Cancer-Related Fatigue: Effective Interventions Still Elusive

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Fatigue is the most common symptom associated with cancer and its treatment, affecting a substantial proportion of patients during and years after chemotherapy.1,2 As many as 80% of patients undergoing chemotherapy or radiation report fatigue as a side effect of treatment.3

Cancer-related fatigue (CRF) is perceived by patients as one of the most distressing symptoms associated with cancer and its treatment—it is even more distressing than nausea and vomiting.2

There is no timeline for CRF. It can occur at any time, including before diagnosis or long after treatment completion.4 By strict ICD-10 (International Statistical Classification of Diseases and Related Health Problems) criteria, CRF of at least 2 weeks' duration within the course of one month has been reported by 50% of those completing chemotherapy within the past year and 33% of those who completed treatment 5 or more years earlier.1  

In more severe cases, patients may be unable to return to work or may withdraw from daily life or connections with family and friends.4 As cancer survival times have increased, persistent CRF represents a clinical challenge and a barrier to survivors' full participation in their lives.

In order to relieve CRF, it must first be identified. Yet screening for and treatment of CRF is less than optimal, because patients either fail to volunteer information or clinicians fail to recognize or ask about it. Patients may believe CRF is inevitable or untreatable and clinicians may be unaware of its prevalence and/or available interventions.2,5

Everyone—especially patients undergoing cancer treatment—feels tired from time to time. CRF differs from normal fatigue in that it is both out of proportion to the individual's level of exertion or hours of sleep and a cause of substantial distress or functional impairment.1,2,4 CRF is more distressing and severe—and less likely to be relieved by rest—compared with fatigue in individuals without cancer.2

Furthermore, it is a subjective condition, and clinicians must rely on the patient's perception in evaluating CRF.2 How patients experience, describe, and are affected by CRF is very specific to the individual, complicating efforts to devise consistent diagnostic criteria or treatment approaches. As in pain evaluation, the patient is the primary source of information regarding their condition; however, family members or friends may provide additional information or context.2

Causes and Risk Factors for CRF

While no clear etiology for CRF has been established, several have been proposed.2 It clearly is multifactorial, reliant on multiple stressors or pathologies. Among the pathophysiologic factors that have been proposed are dysregulation of inflammatory cytokines, genetic polymorphisms for regulatory proteins, and disturbances in hypothalamic regulation, central nervous system serotonin pathways, or circadian melatonin secretion. CRF may develop from actions of the tumor itself, secondary to treatment, or from individual patient factors. Most likely, CRF represents some combination of a number of these factors, all of which warrant further research.4

Risk factors for developing CRF include pain, nausea, and pre-existing depression or other emotional disorders. Patients who experience severe CRF during their first course of treatment are at high risk for persistent or recurrent CRF afterward.4 The National Comprehensive Cancer Network recommends that all patients receiving treatment for cancer be screened for fatigue during and after treatment in follow-up, using a simple 10-point scale (Figure 1). Severe fatigue is associated with marked reductions in physical functioning.2  Therefore, when fatigue is reported, patients should be asked about the onset of symptoms in order to help identify triggers.4


The occurrence and severity of CRF during cancer treatment can be influenced by multiple factors, including direct effects of treatment, sleep quality, lack of physical activity, emotional distress, pain, other medications, or even recurrence of disease. CRF rarely occurs alone; it usually is found within a symptom complex that includes some or all of these factors and should be assessed within the context of coexisting symptoms. If feasible, modifiable factors such as pain, sleep disturbances, anemia, or nutrition should be addressed. About a third of patients with severe CRF have major depressive disorders, and all patients should be assessed for depression and receive treatment if necessary.2,4

CRF that develops or persists after treatment completion may be related to persistent overactivation of the immune system, which includes elevated levels of interleukin-2 receptor antagonist and elevated levels of T lymphocytes. This suggests a role for chronic inflammation, although in reality it is likely multifactorial, involving precancer fatigue or anxiety, patient coping abilities, development of CRF during treatment, and other individual environmental or physical stressors.2 

Developing Treatments for Patients with CRF

Progress in relieving CRF has not advanced to the degree that relief of pain and nausea or vomiting has, but treatment approaches are available that offer some benefit to patients with moderate-to-severe CRF. Treatment goals include relieving factors that worsen CRF, helping patients to cope with stressors, and activating their strength and inner resources.2

Most patients derive some degree of benefit from nonpharmacologic approaches alone or in combination, especially exercise, hypnosis, relaxation techniques, psychosocial education about fatigue, and cognitive behavioral therapy (CBT).4,5 Energy-conservation education designed to help patients with priority setting, pacing, and structuring routines is valuable. Moderate exercise to improve functional capacity and increase activity tolerance ideally should be performed several times a week.4 Nutrition counseling to address eating deficiencies or disturbances ,and sleep counseling to address sleep disturbances are also recommended.

