INTRODUCTION — Fatigue is a common problem in cancer patients. A majority of patients will experience some level of fatigue during their course of treatment, and approximately one-third will have persistent fatigue for a number of years posttreatment [1,2]. Cancer-related fatigue (CRF) profoundly affects quality of life (QOL) of both patients and their caregivers, including physical, psychosocial, and economic/occupational aspects [3,4]. Furthermore, fatigue is routinely identified by patients as one of the most distressing symptoms associated with cancer and its treatment, yet fatigue has been consistently underreported and overlooked as a potentially remediable cause of treatment-related morbidity [5]. More recently, screening for and treatment of CRF during therapy and during the period of cancer survivorship has become a major focus of supportive care in oncology and is the subject of guidelines from several expert groups, including the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network [6-8].
Here we will review the contributory factors and pathogenesis of CRF, and screening for as well as clinical assessment of patients with CRF. Treatment of CRF and issues surrounding fatigue that are specific to palliative care patients are discussed elsewhere. (See "Cancer-related fatigue: Treatment" and "Overview of fatigue, weakness, and asthenia in palliative care".)
DEFINITION — CRF is defined 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 recent activity and that significantly interferes with usual functioning [6]. CRF differs from the fatigue that accompanies everyday life, which is usually temporary and relieved by rest.
The term asthenia has been proposed to describe the condition of chronic pathologic tiredness in patients with cancer [9]. However, the term fatigue has gained widespread acceptance in the medical literature and is preferentially used in the National Cancer Institute (NCI) toxicity grading scale that covers fatigue, asthenia, and malaise (table 1).
Specific diagnostic criteria have been proposed for defining CRF as an independent entity in the International Classification of Diseases, 10th revision (ICD-10) [10,11]. At least 6 of 11 criteria must be met to make the diagnosis of CRF (table 2). In studies of diverse patient populations, approximately 10 to 26 percent of subjects are diagnosed as having CRF using this definition [12-15].
The use of diagnostic criteria such as these provides a greater degree of specificity than the simple question "Do you feel tired?" as was used in two national CRF prevalence studies and that resulted in spuriously high prevalence figures [16,17]. (See 'Prevalence and time course' below.)
However, the formal diagnostic criteria as outlined in the ICD-10 (table 2) are not in widespread use, and patients do not necessarily need to have a minimum number of criteria to receive a clinical diagnosis of CRF. Their use is not recommended in guidelines for screening and assessment of CRF from expert groups, including the National Comprehensive Cancer Network (NCCN) [6,7,18].
PREVALENCE AND TIME COURSE — CRF is a common problem. A majority of patients will experience some level of fatigue during their course of treatment, and approximately one-third will have persistent fatigue for a number of years posttreatment [1,2,19].
The true incidence of CRF in cancer patients is difficult to ascertain; published studies are restricted to prevalence data. Estimates are that CRF affects between 15 and 90 percent of cancer patients overall [12,16,17,20-33] and more than 75 percent of those with advanced cancer or bone metastases [20,34]. The wide range of these estimates likely reflects variable diagnostic criteria used to define CRF.
The prevalence and severity of CRF were studied in two United States national surveys commissioned by the Fatigue Coalition, a multidisciplinary group of practitioners, researchers, and patient advocates [16,17]:
●In the first survey, 419 cancer patients who were members of 1700 randomly selected American families were interviewed by telephone [16]. Fatigue was defined as a positive response to the single question "Do you feel tired?" The majority had solid tumors, and treatment consisted of chemotherapy (59 percent), radiation therapy ([RT] 63 percent), or both (24 percent). More than one-half had received therapy within the last year. In a separate mail survey, 197 of 600 randomly sampled oncologists responded to a questionnaire assessing perceptions and attitudes concerning CRF.
Overall, 74 percent of patients reported fatigue at some point during the course of their illness, with 32 percent reporting daily fatigue. However, only 50 percent of patients had discussed fatigue with their clinician, and in only one-fourth of cases was any intervention proposed. Patients and oncologists disagreed on the importance of CRF. Although doctors believed that pain affected patients to a greater degree than fatigue, patients thought that CRF adversely affected their daily lives to a greater degree than pain.
