancer chemotherapy. As an example, in one study of 4382 anemic cancer patients receiving chemotherapy, improvement of hemoglobin ≥2 g/dL after treatment with an ESA was significantly correlated with improvement of fatigue, with maximum benefit occurring when the hemoglobin improved to 12 g/dL [15].
Although treatment of anemia has been shown to decrease fatigue in patients receiving ESAs along with palliative chemotherapy, this has not been demonstrated in other groups [44-46]. Furthermore, use of these agents has become controversial in certain patients with cancer, in particular those with anemia unrelated to chemotherapy and in those receiving myelosuppressive chemotherapy with the intent of cure, because of concerns about thromboembolic side effects, higher mortality rates, and the possibility of adverse cancer outcomes. This subject is addressed in detail elsewhere. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Clinical use of ESAs in cancer patients'.)
Thus, use of ESAs for palliative care patients with fatigue related to anemia should be restricted to those with chronic kidney disease (to avoid transfusion) and to those patients who are being treated for HIV infection or who are receiving palliative myelosuppressive chemotherapy for cancer. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer" and "HIV-associated cytopenias", section on 'Indications for transfusion and erythropoietin'.)
Symptom management
Pharmacologic approaches — There are a limited number of pharmacologic agents that have demonstrated efficacy in the treatment of fatigue in palliative care populations; a Cochrane review concluded that no specific drug could be recommended for treatment of fatigue in palliative care patients due to the limited evidence [47]. The lack of good studies is related to the complex nature of fatigue in this population and the paucity of randomized controlled studies in the palliative care setting.
Glucocorticoids — Glucocorticoids may be most helpful for patients with fatigue who are in the terminal phases of advanced cancer or another serious and/or life-threatening illness. Glucocorticoids decrease fatigue, and the proposed mechanisms include 1) a decrease of the cytokines interleukin (IL) 1, IL-6, and tumor necrosis factor (TNF) alpha, which are associated with fatigue; and 2) an effect on hypothalamic-pituitary axis function. As noted above, disturbances in hypothalamic-pituitary axis function have been observed in other chronic inflammatory and fatigue-related disorders [48-53]. (See 'Role of inflammatory cytokines' above.)
Preliminary studies have found that glucocorticoids reduce symptoms such as fatigue, pain, and nausea and improve appetite and overall quality of life in patients with advanced cancer [54-59]. It is not evident that there is any difference between different types of glucocorticoids; however, dexamethasone appears to be the most intensively investigated. A randomized placebo-controlled trial of 84 evaluable patients with advanced cancer, oral dexamethasone (8 mg per day for 14 days) significantly improved fatigue [60]. The mean (standard deviation) improvement in the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue subscale (FACIT-F) at day 15 was significantly higher in the dexamethasone group than in the placebo (mean and standard deviation were 9 [10.3] versus 3.1 [9.59] for dexamethasone and placebo, respectively; p = 0.008). The numbers of grade ≥3 adverse effects did not differ between groups (17 out of 62 versus 11 out of 58; p = 0.27). Another randomized placebo-controlled double-blind study found that 32 mg/day of oral methylprednisolone for a period of seven days in 50 patients with advanced cancer receiving opioids significantly improved fatigue and anorexia [61].
Unfortunately, side effects limit the long-term use of glucocorticoids. The severity of most toxicities is dose-dependent. Side effects observed in some patients include infection, oral thrush, insomnia, mood swings, myalgia, and elevation of blood glucose. Prolonged use (for more than a month) of dexamethasone may cause gastritis (especially with concurrent use of nonsteroidal antiinflammatory drugs [NSAIDS]), hiccups, edema, muscle weakness, easy bruising, dizziness, unusual hair growth on the face and body, bone loss, visceral perforation, decreased wound healing, and cardiovascular disease, including atrial fibrillation in some patients. (See "Major side effects of systemic glucocorticoids".)