There are a limited number of pharmacologic treatments of proven benefit for CRF. Medications to address comorbid conditions, such as pain or depression, should be used. However, antidepressants are ineffective for CRF unless it is associated with depression; for this reason, it is not recommended for those without a depression diagnosis. Recombinant erythopoietins to treat anemia have a positive effect on CRF during cancer treatment within current guidelines for their use.2,5

Both during and after cancer treatment, medications directed at CRF itself offer limited relief. The psychostimulants modafinil and methylphenidate have been studied and have demonstrated some benefit in reducing fatigue versus placebo.2 A meta-analysis of trials with methylphenidate found a small absolute benefit (–0.28, P=0.005) in relieving CRF, with no difference in adverse events between active treatment and placebo groups.6

A review of randomized and open-label trials with modafinil found small but significant reductions in CRF with use for patients undergoing cancer treatment.7 In a phase 3 study of modafinil with 631 patients receiving chemotherapy, a small reduction in CRF as measured by item 3 of the Brief Fatigue Inventory (BFI) was reported. However, benefit was limited to patients with the most severe CRF at baseline (BFI-3 ≥7), who saw significant reductions in CRF (Figure 2).8


Corticosteroids have also demonstrated benefit for CRF patients. A study published in July 2013 evaluated treatment with dexamethasone for moderate-to-severe CRF in patients with advanced cancer, and found a benefit at 15 days of treatment versus placebo on the Functional Assessment of Chronic Illness—Fatigue subscale (P=0.008).9 However, corticosteroid use is contraindicated for long-term therapy, limiting the potential of this finding for patients with expected long-term survival.2

RELATED: Dexamethasone Better Than Placebo for Cancer-Related Fatigue

Summary

CRF is a common and distressing side effect of cancer and its treatment. It can affect patients during and often years after treatment. In severe cases, it can lead patients to withdraw from work, family, and friends. The etiology of CRF is a subject of widespread interest, and may be related to immune system dysregulation secondary to treatment or the cancer itself.

Persistent inflammation has been implicated as well. At present, therapy is directed toward helping patients manage their energy, coping skills, and physical activity. A truly effective pharmacologic treatment remains elusive, although psychostimulants provide moderate benefits. Overall, more research is needed to identify the causes and improve treatment options available for CRF so that patients who survive cancer can derive the most out of life.



References

1. Cella D, Davis K, Breitbart W, Curt G for the Fatigue Coalition. Cancer-related fatigue: prevalence of proposed diagnostic criteria in a United States sample. J Clin Oncol. 2001;19(14):3385-3391.

2. National Comprehensive Cancer Center. NCCN Clinical Practice Guidelines. Cancer-related fatigue. Version 1.2013. Available from: www.nccn.org. Accessed September 10, 2013.

3. Henry DH, Viswanathan HN, Elkin EP,  et al. Symptoms and treatment burden associated with cancer treatment: results from a cross-sectional national survey in the United States. Support Care Cancer.  2008;16(7):791-801.

4. Horneber M, Fischer I, Dimeo F, et al. Cancer-related fatigue. Epidemiology, pathogenesis, diagnosis, and treatment. Dtsch Arztebl Int. 2012;109(9):161-172.

5. Campos MPO, Hassan BJ, Riechelmann R, Del Giglio A. Cancer-related fatigue: a practical review. Ann Oncol. 2011;22(6):1273-1279.

6. Minton O, Richardson A, Sharpe M, et al. Psychostimulants for the management of cancer-related fatigue: a systematic review and meta-analysis. J Pain Symptom Manage. 2011;41(4):761-767.

7. Cooper MR, Bird HM, Steinberg M. Efficacy and safety of modafinil in the treatment of cancer-related fatigue. Ann Pharmacother. 2009;43:721-725.

8. Jean-Pierre P, Morrow GR, Roscoe JA, et al. A phase 3 randomized, placebo-controlled, double-blind, clinical trial of the effect of modafinil on cancer-related fatigue among 631 patients receiving chemotherapy.  Cancer. 2010;116:3513-3520.

9. Vennurajalingam S, Frisbee-Hume S, Palmer JL, et al. Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-controlled trial in patients with advanced cancer. J Clin Oncol. 2013;31(25):3076-3082.

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