●Similar results were noted in a second telephone survey of 379 patients who had received chemotherapy with or without RT for some form of malignancy, identified from a representative sample of 6125 families obtained from the US Bureau of the Census [17]. Fatigue, defined the same way as in the first study, was present on at least some days of the month during chemotherapy in 76 percent of patients, with 30 percent suffering from fatigue on a daily basis. Patients reported fatigue as the symptom that most affected quality of life (QOL), followed by nausea, depression, and pain. The economic impact of CRF was considerable. Of the 177 employed patients, 75 percent changed their employment status as a result of fatigue, and 65 percent reported that their caregivers had to take at least one day (mean 4.5 days) off from work in a typical month.
●Comparable findings also were noted in a survey of patients and health care practitioners conducted by the All-Ireland Fatigue Coalition [35]. However, all of these surveys consist of retrospective cross-sectional data and are biased by recall and the use of nonvalidated diagnostic criteria.
As expected, a lower prevalence of CRF has been found in studies applying stricter diagnostic criteria [12,13,36]. This was illustrated in a validation study of the CRF diagnostic criteria being proposed for use in the International Classification of Diseases, 10th revision (ICD-10) (table 2) that was carried out in 379 individuals receiving chemotherapy with or without RT [12]. Overall, 141 patients (37 percent) had fatigue for at least two weeks in the prior month (ie, one of the proposed criteria), although only 66 (17 percent) met the proposed definition of CRF.
An additional problem with prevalence data is that CRF tends to fluctuate over the course of cancer treatment. For patients receiving chemotherapy, CRF is commonly cyclic and worst when blood counts are at their nadir (usually 10 to 14 days following treatment initiation). In contrast, the intensity of CRF in patients undergoing RT typically peaks toward the end of therapy, gradually decreasing thereafter [30,37-43].
Although CRF is most prevalent during active cancer therapy, a sense of fatigue may persist in survivors for months or even years after cessation of treatment [1,2,19,32,41,44-54]. The available data suggest that up to one-third of cancer survivors will have persistent posttreatment fatigue, which can be severe [1,2,19]. A small minority of patients who are presumably cured of their cancer are so debilitated by fatigue that they are still unable to work or regain their premorbid lifestyles years after completing treatment. Because of the lack of objective findings, many have problems maintaining disability status, causing additional stress and anxiety for themselves and their caregivers.
Given the persistence of fatigue following completion of active cancer therapy, guidelines from expert groups including the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) recommend screening for fatigue at the end of primary therapy and as clinically indicated (at least annually) during the period of survivorship care [6,18].
MAIN CONTRIBUTORY FACTORS — Although typically multifactorial, the main contributory factors to CRF include the following [6]:
●Cancer therapy, including cytotoxic agents, biologic response modifiers, molecularly targeted therapies (especially those targeting the vascular endothelial growth factor and epidermal growth factor receptor), hormonal therapies (eg, androgen deprivation therapy), and RT
●Progressive tumor growth
●Unrelieved pain
●Anemia
●Metabolic/nutritional/hormonal issues, such as poor nutrition, fluid/electrolyte disturbances, hypothyroidism, male hypogonadism, menopause, and dehydration
●Comorbidities, including cardiac, respiratory, renal, hepatic, and endocrine dysfunction, infection, neuromuscular disorders
●Medication side effects, especially sedation from opioid analgesics
●Deconditioning
●Depressed mood, emotional distress, and sleep disturbance
Cancer therapy and pathogenesis of fatigue — In many cases, the mechanisms that are responsible for CRF are poorly understood. Major obstacles to defining the relevant pathophysiology include the inherent subjectivity of fatigue, the difficulty in establishing objective behavioral correlates, and the wide variety of phenomena (including conditions that are unrelated to cancer or its treatment) that contribute to fatigue [55].
A variety of pathophysiologic hypotheses have been proposed for CRF, although none have been proven:
●Direct central nervous system toxicity of cancer treatment (ie, drugs that cross the blood-brain barrier, cranial irradiation).
●Anemia from blood loss or chemotherapy-related myelosuppression.
●Loss of muscle mass, defective muscle energy metabolism, and/or abnormalities in the generation or use of adenosine triphosphate (ATP) [23].
●Neurophysiologic skeletal muscle changes (the so-called vagal afferent hypothesis) [23].
●Chronic stress response, possibly mediated through the hypothalamic pituitary axis [23,56].
●Systemic inflammatory response [57-60].