Hiccups are an indirect side-effect of glucocorticoids; rotation to a different glucocorticoid may help. A retrospective study of 40 cancer patients receiving chemotherapy treatment who had dexamethasone-related hiccups found significant improvement in the hiccup intensity and duration after rotation to methylprednisolone from dexamethasone during the next cycle of chemotherapy [62]. There was no significant loss of protection against chemotherapy induced nausea and vomiting with this corticosteroid rotation.
Megestrol acetate — Anorexia-cachexia is an important contributory factor to fatigue in palliative care patients. Loss of more than 5 percent of premorbid body weight results in significant physical and psychological morbidity and is an independent risk factor for early mortality. In randomized placebo-controlled trials conducted in patients with advanced cancer and anorexia, megestrol acetate significantly improved fatigue (activity) in addition to beneficial changes in appetite and overall wellbeing [63]. However, treatment with megestrol is complicated by significant risks, including edema, thromboembolic phenomena, and increased mortality. A Cochrane review [64] of 35 trials of megestrol for treatment of anorexia-cachexia syndrome related to cancer, acquired immunodeficiency syndrome (AIDS), or another underlying pathology concluded that approximately one in four will have an increase in appetite, 1 in 12 will have a weight increase, and 1 in 23 will die as a result of treatment-related complications [64]. Given the potential for these significant risks and other toxic effects (hypertension, hyperglycemia, adrenal suppression with insufficiency upon abrupt termination), the decision to use megestrol must be carefully considered, balancing the severity of symptoms and potential benefit with expected side effects and the possibility of mortality. (See "Management of cancer anorexia/cachexia", section on 'Progesterone analogs'.)
Psychostimulants — Both fatigue and depression in patients receiving palliative care can be treated with the psychostimulants such as dextroamphetamine, methylphenidate, pemoline (not available in the United States), or modafinil. Psychostimulants act rapidly and are generally well tolerated and safe. However, they should be used with caution in patients with heart disease or cognitive disturbances (eg, delirium).
All of the available data addressing the role of psychostimulants in management of fatigue patients with serious and/or life-threatening illness are in cancer patients, in whom the benefit has been best shown for methylphenidate and modafinil in patients with severe fatigue; benefit is less certain in patients with mild to moderate fatigue. The role of psychostimulants in the management of fatigue in terminally ill patients with diseases other than cancer needs to be defined by randomized controlled trials, and in these setting, these are considered investigational approaches. However, a trial of psychostimulants such as methylphenidate or modafinil is reasonable for patients with opioid-related sedation and for patients with severe fatigue who do not respond to a glucocorticoid or megestrol or who have a contraindication to the use of either of these classes of drugs.
Methylphenidate — In patients with cancer, methylphenidate has been used to manage fatigue, but benefit, particularly in those with mild to moderate fatigue, has been difficult to prove. Benefits are best established in the setting of opioid-induced sedation [65,66], cognitive dysfunction associated with brain tumors [67], and depression [68]. Its mechanism of action is stimulation of the central nervous system by blockade of presynaptic norepinephrine and dopamine reuptake [69,70]. (See "Cancer-related fatigue: Treatment", section on 'Methylphenidate and dexmethylphenidate' and "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Psychostimulants'.)
Methylphenidate is usually administered twice a day at breakfast and lunch in order to minimize nighttime insomnia. Assessment of benefit can be relatively rapid. In a pooled analysis of 82 advanced cancer patients in two prospective, controlled, clinical trials who had received methylphenidate for cancer-related fatigue, the factors associated with response to methylphenidate at day 8 were severity of fatigue and improvement of symptoms within the first 24 hours of administration (85 percent sensitivity, 67 percent positive predictive value) [71].
Modafinil and armodafinil — Modafinil and armodafinil were found to be effective and well tolerated for the treatment of excessive daytime sleepiness (EDS) in patients with narcolepsy and for conditions such as Parkinson disease and obstructive sleep apnea [72-76]. As with methylphenidate, benefit of these agents in cancer-related fatigue has been difficult to prove. (See "Cancer-related fatigue: Treatment", section on 'Modafinil'.)
