Abstract
Cancer-related fatigue (CRF) is a distressing, persistent subjective sense of physical, emotional, and/or cognitive tiredness that affects up to 100% of cancer patients during and following treatment. CRF is strongly associated with degraded quality of life, physical functioning, and vocational potential. A CRF diagnosis is based on history and should be made after ruling out alternative causes of fatigue such as anemia and hypothyroidism. Validated patient-reported outcome tools can help to diagnose CRF and assess its intensity and response to treatment. Co-occurring symptoms and comorbidities are common. Patients with CRF should be assessed for depression, anxiety, and degraded sleep quality. Resistive and aerobic exercises are the most effective treatments for CRF. Psychoeducational interventions emphasizing activity and stress management, mindfulness training, coping skills and problem solving training, and cognitive-behavioral therapy have also been shown capable of significantly reducing CRF. Referral to occupational and physical therapy for training in energy conservation strategies, use of adaptive equipment, and progressive resistive exercise will benefit appropriate patients. Pharmacologic approaches for cancer fatigue center predominantly around the administration of psychostimulants. Overly aggressive aerobic conditioning or strengthening programs may worsen CRF, but treatments are generally safe and well tolerated.
Definition
The National Comprehensive Cancer Network defines cancer-related fatigue (CRF) 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 interferes with usual functioning. The belief that fatigue is solely a transient, relatively benign, and generally treatment-linked inconvenience is inaccurate and profoundly damaging to patients and society. CRF degrades quality of life (QoL) and mood in over 7 million cancer survivors including more than 80% of those undergoing treatment, almost a third of disease-free survivors, and three-quarters of those with metastatic disease. In addition, fatigue explains over 30% of the functional decline that occurs across a broad range of cancer types and stages. Reports confirm that it is the strongest predictor of impending disability among patients with metastatic disease. Alarming levels of CRF have been reported among virtually all cancer populations, irrespective of type or stage. However, patients with advanced disease and those receiving anti-androgen therapies most commonly report severe and function-degrading level of CRF.
On a vocational level, fatigue’s intensity predicts absenteeism and is the principal cause of failure to remain employed. In all, more than a million cancer survivors receive fatigue-related disability payments. Furthermore, fatigue radically increases healthcare utilization and is the primary complaint for 20% of emergency department and unplanned office visits among patients with cancer. Unplanned admissions follow a similar pattern, with almost 90% of hospitalized patients with cancer reporting at least moderate fatigue. CRF is also associated with longer hospital stays and higher post-acute care needs. Nearly half of the over $150 billion annual US cancer expenditures are for hospitalizations, with fatigue as either the instigating causal or a major contributing factor. Finally, fatigue is among the most common reasons for nonadherence to cancer treatment, thereby contributing to dose reductions, increased cost, and lessened treatment effectiveness.
Symptoms
A patient’s status on the cancer trajectory informs the history taking and physical examination. Three important distinctions must be made:
- 1.
Is the patient receiving anti-cancer treatment?
- 2.
Does the patient have evidence of persistent cancer?
- 3.
Is the patient deemed curable?
The willingness and capacity of a patient to engage in the rehabilitation process will be reflected in their answers to these questions.
A characteristic constellation of symptoms should not be anticipated in patients reporting CRF. Patients’ cancer type, treatment, and disease trajectories are variable. CRF may therefore present differently, contingent on the particulars of each case. Any of the following subjective complaints should raise concern about possible CRF, particularly since CRF may co-occur with other symptoms and impairments related to cancer or comorbid conditions: weakness (generalized or proximal), dyspnea on exertion, orthostatic hypotension, sedation, hyper-somnolence, exertional intolerance, or cognitive compromise (e.g., attention or concentration deficits, short-term memory dysfunction). Patients may report the sensation that their legs are leaden or that they are walking through water. Validated self-report fatigue scales (e.g., Brief Fatigue Inventory, Functional Assessment of Cancer Treatment—Fatigue, Profile of Mood States, Patient Reported Medical Information System Fatigue Short Form) can be exceedingly useful to quantify severity of symptoms and to monitor treatment response. A brief screen for depression or other mood disorders is essential, and validated screening tools for anxiety, depression, and distress are available. Querying patients about life stressors, as well as effective coping strategies and stress reduction approaches, may identify opportunities for therapeutic intervention that target key deficits or that leverage beneficial health behaviors.
Patients’ cancer histories warrant attention, including prior and ongoing radiation therapy and chemotherapy as well as any surgical procedures. Associations between CRF and virtually all anti-cancer treatments have been reported. A patient’s recent treatment is relevant, since many patients gradually improve after finishing treatment. Severely fatigued patients who lack a history of recent treatment have a prognosis and lower likelihood of improvement in the absence of treatment. Information comparable with that solicited through a good pain history should be elicited for fatigue: acuity of fatigue onset, activity- or treatment-related precipitants, diurnal fluctuation, associated symptoms (e.g., pain, nausea), progressive worsening or improvement, exacerbating and alleviating factors, as well as prior treatments and degree of response. Questions about sleep patterns, sleep hygiene, and daytime napping are useful. Reports suggest that frequent daytime napping may worsen fatigue.
The extent to which fatigue limits vocational, avocational, and familial pursuits as well as autonomous mobility and self-care should be comprehensively reviewed. Because CRF impedes activities requiring stamina and exertional tolerance, changes in a patient’s comfortable walking distance, duration of physical activity, and willingness to climb stairs will help characterize the impact of fatigue.