●Immune activation associated with production of proinflammatory cytokines [61,62] and/or circulating T cells [63].
●Disrupted sleep or circadian rhythms [64-68].
●Hormonal changes (eg, premature menopause in women).
A detailed description of these hypotheses and the data upon which they are based is beyond the scope of this review and provided elsewhere [55,62,69-71]. What follows is a brief overview of the mechanisms underlying CRF that are directly related to cancer therapy.
Chemotherapy and molecularly targeted therapy — Chemotherapy and molecularly targeted therapy with small molecule tyrosine kinase inhibitors or therapeutic monoclonal antibodies may contribute directly to the development of CRF. Among the agents that are most commonly associated with fatigue are cetuximab and thalidomide (80 to 90 percent), lenalidomide, imatinib, sunitinib, and sorafenib (30 to 50 percent), fludarabine, cladribine, bevacizumab, panitumumab, and alemtuzumab (15 to 30 percent). Other conventional cytotoxic agents that cross the blood brain barrier (eg, methotrexate, ifosfamide, cisplatin, vincristine, irinotecan, paclitaxel, docetaxel, gemcitabine) may also induce fatigue via a direct neurotoxic effect [72].
These agents can also indirectly contribute to CRF by causing or interacting with other mechanisms that induce or exacerbate fatigue [20]. Examples include chemotherapy-induced premature menopause [73,74] and the higher rates of posttreatment fatigue that have been seen in patients receiving chemotherapy who have preexisting poor mental health [75]. (See "Ovarian failure due to anticancer drugs and radiation" and "Acute side effects of adjuvant chemotherapy for early-stage breast cancer".)
Long-term effects of chemotherapy on organ function may also contribute to CRF. Some examples are sunitinib-induced hypothyroidism, chronic heart failure from anthracycline-induced cardiomyopathy, and bleomycin-related pulmonary dysfunction [76]. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Thyroid dysfunction' and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity" and "Bleomycin-induced lung injury".)
Biologic response modifiers — Fatigue is nearly universal in patients receiving interferon (IFN) or interleukin-2 (IL-2) for melanoma or renal cell cancer.
Mechanisms that may contribute to this effect include the following:
●Disturbances of the hypothalamic-pituitary-adrenal axis, which can affect levels of plasma corticotropin (ACTH) and corticotrophin-releasing hormone, and ultimately the secretion of cortisol by the adrenal cortex [77-79]. This may be mediated through the production of proinflammatory cytokines or by a direct inhibition.
●Effects on neurotransmitter levels (eg, dopamine, serotonin).
●Drug-induced hypothyroidism [80-83].
Androgen deprivation therapy — Fatigue is a common problem in men undergoing androgen deprivation therapy for prostate cancer; the mechanism is unclear. The extent of fatigue does not seem to correlate with anemia, loss of lean muscle mass, or emotional cognitive issues. Inherited variations in genes that regulate immune function have been implicated [84,85]. (See "Side effects of androgen deprivation therapy", section on 'Fatigue'.)
Radiation therapy — Fatigue is a common early and chronic side effect of RT. It is reported in up to 80 and 30 percent of patients during RT and at follow-up visits, respectively [3,86-88]. In general, fatigue tends to worsen during treatment.
Fatigue is most common in patients receiving cranial irradiation and presumably related to direct effects on normal brain parenchyma or radiation-induced edema. This is often enhanced by the concomitant use of high-dose glucocorticoids. Although most patients have mild to moderate fatigue, a rare somnolence syndrome has been described. The etiology of this rare complication of cranial irradiation is unclear. (See "Acute complications of cranial irradiation", section on 'Fatigue'.)
The pathophysiology underlying fatigue in patients undergoing RT to extracranial sites is unclear. Sometimes anemia is contributory, but other mechanisms are probably operative [89]. As examples, in patients treated for pelvic malignancies, severe diarrhea during treatment may exacerbate fatigue [90], hypothyroidism may be a consequence of neck irradiation [91], and fatigue may accompany the concurrent use of androgen deprivation therapy in men receiving RT for prostate cancer. Psychological mechanisms have been proposed to explain fatigue in women receiving RT for early breast cancer [3], whereas a decline in neuromuscular efficiency has been proposed among men undergoing RT for prostate cancer [92].