The exact mechanism of action of modafinil and its levorotatory enantiomer armodafinil is unclear, although a murine study implicates non-noradrenergic, dopamine-dependent adrenergic signaling in the wake-promoting mechanism of modafinil [77]. Modafinil is typically administered as a single daily dose of 200 mg/day in the morning whereas the dose of armodafinil is 150 mg/day in the morning [78].
Testosterone for hypogonadal males — As noted above, hypogonadism affects two-thirds of men with advanced cancer; low testosterone levels in men with cancer are associated with fatigue, anorexia, depression, and insomnia. (See 'Male hypogonadism' above.)
Testosterone replacement improves quality of life and diminishes fatigue for hypogonadal men with non-cancer conditions. (See "Clinical features and diagnosis of male hypogonadism".)
Guidelines are available from the Endocrine Society for replacing testosterone in chronic illnesses such as HIV, end-stage kidney disease, and chronic obstructive pulmonary disease (COPD); however, there are no recommendations specifically for cancer patients [25]. (See "Testosterone treatment of male hypogonadism", section on 'Clinical benefits of testosterone therapy in hypogonadal men'.)
The following data are available in cancer patients:
●A systematic review of male hypogonadism in advanced cancer found no definitive association with nutrition, function, or quality-of-life outcomes [79]. However, this review excluded intervention trials and found only six studies that were eligible for inclusion.
●A prospective study in males with advanced cancer demonstrated clinical benefit from replacement therapy [80]. In this small trial, 16 men treated with placebo and 13 men treated with testosterone (weight-based intramuscular testosterone administered every 14 days to achieve a bioavailable testosterone level 70 to 270 ng/dL) were evaluable for the primary outcome at day 29. Although no statistically significant difference was found for fatigue (FACIT-F) scores between arms at four weeks, Sexual Desire Inventory Score and performance status improved in the testosterone group, and fatigue subscale scores from the Edmonton Symptom Assessment Scale were significantly better in those treated with testosterone by day 72.
Although the size of this study is limited, these data support clinical benefit for replacement therapy in hypogonadal men with cancer.
However, Endocrine Society guidelines specifically recommend against testosterone supplementation in men with active breast or prostate cancer given concerns for acceleration of disease growth [25]. Relative contraindications, such as an undiagnosed prostate nodule or an elevated serum prostate-specific antigen (PSA) level, may be reconsidered on an individual basis depending on the overall prognosis [24]. A more in-depth discussion about contraindications to testosterone replacement therapy and an overview of monitoring during therapy are provided elsewhere. (See "Testosterone treatment of male hypogonadism", section on 'Contraindications to use' and "Testosterone treatment of male hypogonadism", section on 'Monitoring'.)
Complementary medicines — For patients who have moderate to severe fatigue who are undergoing active anticancer therapy, a therapeutic trial of American ginseng is reasonable as long as the patient is not receiving drugs that may interact unfavorably with ginseng, such as anticoagulants.
Early studies have suggested efficacy for American ginseng and possibly guarana (a stimulant derived from an extract of seeds from a plant in the Amazon [Paullinia cupana]) for the treatment of cancer related fatigue. As an example, in a multicenter, double-blinded, randomized study, 2000 mg/day of oral American ginseng (Panax quinquefolius) extract was associated with significant improvement in fatigue after eight weeks of treatment [81]. Concern has been raised as to the potential for drug interactions with ginseng (especially with warfarin [82,83]); clinically relevant interactions with other drugs have not been described. (See "Cancer-related fatigue: Treatment", section on 'Ginseng and guarana'.)
On the other hand, benefit is less clear for Asian ginseng (Panax ginseng); trial results are disparate (see "Cancer-related fatigue: Treatment", section on 'Ginseng and guarana' and "Complementary and alternative therapies for cancer", section on 'Ginseng and guarana for fatigue'):
●In a randomized controlled study of Asian ginseng versus placebo in 112 patients with advanced cancer, Asian ginseng was not significantly superior to placebo after four weeks of treatment [84]. Furthermore, the placebo group actually reported a higher frequency of side effects compared with the ginseng group.
