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Understanding and Treating Cancer-Related Fatigue

Understanding and Treating Cancer-Related Fatigue

Fatigue is the most common side effect of cancer and its treatment, and it frequently goes unrecognized and untreated. While the exact etiology of fatigue is unclear, numerous contributing factors that worsen fatigue can be clinically addressed. Substantial research supports physical exercise as an intervention for fatigue.

Cancer-related fatigue (fatigue) is the most common side effect of cancer and its treatment. An exact cause of this complex, subjective, multicausal, multidimensional side effect of cancer and its treatment has eluded researchers.[1]

Among patients on active treatment, the prevalence of fatigue ranges from 60%–96%.[2] While sometimes present at diagnosis, fatigue is commonly associated with treatment (radiation therapy, chemotherapy, surgery, and biotherapy) and with patients who have advanced disease.[2] Survivorship research has demonstrated that fatigue may persist for months and years following completion of treatment, with a prevalence ranging from 30%–45% of survivors.[3–7]

The fatigue experienced during and following treatment adversely affects quality of life. Some studies have reported that fatigue impairs quality of life more than pain and other symptoms, and that fatigue has a negative impact on the workplace, with one study reporting 75% of patients changing their work hours to accommodate fatigue.[8–11]


Fatigue is a pervasive, underdiagnosed, and poorly understood side effect. Treatment that focuses on the cause of fatigue is most effective; however, in the vast majority of cases, the etiology of fatigue is not clear. Patients often experience anemia, metabolic disturbances, infections, paraneoplastic syndromes, cachexia, pain, stress, and mood disturbances that may contribute to fatigue, but even when these conditions are corrected, fatigue persists. Proinflammatory cytokines (interleukin-1 (IL-1) beta, IL-6, tumor necrosis factor) are often implicated in the comorbid process.[12] These cytokines act on the central nervous system, causing fatigue and "sickness behaviors" (eg, sleep disturbance, depressed mood, and decreased activity). Reduced functional capacity and physical strength may also cause or be contributing factors to fatigue. As patients become more sedentary and inactive, they become debilitated, and the effort to perform routine tasks becomes fatiguing.[13,14]


NCCN Guidelines

The National Comprehensive Cancer Network (NCCN) has proposed a comprehensive, step-by-step approach to the evaluation and management of fatigue.[15] Seven factors are identified as frequent contributors to fatigue: pain, emotional distress, sleep disturbances, anemia, nutritional deficiencies, deconditioning, and comorbidities. NCCN guidelines recommend that these factors be evaluated and treated first.[16]

Ideally, fatigue would be monitored on a routine basis when the patient is seen in the clinical setting. A clinically relevant and easy measurement of fatigue is the 0-to-10 scale for fatigue assessment. The NCCN recommends that patients with a fatigue score of 1 through 3 receive education and ongoing assessment, and that patients with higher scores begin a formal screening for pain, distress, sleep disturbances, anemia, and hypothyroidism.[15]

The MID as an Intervention Benchmark

Determining when to intervene is most important. Several studies have examined the minimally important difference (MID) in fatigue; that is, the smallest amount of change between two scores that is subjectively meaningful to the patient.[13] The MID has been evaluated for several different scales, including the 0-to-10 scale. A change of 1 point on the 0-to-10 scale was found to be meaningful to patients. This finding suggests that patients with as little as a 1-point increase in fatigue should receive some intervention (eg, education or more thorough evaluation or referral to exercise).

Comprehensive Patient Review

A strong body of research supports the relationship between fatigue and anemia,[17] pain,[18,19] distress,[20] and deconditioning.[13,14] Therefore, a careful review of systems, evaluation of disease status, and review of medications is an important initial step in evaluating and treating fatigue. Unfortunately, in many cancer patients a clear cause of fatigue cannot be identified, and the management approach becomes more generalized.

An assessment of fatigue is not complete without a medication review. Polypharmacy is common in cancer patients, and many drugs, alone and in combination, cause fatigue. Sedation is associated with some of the older antidepressants, especially tricyclic antidepressants. Selective serotonin reuptake inhibitors (SSRIs) and the atypical antidepressants cause less sedation and are a better choice for these patients. Antiemetics (eg, promethazine, prochlorperazine, trimethobenzamide) and benzodiazepines also cause sedation. Sedation may be reduced by prescribing less-sedating antiemetics (dolasetron, palonosetron [Aloxi], aprepitant [Emend], granisetron [Kytril], ondansetron) or reserving sedating medications for use on an as-needed basis.

Opioids commonly cause sedation, but patients often develop tolerance to their sedative effect. While pain relief is an important goal, it is also important to regularly evaluate pain and assess the possibility of decreasing the opioid dose. Though it is not reasonable to expect to withdraw a patient from a needed medication, a realistic approach is to assess the type of drug being used and consider the availability of alternative, less-sedating medications.

Other comorbid conditions are known to contribute to fatigue. Electrolyte disturbances, anemia, dehydration, hypothyroidism, pain, hypocortisolism, new or worsening cardiac disease, infection, and hypoxia should all be evaluated as potential causes of fatigue. Identifiable and modifiable causes of fatigue need to be ruled out or treated. Unfortunately, the cause of fatigue for many cancer patients is not easily elucidated, or well understood.


Interventions for fatigue can be categorized as pharmacologic and nonpharmacologic. Pharmacologic therapy includes erythropoietin for chemotherapy-induced anemia, antidepressants when fatigue is related to depression, and psychostimulants to give patients more energy to overcome their fatigue.


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