Surgery — Among the potential contributory factors to postoperative fatigue are operative blood loss, medication effects, decreased ventilatory capacity, immobilization, infection, perioperative nutritional depletion, altered sleep patterns, and anxiety.
Anemia — Anemia is common in cancer patients, both as a consequence of the cancer itself (anemia of chronic disease, iron deficiency anemia due to gastrointestinal blood loss) or its treatment (surgery, systemic therapy, and RT). The full spectrum of other causes of anemia also needs to be considered in these patients (ie, hemolysis, nutritional deficiency). (See "Anemia of chronic disease/anemia of inflammation" and "Diagnostic approach to anemia in adults" and "Causes of anemia in patients with cancer".)
Although early studies were unable to demonstrate a clear correlation between hemoglobin levels and the severity of CRF, a direct relationship between anemia, fatigue, and quality of life (QOL) has been seen in later studies that used more refined evaluation instruments, such as the Functional Assessment of Cancer Therapy-Anemia (FACT-An) subscale (table 3) [9,93-97]. Correction of anemia has been associated with an improvement in both health-related QOL and fatigue. (See "Cancer-related fatigue: Treatment", section on 'Anemic patients'.)
Emotional disturbance/mood disorder — Fatigue seldom occurs by itself, and it commonly clusters with emotional distress, mood disorders, sleep disturbance, and/or pain [98-102]. In particular, there is a strong correlation between fatigue and depression [67,103-108], and in some cases, it may be difficult to distinguish between the two as the source of distress [108,109].
The precise relationship between CRF and emotional distress is not clear. Fatigue can be a symptom of depression and/or anxiety, but high levels of fatigue also can result in emotional distress when valued roles and activities are affected. Some data support the view that depression and fatigue, although linked, follow a different time course in patients with cancer [110] and that they respond differentially to therapeutic intervention [111]. As an example, placebo-controlled randomized trials in patients undergoing cancer treatment have failed to demonstrate any improvement in CRF in patients randomly assigned to receive an antidepressant despite its benefit in reducing symptoms of depression. (See "Cancer-related fatigue: Treatment", section on 'Antidepressants'.)
Sleep disturbance — Sleep disturbances in patients with cancer range from hypersomnia to insomnia. Although patients undergoing active cancer treatment tend to spend greater amounts of time resting and sleeping than individuals without cancer, sleep patterns often are disrupted, resulting in poor quality of sleep [64,112,113]. Insomnia symptoms affect between 30 and 50 percent of cancer patients, and 20 to 40 percent meet the diagnostic criteria for insomnia syndrome [114-118]. Sleep-wake disturbances may persist in long-term survivors [119].
Poor sleep hygiene (eg, frequent daytime naps late in the day) may contribute to inadequate nighttime rest. Medications may also contribute to insomnia. Patients with a history suggestive of sleep apnea should be referred for formal sleep evaluation. (See "Risk factors, comorbidities, and consequences of insomnia in adults" and "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)
SCREENING — All patients with malignant disease should be screened for CRF at the initial visit, at the end of primary therapy, as clinically indicated (and at least annually) during follow-up survivor care, when the diagnosis of advanced disease is made, and at each chemotherapy visit [6]. Screening should be performed and documented using a quantitative or semiquantitative assessment. One example is a visual analog scale (VAS, "How would you rate your fatigue on a scale of 0 to 10?"), with 0 representing no fatigue and 10 the worst imaginable fatigue [6-8,120]. Mild, moderate, and severe fatigue are represented by scores of 1 to 3, 4 to 6, and 7 to 10, respectively.
Multiple other instruments have been developed and validated to quantify fatigue in patients with serious illness, including cancer (table 4). Some of the more commonly used and best validated are the fatigue and anemia subscales of the Functional Assessment of Cancer Therapy instrument (FACT-F discussed above), the Brief Fatigue Inventory (BFI) (table 5) [120], the bidimensional fatigue scale [121,122], the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) [123], and the European Organisation for Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ C30), fatigue subscale [124].
Because fatigue is subjective, the clinician must rely upon patient self-reports to assess its presence and severity, which can then be supported by additional sources of information, such as physical examination, laboratory data, or the descriptions of family members. At least some data from the PROTECT randomized trial suggest that routine screening for fatigue using electronic symptom monitoring during treatment for metastatic cancer and subsequent intervention that is triggered by severe or worsening symptoms substantially improves patient-reported fatigue outcomes [125]. (See "Cancer-related fatigue: Treatment", section on 'General approach'.)