●On the other hand, a benefit for Asian ginseng (2000 mg/day) was suggested in a preliminary report of a second larger controlled trial conducted in 438 patients with colorectal cancer being treated with combination chemotherapy [85]. Ginseng-treated patients had significantly better fatigue scores at 16 weeks, and there were no discernable toxicities associated with treatment.
There are no studies with fatigue as a primary outcome that confirm benefit from fish oil or melatonin, and these treatments should not be suggested for symptomatic therapy until further studies confirm their efficacy [86-88].
Placebo for treatment of fatigue — Placebo has been shown to improve fatigue in cancer survivors [89]. For example, a trial of 21-day open-labeled placebo for symptoms of fatigue in cancer survivors reported greater improvement in fatigue compared with treatment as usual (29 versus 10 percent) [90].
Nonpharmacologic approaches
Exercise — Physical activity is important to maintain a sense of well-being and to enhance quality of life [91]. Most palliative care patients experience multiple symptoms, such as fatigue, pain, dyspnea, and nausea, which may all contribute to reduced physical activity, or even inactivity, and thereby reduced physical functioning. Exercise rehabilitation during or after curative or life prolonging treatment is considered as an effective means of restoring physical and psychological function [92,93].
The benefits of exercise in terms of improving physical performance have been shown in many trials conducted in patients with advanced cancer, although benefit in terms of fatigue has been more difficult to show. As an example, in a large randomized control study of 231 patients with incurable cancer and a life expectancy of three months to two years, physical exercise (60 minutes twice a week for eight weeks) provided significant improvement in physical performance as assessed by a hand grip strength test and the shuttle walk test, whereas fatigue, the predefined primary endpoint, was not significantly reduced [94]. (See "Cancer-related fatigue: Treatment", section on 'Exercise'.)
Additional randomized controlled trials are required in palliative care settings to assess the overall efficacy of exercise [95]. However, moderate exercise is a reasonable recommendation, if patients are able to tolerate it.
Yoga — In a meta-analysis of 17 trials (2183 patients), yoga improved cancer-related fatigue in breast cancer patients during and following treatment [96]. (See "Cancer-related fatigue: Treatment", section on 'Yoga'.)
Qigong/tai chi — Qigong is a traditional Chinese exercise therapy commonly used for the treatment of cancer-related fatigue. In a systematic review of 22 studies (1283 participants with various cancers), a 3- to 12-week Qigong intervention was associated with significant improvement in cancer-related fatigue [97].
Sleep hygiene — In patients with advanced cancer or other life-limiting disease states, it is common to have multiple symptoms occurring simultaneously hence it is difficult to determine that sleep disturbance is the sole causative mechanism for fatigue, or if fatigue is contributing to sleep disturbance. Sleep disturbance may be influenced by numerous factors including daytime naps, pain, depression, anxiety, medication, sleep interruption because of sleep apnea, nocturia or hot flashes, and evening food and/or beverage intake.
Few studies have evaluated sleep interventions to manage fatigue in advanced cancer and other life-limiting illnesses; the results are conflicting. Cognitive-behavioral therapy and stress reduction may help. Other suggestions for improving sleep patterns include taking a warm bath or drinking a glass of warm milk prior to bedtime, avoiding caffeinated beverages following dinner, emptying the bladder just before going to bed, and scheduling naps earlier in the day (table 9). Some patients require medications to help them sleep. (See "Overview of the treatment of insomnia in adults" and "Cancer-related fatigue: Treatment", section on 'Sleep disturbance'.)
Behavioral and psychosocial interventions — Cognitive-behavioral and psychosocial interventions (including mindfulness-based stress reduction) have also been found to be an effective modality for the treatment of cancer-related fatigue and for improving sleep in cancer survivors [98,99]. This subject is discussed in detail elsewhere (see "Cancer-related fatigue: Treatment"). Further well-designed studies are needed in a broad variety of palliative care patients before this approach can be recommended in advanced serious illnesses other than cancer.
Acupuncture — In a meta-analysis of 10 trials, acupuncture improved cancer-related fatigue [100]. Most trials utilized sessions of 20 to 30 minutes over three to six weeks.
