Understanding and Treating Cancer-Related Fatigue

October 1, 2007

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.

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]

Pathophysiology

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]

Evaluation

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.

Treatment

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.

Pharmacologic Interventions

The benefit of erythropoietic agents in ameliorating fatigue in cancer patients with chemotherapy-induced anemia is under debate. Trials that have assessed fatigue as a secondary endpoint noted improvements in fatigue across different types of cancer, types of treatment, and measurement scales.[21–24] These studies concluded that patients who responded to erythropoietic agents reported increased energy and activity levels, and improved overall quality of life.[22–24] In earlier investigations, researchers reported that recombinant erythropoietin at dosages of 150 U/kg three times a week, 10,000 U/kg three times a week, or 40,000 U/kg weekly and darbepoetin alfa at dosages of 500 mg every 3 weeks appeared to effectively increase hemoglobin and improve quality of life in patients with chemotherapy-induced anemia.[21–25] However, correcting anemia frequently does not ameliorate fatigue, and many fatigued cancer patients are not anemic.[26]

Notably, in March 2007, the US Food and Drug Administration issued a product labeling alert to provide new safety information for erythropoietin-stimulating agents (ESAs), based on analysis of four new studies of their use in patients with cancer. Also, based on the newer study data, the FDA recommended that, "Physicians who prescribe ESAs should ... understand that in patients with cancer whose anemia is caused by chemotherapy ... there are no data to support claims of improvement in health-related quality of life, including effects on fatigue, energy, or strength. (See http://www.fda.gov.cder/drug/advisory/RHE2007.htm)

Fatigue is common in depression, and one might assume that antidepressant therapy may be a logical approach to managing cancer-related fatigue. Paroxetine (Paxil) was used in one study and demonstrated no effect on fatigue.[27] Because many antidepressants cause sedation and have a delayed onset of action, they do not appear to play a role in the management of fatigue, and their use should be limited to patients diagnosed with depression.

Limited research has examined the effects of psychostimulants on fatigue. Methylphenidate appears to improve fatigue and concentration and to reduce sedation.[28,29] Doses of methylphenidate used in these studies ranged from 5 mg to 10 mg quick-release formula administered at 8 am and 12 pm, and 20 mg extended release administered at 8 am. Early trials with dextromethylphenidate, the racemic form of methylphenidate, have demonstrated safety and efficacy, as well as decreased fatigue and improved memory.[30] These studies are intriguing; trials with larger sample sizes and more diverse populations are needed to determine the efficacy of these drugs on fatigue.

Complementary alternative therapies with herbal supplements have been systematically studied, to a limited degree. Lectin-standardized mistletoe extract, levocarnitine supplements, and ginkgo biloba have demonstrated positive effects on cancer-related fatigue.[31–33] Although current data are insufficient to warrant recommendation of these agents, additional studies are being conducted to further understand the effects of these products.

Nonpharmacologic Interventions

Nonpharmacologic approaches to cancer-related fatigue have been tested more extensively than most of the pharmacologic approaches and many have demonstrated efficacy. Strong evidence from clinical trials supports exercise, and the NCCN recommends exercise as an intervention to reduce fatigue.[13,14,29,33–37] Both aerobic and resistance exercise have consistently demonstrated a powerful effect on reducing fatigue, with declines in fatigue levels of 40% to 50% among exercising subjects. Exercise is beneficial both during and following cancer treatment, and exerts its effect by improving aerobic capacity and muscle strength so that patients are able to pursue activities they find meaningful and important. The effects of exercise not only improve fatigue, but also improve quality of life.[38,39] Exercise for patients with advanced cancer also appears to reduce fatigue.[40] Exercise prescriptions in these studies ranged from low to moderate intensity, 10 to 30 minutes in duration, and from 3 days a week to every day. While some of these studies examined fatigue at different points in treatment or survivorship, it is clear that early intervention, before fatigue becomes too debilitating, is important to maintaining functional ability and quality of life.

Compelling evidence suggests psychosocial interventions that include education, energy conservation, stress management, and individual counseling and support groups improve energy and reduce fatigue. Energy conservation teaches patients to limit their energy by doing such things as delegating responsibilities so they are able to perform more valued activities.[41,42]

Knowledge is a powerful tool. Knowing that fatigue is a common side effect of cancer and its treatment can help patients feel less worried and less afraid of the significance of their fatigue. Educating patients about sleep hygiene, maintaining a normal sleep/wake cycle at night, and refraining from caffeine and stimulating activities several hours before bed can help to normalize sleep. Individual counseling and support groups can be helpful to reassure patients know that they are not alone in their experience, and to teach coping, stress management, and distraction techniques.[43–45]

Nursing Interventions

Fatigue is a side effect of cancer and its treatment that offers nurses an important opportunity to suggest an exercise routine for fatigued patients, to refer them to an exercise rehabilitation program, to educate them about fatigue and strategies that can address it (eg, sleep hygiene, energy conservation, stress management), and to recommend support groups for further education and counseling.

Implications for Nursing Practice

Nurses are at the forefront of patient care and should become advocates for patients. Nurses are positioned to identify patients who are struggling with fatigue early in the cancer-treatment process, before the fatigue becomes severe. Administering a simple 0-to-10 scale and recording changes over time will quickly alert a nurse to fatigue changes that need intervention. Regular review of the patient's record for physiologic causes of fatigue and time spent educating patients about the nonpharmacologic interventions for fatigue management (eg, exercise, education, etc) will improve patient care, reduce fatigue, and perhaps improve a patient's clinical outcome.

Summary

Fatigue is, without a doubt, one of the most debated, discussed, and researched topics in oncology in recent years. Despite efforts to determine the cause(s) and optimal treatment(s), we are still left with many questions. In appropriate patients, exercise intervention is strongly encouraged. The NCCN practice guidelines are a useful tool to assess and manage cancer-related fatigue. Nurses should strive to take a leadership role in addressing cancer-related fatigue in their patients.

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