Even when asked, patients may be hesitant to report fatigue to their healthcare provider [5,126]. Patients may believe that fatigue is an expected and inevitable side effect of treatment [16,127], fear that they will be labeled a "complainer," or be afraid that they will receive suboptimal cancer treatment if they admit to being fatigued. Patients also may be anxious because they believe that fatigue is a sign of recurrent or progressing disease.
CLINICAL ASSESSMENT
Need for focused evaluation — The need for a further fatigue-focused clinical evaluation is based upon the level of CRF.
●If the reported intensity level is mild (visual analog scale [VAS] or Brief Fatigue Inventory [BFI] score 1 to 3) and does not interfere with the activities of daily living (ADLs), focused fatigue evaluation is not needed. The patient can be reassured and educated as to some common strategies to minimize energy expenditure (table 6). ADLs includes basic activities such as bathing, dressing, grooming, toileting, continence, eating, transferring and walking, as well as "instrumental" ADLs (IADLs) such as traveling, shopping, preparing meals, doing housework, taking medications, managing money, and using the telephone.
Periodic reassessment should be undertaken. Patients who are no longer receiving active therapy as well as long-term cancer survivors must still be monitored for CRF, which may persist beyond the period of active treatment. If fatigue worsens, a focused fatigue assessment should then be undertaken.
●Moderate to severe CRF (as defined by a score ≥4 on a scale of 1 to 10) is associated with significantly greater symptom interference compared with mild fatigue [128]. It requires a more focused history and physical examination to search for potentially reversible or treatable contributory factors.
Components — The components of an in-depth fatigue assessment include a focused fatigue history, an assessment of disease status and potentially treatable contributory factors, and appropriate referrals to trained professionals (eg, cardiologist, endocrinologist, mental health professional, internist) as needed [6].
History — A focused fatigue history includes the onset, duration, and pattern of fatigue, and associated or alleviating factors [6]. The effect of CRF on physical and cognitive functioning and on the patient's ADLs or enjoyment of life should be noted. A comprehensive review of systems is warranted to ascertain the various organ systems affected and to direct the physical examination and diagnostic work-up. Additional relevant information includes a history of smoking, alcohol and any illicit drug use, work history, and review of activity level and exercise tolerance.
Assessment of disease status — Accurate assessment of the patient's current disease status, type of treatment, and response to treatment is an important component of the initial evaluation. The risk of recurrence can be estimated based upon stage, pathologic factors, and treatment history [6]. The review of symptoms may reveal other symptoms that substantiate suspicion for recurrence. If it is determined that fatigue is unrelated to disease progression or recurrence, informing patients and their family members of this fact may substantially reduce anxiety levels.
Assess for potentially remediable contributing factors — Factors that are often causally related to CRF should be specifically assessed, including anemia, unrelieved pain, emotional distress, sleep disturbance, nutritional issues and electrolyte disturbances, decreased activity level/deconditioning, alcohol and other substance abuse, and the presence of cardiac, endocrine, pulmonary, hepatic, and renal dysfunction [6]. A recommended approach to initial laboratory evaluation is outlined in the table (table 7).
Comorbidities that may be unrelated to the cancer or its treatment (eg, infection, cardiopulmonary, renal, hepatic, neurologic, or endocrine dysfunction) may contribute significantly to symptoms of fatigue. CRF may be improved by optimizing treatment for conditions that have been previously unrecognized (eg, hypothyroidism) or suboptimally treated (eg, recurrent heart failure because of doxorubicin-induced cardiomyopathy). Hypothyroidism is particularly prevalent and may be related to irradiation for lymphoma, head and neck cancer, breast cancer, or total body irradiation prior to hematopoietic stem cell transplantation. In addition, several anticancer drugs (most notably sunitinib and sorafenib) can cause hypothyroidism.
Potential comorbid conditions and other treatable contributory factors that may be associated with fatigue symptoms, and suggested diagnostic evaluation strategies are provided in the table (table 8).
If any of these factors known to be associated with CRF are identified, they should be treated as the initial approach to fatigue. The clinical team must decide when/if referral to an appropriate professional is needed.