Bright light therapy — Light has an effect on the sleep-wake cycle by its action of suprachiasmatic nucleus in the brain [101].
A trial of exposure to bright white light therapy (30 minutes daily for four weeks) demonstrated benefit in cancer-related fatigue when compared with exposure to dim red light, although the mechanism was not clear [102].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Palliative care".)
SUMMARY AND RECOMMENDATIONS
●Fatigue (asthenia, weakness) is the most common symptom in palliative care; it is also one of the most underdiagnosed and undertreated. Untreated or undertreated fatigue significantly affects the quality of life of patients receiving palliative care; appropriate assessment and management of fatigue is essential. (See 'Prevalence' above.)
●Fatigue is a typically a multidimensional symptom. Among patients seen in a palliative care setting, acute fatigue may be due to an acute, potentially reversible medical condition (eg, cardiac decompensation, infection), while chronic fatigue, as typified by fatigue related to cancer, may have multiple contributing causes (table 8) (see 'Causes and pathophysiology' above). Some of the common treatable causes of fatigue in cancer patients at end of life include deconditioning, infection, dehydration, metabolic and endocrine disorders, and cancer-related symptoms such as pain, anorexia, insomnia, and psychological symptoms [1,2]. Anemia is a particularly important contributor in patients undergoing cancer treatment. Anemia is a less common contributor to fatigue in cancer patients nearing the end of life.
●The intensity of fatigue can be assessed using a “0 to 10” visual analog scale or instruments, such as the Brief Fatigue Inventory, which measure not only intensity but also functional impact (table 5). A comprehensive history and physical examination is indicated to identify potentially reversible etiologies. Review of all medications, both prescription and over the counter, is particularly important to identify side effects and potential drug-drug interactions that may be contributing to fatigue. Simply altering the dose or dosing interval may substantially improve fatigue. (See 'Polypharmacy' above and 'Clinical assessment' above.)
●When considering how to treat fatigue, a multidimensional approach is preferred. It is important to determine whether the etiology is reversible and to treat these reversible causes as best as possible (table 8).
●Optimal management of symptomatic anemia requires an accurate diagnosis to identify potentially remediable causes (eg, ongoing blood loss, hemolysis, or deficiency of iron, folic acid, or vitamin B12). If a potentially treatable cause cannot be identified, treatment options include red blood cell transfusion or, for selected patients (chronic kidney disease, HIV infection, patients receiving palliative chemotherapy for cancer), an erythropoiesis-stimulating agent (ESA) (see 'Treatment of anemia' above). ESAs should not be given in patients not fitting these categories, due to the excess death risk with thrombosis.
●If a specific cause cannot be identified, we suggest symptomatic management:
•All patients should be counseled as to coping strategies that conserve energy (table 10 and table 11), and about good sleep hygiene (table 9).
•For patients who are in the terminal phase of their illness who have a high symptom burden that includes fatigue, we suggest a two-week trial of a glucocorticoid (eg, dexamethasone 8 mg/day) (Grade 2C).
In our view, the use of megestrol acetate needs to be carefully considered given its modest degree of benefit and the potential for significant side effects and increased mortality. (See 'Glucocorticoids' above and 'Megestrol acetate' above.)
•The role of psychostimulants is not well defined, particularly for patients with serious and/or life-threatening illnesses other than cancer. However, a trial of methylphenidate, or modafinil and armodafinil, is reasonable for patients with opioid-related sedation and for patients with severe fatigue who do not respond to a glucocorticoid or megestrol or who have a contraindication to the use of these classes of drugs. (See 'Psychostimulants' above.)
•For patients who have moderate to severe fatigue who are undergoing active anticancer therapy, a therapeutic trial of American ginseng is reasonable as long as the patient is not receiving drugs that may interact unfavorably with ginseng, such as anticoagulants. (See 'Complementary medicines' above.)
•Other nonpharmacologic approaches that may be helpful include moderate exercise, yoga, and cognitive-behavioral therapy, including mindfulness-based stress reduction.