Physical Examination
Special tests are rarely indicated on physical examination. Rather, clinicians should perform a comprehensive evaluation with emphasis on musculoskeletal and neurologic elements. Assessment of range of motion, gait (including tandem and toe/heel walking), static and dynamic balance, and ability to squat repetitively may identify potential contributing factors amenable to therapeutic exercise. Examination may reveal evidence of congestive heart failure or pulmonary compromise. Signs of hypothyroidism should be sought, particularly in patients radiated for head and neck cancers, or taking immunomodulatory medications. For patients without evidence of cancer, the neurologic examination findings should be normal beyond chemotherapy-related peripheral neuropathy. Weakness in proximal hip and shoulder musculature suggests steroid myopathy or sarcopenia. Identification of new neurologic deficits should trigger evaluation for malignant progression or emerging treatment toxicity. The mental status examination may reveal evidence of compromised arousal, attention, memory, or concentration, particularly in patients who have received whole-brain radiation therapy or intrathecal chemotherapy. Additionally, delirium is prevalent among patients with advanced stage cancer, particularly those who are elderly and receiving anti-cancer therapies. The Confusion Assessment Method may help to distinguish delirium from other sources of cognitive fatigue.
Functional Limitations
Although fatigue is rarely so severe that it undermines basic mobility or performance of activities of daily living apart from the case of patients with far advanced disease, evaluation of these functional domains is integral to comprehensive evaluation. Severe functional compromise may be a red flag indicating significant comorbidity or recurrent cancer. Common functional limiting and potentially remediable comorbidities that occur with CRF include cancer-related cardiac or pulmonary dysfunction, steroid myopathy, or generalized muscle weakness and sarcopenia. Affected patients frequently complain of dyspnea with ambulation or difficulty rising from low surfaces, such as a toilet, soft chair, or car seat. These patients may also demonstrate decreased ability to independently complete their activities of daily living in a reasonable time frame. In contrast, the majority of patients with CRF but lacking functionally relevant comorbidities describe generalized heaviness of the limbs and global decrements in activity level without precise limitations.
CRF-related dysfunction in social, vocational, psychological, and sexual domains may be present. Patients should be questioned about compromised social interactions, sleep, and intimacy as well as work-related and leisure pursuits. Many patients abandon their avocational activities as a consequence of fatigue, with the potential for isolation and secondary depression. Patients with cognitive deficits related to radiation therapy or chemotherapy may experience difficulty in maintaining their vocational productivity. Financial and domestic management skills may be compromised as well.
Diagnostic Studies
The selection of diagnostic tests should be informed by patients’ symptoms and findings on clinical examination. Dyspnea should be assessed with pulse oximetry during activity, chest radiography, pulmonary function tests, and electrocardiography. Patients who exhibit severe dyspnea with minimal activity may have pulmonary fibrosis. Definitive diagnosis may require computed tomographic scanning or magnetic resonance imaging. Positron emission tomography may help distinguish fibrosis from cancer involving the lung parenchyma. Patients with cancer are at an elevated risk for venous thrombosis; therefore, a venous duplex study and studies to evaluate for pulmonary embolism should be considered for persistent shortness of breath. Patients who have received doxorubicin or trastuzumab should be evaluated with a multigated acquisition scan to rule out possible chemotherapy-related cardiac toxicity. Most patients will have undergone multigated acquisition screening before the administration of chemotherapy. The results of baseline tests can be compared with new evaluations for evidence of deterioration. Pericardial effusions may be a consequence of malignant spread or radiation-induced irritation, or occur as a paraneoplastic phenomenon. An echocardiogram should be obtained for patients with a suggestive history and physical examination. Patients reporting insomnia or a failure to feel rested after a night’s sleep may benefit from a sleep study to rule out sleep apnea or related disorders.
Serologic evaluation may include thyroid-stimulating hormone concentration (to screen for thyroid myopathy in patients who have received irradiation to the anterior neck or immunomodulatory drugs), calcium concentration, electrolyte values (Addison disease may occur with adrenal metastases or irradiation), hemoglobin concentration, and hematocrit. Hypercalcemia or persistent mechanical pain should be evaluated with a bone scan or plain films. Multiple myeloma and malignant neoplasms producing lytic metastases may fail to generate an abnormal bone scan despite diffuse skeletal involvement . Blood levels of centrally acting medications (e.g., tricyclic antidepressants, anticonvulsants) should be checked in patients who describe fatigue with a significant cognitive dimension.
For patients with focal neurologic deficits, imaging of those portions of the neural axis implicated on physical examination should be performed. Magnetic resonance images should be obtained with gadolinium. Steroids administered in conjunction with chemotherapy may be of sufficient doses to cause myopathy. Electrodiagnostic studies can rule out alternative, treatable sources of neurologic compromise.
Patients complaining of generalized cognitive dysfunction may benefit from neuropsychological evaluation. Cognitive deficits have been detected after chemotherapy. Multifocal brain metastases may present with a global decrement in mental acuity and capacity to attend. Enhanced computed tomographic scanning of the head may be warranted when there is a high clinical probability of brain metastases (e.g., patients with systemic melanoma and breast or lung cancers).
Screening for depression, anxiety, and other psychological distress is integral to the CRF evaluation. The Patient Health Questionnaire (PHQ-9) is a brief and valid screen for use in cancer populations. The PHQ-9 distinguishes both the presence and severity of depression. The Generalized Anxiety Disorder (GAD-7) screen is another valid measure with low respondent burden that can be facilely integrated into routine history taking.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