Medications — Medications are an often overlooked major contributor to fatigue. Review of all medications (both prescribed and over the counter) may reveal potential side effects or drug-drug interactions. As examples, beta-blockers can cause bradycardia and exertional fatigue, while excessive drowsiness may result from combinations of opioids with antidepressants or antihistamines, or incorrectly dosed pain medications. In some cases, altering the dose or dosing interval of a medication may substantially improve fatigue. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Somnolence and mental clouding'.)
Activity level — Patients with moderate to severe CRF should be asked about their overall activity level, including the influence of deconditioning. Patients should be asked whether they are able to maintain their basic and instrumental ADLs and whether they participate in either formal or informal exercise programs. Although exercise may be beneficial in improving CRF in certain patients, the level of deconditioning must be assessed before recommending an exercise program. If a severely deconditioned patient begins an exercise program too rapidly, complications may develop (eg, muscle strain) that may leave them discouraged and increasingly fatigued. (See "Cancer-related fatigue: Treatment", section on 'Exercise'.)
Nutritional assessment — Nutritional assessment should include an evaluation for weight gain or loss, changes in and impediments to adequate caloric intake, and fluid and electrolyte imbalances. Oral intake can be adversely affected by anorexia, nausea, vomiting, mucositis, odynophagia, bowel obstruction, or constipation. Imbalances in sodium, potassium, calcium, and magnesium may be associated with fatigue, which is potentially reversible with adequate supplementation (table 7).
Efforts directed at improving or maintaining nutritional status can decrease or prevent CRF. Patients with poor dietary intake or decreased absorption may need further assessment by a nutritionist. Treatment-related side effects such as nausea, vomiting, or diarrhea should be minimized. A detailed discussion of cancer-associated anorexia and cachexia is provided elsewhere. (See "Prevention of chemotherapy-induced nausea and vomiting in adults" and "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation" and "Pathogenesis, clinical features, and assessment of cancer cachexia" and "Management of cancer anorexia/cachexia".)
GUIDELINES FROM EXPERT GROUPS — Guidelines for screening and assessment of adults with CRF during and after therapy are available from several expert groups, including the NCCN [6,7,18].
A year 2014 clinical practice guideline for screening, assessment, and management of fatigue in adult cancer survivors is available from ASCO; specific recommendations for screening and assessment are outlined in the table (table 9) [6]. Pan-Canadian guidelines for screening and assessment of CRF, which cover both survivors and patients undergoing active treatment, are also available (table 10) [7].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: When your cancer treatment makes you tired (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition and presentation – 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 that significantly interferes with usual functioning [6]. Although most common during active cancer therapy, CRF may affect patients long after cancer treatment has been completed. (See 'Definition' above.)
●Screening
•All patients with malignant disease should be screened for CRF at the initial visit, at the end of primary therapy, as clinically indicated (and at least annually) during follow-up survivor care, when the diagnosis of advanced disease is made, and at each chemotherapy visit.
•Quantitative or semiquantitative instruments should be used. One example is a visual analog scale (VAS), "How would you rate your fatigue on a scale of 0 to 10?", with 0 representing no fatigue and 10 the worst imaginable fatigue. Mild, moderate, and severe fatigue are represented by scores of 1 to 3, 4 to 6, and 7 to 10, respectively. (See 'Screening' above.)
●Diagnostic evaluation
•Patients with mild CRF (VAS score 1 to 3) that does not interfere with activities of daily living (ADLs) can be reassured and counseled as to coping strategies that conserve energy (table 6). CRF that is moderate to severe (4 or higher on the VAS scale) or interferes with basic or instrumental ADLs requires a focused fatigue evaluation. (See 'Need for focused evaluation' above.)
•The evaluation should include a focused fatigue history, an assessment of disease status, review of all (prescription and over the counter) medications, assessment of activity levels, and nutritional assessment. (See 'Components' above.)
•Factors that are often causally related to CRF that should be specifically assessed include anemia, pain (and its treatment), emotional distress/mood disturbance, sleep difficulties, poor nutrition and electrolyte disturbances, activity level, comorbidities such as cardiopulmonary or endocrine dysfunction, and hypogonadism (table 8). A suggested initial laboratory evaluation is suggested in the table (table 7). (See 'Assess for potentially remediable contributing factors' above.)
•If any of these factors known to be associated with CRF are identified, they should be treated as the initial approach to fatigue. The clinical team must decide when/if referral to an appropriate professional is needed.
