123: Cancer-Related Fatigue

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Cancer-Related Fatigue

Andrea Cheville, MD, MSCE


Cancer-related fatigue syndrome

Paraneoplastic dysfunction

ICD-9 Codes

357.6   Polyneuropathy due to drugs

780.79  Other malaise and fatigue

781.2   Abnormality of gait

ICD-10 Codes

G62.0   Drug-induced polyneuropathy

R53.81  Other malaise

R26.9   Abnormalities of gait and mobility


Cancer causes one in four deaths in the United States and is a major public health problem worldwide. Projections for 2013 were that more than 1,660,290 new cancer cases would be diagnosed and that more than 580,305 patients would die of cancer [1]. Cancers vary widely in prognosis, natural history, management, treatment responsiveness, adverse sequelae, and associated physical impairments. As a consequence, cancer rehabilitation is not amenable to one-size-fits-all treatment approaches. Physical impairments vary with the location and stage of cancer as well as by the type of treatment. For example, cancers of the head and neck may require neck dissection and irradiation. Common sequelae include shoulder dysfunction and fibrosis of cervical soft tissue. In contrast, primary breast cancer treatment may cause myofascial pain and upper extremity swelling. The reader is referred to chapters specific to these conditions and anatomic locations (e.g., scapular winging, lymphedema).

A more uniform approach can be applied to the management of cancer-related fatigue (CRF). The National Comprehensive Cancer Network defines CRF as a distressing, persistent, subjective sense of physical, emotional, or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning [2]. CRF is the most common cancer-associated symptom among the more than 12 million cancer survivors in the United States [3]. Its effects can be overwhelming and, depending on the nature and treatment of the cancer, can limit the lives of as many as 70% of disease-free survivors [47]. Whereas severe post-treatment CRF is particularly common among lung cancer survivors [8,9], high levels of persistent CRF are also reported among the survivors of most malignant neoplasms, including but not limited to those of the breast, brain, head, and neck and childhood malignant neoplasms [721]. CRF, even at it mildest levels, affects all health-related quality of life domains [4,2224]. On a vocational level, CRF intensity predicts failure to return to work [4,2527], and it is estimated that 1 million cancer survivors may be receiving disability payments as a consequence of its persistence [28]. On a general level, multiple investigators have found that increased CRF is considered an important unmet care need by patients [2931] and explains a significant proportion of performance and mobility degradations [3238] across a wide range of cancers [3942]. Not surprisingly, the indirect costs associated with patients with CRF are increased, with research showing that patients with CRF visit general practitioners 50%, specialists 350%, physical therapists 130%, and complementary caregivers 520% more often than those without the condition do [4,43,44]. Fortunately, effective CRF treatment has been shown to improve vocational productivity and performance of activities of daily living while reducing family stress and caregiver burden [45].


Before formal evaluation is undertaken, it is important to establish the patient’s current place on the cancer trajectory, which influences all elements of the history and physical examination. Three important distinctions must be made:

1. Is the patient receiving active treatment?

2. Does the patient have residual cancer?

3. Is the patient deemed curable?

The willingness and capacity of patients to engage in the rehabilitation process will be reflected in the answers to these questions.

A characteristic constellation of symptoms should not be anticipated in patients’ reporting of CRF. As emphasized before, patients’ neoplasms, treatment regimens, and disease trajectories are variable. CRF may therefore be manifested differently, contingent on the particulars of each case. Patients’ descriptions of their fatigue may be inconsistent and, at times, puzzling to clinicians. Any of the following subjective complaints should raise concern about possible CRF: weakness (generalized or proximal), dyspnea on exertion, orthostatic hypotension, sedation, hypersomnolence, 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) can be exceedingly useful to quantify severity of symptoms and to monitor treatment response [46]. A brief screen for depression or other mood disorders is essential, and validated screening tools are widely available.

Patients’ cancer histories warrant attention, including prior and ongoing radiation therapy and chemotherapy as well as any surgical procedures. Awareness of a patient’s primary cancer will shift the focus toward particular causes of symptoms. 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, and prior treatments and degree of response. Questions about sleep patterns, sleep hygiene, and daytime napping are useful. Reports suggest that frequent daytime napping may actually worsen fatigue [47].

The extent to which fatigue limits vocational, avocational, and familial pursuits as well as autonomous mobility and self-care should be comprehensively reviewed. Because fatigue most commonly interferes with 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), 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 irradiated for head and neck cancers. 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. 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.

Functional Limitations

Although fatigue is rarely so severe that it undermines basic mobility or performance of activities of daily living apart from the palliative context [48], evaluation of these functional domains is integral to comprehensive evaluation. Severe functional compromise may be a red flag, contingent on the clinical context that triggers evaluation for significant comorbidity or recurrent cancer. Ambulation for moderate distances may produce limiting dyspnea in patients with cancer-related cardiac or pulmonary dysfunction. Patients with steroid myopathy or generalized muscle weakness may have difficulty in 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. As suggested previously, many patients describe generalized heaviness of the limbs and global decrements in activity level without precise functional limitations.

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

Diagnostic tests should be informed by patients’ symptoms and findings on clinical examination. Dyspnea should be assessed with pulse oximetry during activity, chest radiography, and electrocardiography. Patients who exhibit severe dyspnea with minimal activity may have pulmonary fibrosis. Definitive diagnosis may require computed tomographic scanning. 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 possibly a ventilation-perfusion scan should be considered for persistent shortness of breath. Patients who have received doxorubicin (Adriamycin) or trastuzumab (Herceptin) 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), 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) may warrant assessment 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 [49]. Multifocal brain metastases may be manifested 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 melanoma, 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 [50]. The Generalized Anxiety Disorder (GAD-7) screen is another valid measure with low respondent burden that can be facilely integrated into routine history taking [51].

Differential Diagnosis


Nutritional insufficiency



Metabolic or endocrine abnormality (e.g., hypercalcemia, hypothyroidism, adrenal insufficiency)

Steroid myopathy

Medication side effects

Chemotherapy- or radiation therapy–induced cognitive dysfunction


Pulmonary parenchymal disease, bleomycin toxicity, radiation therapy–induced fibrosis

Pleural or pericardial effusion

Doxorubicin- or trastuzumab-related cardiotoxicity

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