The 2012 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."1 Fatigue is one of the most common symptoms that cancer patients experience when receiving treatment with chemotherapy and/or radiation. Percentages of patients who experience CRF vary across studies from 25% to 100% depending on the type of treatment and the type and stage of cancer.2-5 Curt and colleagues6 telephone surveyed 379 patients who had received chemotherapy and found that 76% experienced fatigue at least a few days during the last course of chemotherapy and 30% experienced fatigue every day. Cancer-related fatigue has been experienced by patients from time of diagnosis to clinical remission and, for breast cancer survivors in particular, 5 to 10 years after diagnosis.4,7-11 As treatment for cancer advances, there are more survivors with CRF years after treatment has ended.

Fatigue also affects patients with other diseases. Solano and colleagues12 conducted a systematic search of medical databases and textbooks and, from 64 original studies, identified 11 common symptoms among patients with terminal cancer, acquired immunodeficiency syndrome, heart disease, chronic obstructive pulmonary disease, or renal disease. Pain, breathlessness, and fatigue were experienced by more than 50% of the patients across all 5 diseases, suggesting the possibility of a common pathway that patients with terminal diseases face. Thus, palliative care is appropriate for noncancer patients as well.

CLINICAL CHARACTERISTICS

The pathophysiology of CRF is not well understood even today. Since the late 1800s, basic scientists and clinicians have been attempting to explain the causes of CRF.13 Given the similar constructs of the models, Mitchell10 organized them into 4 themes: energy balance/energy analysis, fatigue as a stress response, neuroendocrine-based regulatory fatigue, and hybrid models. Energy balance/energy analysis posits an imbalance of energy intake, metabolism, and expenditure, thus facilitating the development of fatigue. Fatigue as a stress response suggests that there is a continued adaptation along a continuum that is differentiated in both behavioral and symptom characteristics. Neuroendocrine-based regulatory fatigue theorizes that the multidimensionality of fatigue is due to a dysregulation of the neuroimmunoendocrine system, which is interrelated both anatomically and functionally and includes the hypothalamic-pituitary-adrenal axis, cytokines, circadian rhythms, and neurotransmitters.10,14,15 Hybrid models include those that suggest that stressors caused by cancer and cancer treatments generate a decline in 4 particular areas (cognitive function, nutrition, muscle endurance, and quality of sleep), which impedes ability to adapt, as well as those that propose that biological, psychological, and functional variables induce CRF.10

Fatigue can be peripheral or central.16 Peripheral fatigue can be referred to as muscle fatigability caused by muscle and neuromuscular disorders. It occurs when there is a lack of neuromuscular system response after central stimulation. Central fatigue results when transmission of motor impulses has failed or there is an inability to perform voluntary activities.17 It affects not only the physical body but also cognition such that patients find it difficult to concentrate mentally.16

Contributing factors to fatigue, sometimes referred to as secondary fatigue, include age, physical symptoms, psychological symptoms, comorbidities, advanced disease, treatment side effects, and abnormal laboratory values (Table 1).1,13,18-21 With advanced cancer, the impact of each factor contributing to fatigue will vary throughout the disease trajectory.21

TABLE 1 Contributing Factors to Fatigue

EFFECTS OF FATIGUE ON QUALITY OF LIFE

Both CRF and non-CRF greatly affect the patient's quality of life (QOL) physically, mentally, emotionally, socially, and spiritually.11,22-25 Studies have shown that CRF interferes with performing activities of daily living, decreases functional status, and limits QOL especially for elderly individuals. In addition, CRF is associated with decreased survival and interferes with employment, enjoyment of life, relationships, and motivation to battle the cancer.4,26,27 Cancer-related fatigue has been linked to increased depression, anxiety, and mood disturbance and can impact the family's financial status.4 Similarly, noncancer patients experiencing fatigue describe it as feeling tired, weak, and having little energy and perceive it as one of their worst symptoms.21,28,29 For many patients, fatigue can be demoralizing as it robs them of who they used to be. They grieve the loss of their usual roles and responsibilities.28

The literature is replete with data confirming the effects of fatigue on QOL, except in the area of spirituality. A small phenomenological study conducted by Potter25 revealed that most participants described feelings of hopelessness about their situation. Six patients with advanced cancer in a palliative day care unit who, unprompted, expressed suffering from fatigue were interviewed for the study. Fatigue was discussed in relation to their cancer and dying. For these patients, fatigue was used as a measurement of where they were in the illness trajectory. Inability to control fatigue and the limitations it forced on them were constant battles for these patients. Those who placed more importance on spiritual and religious beliefs were more accepting of their fatigue. The effects on spirituality of non-CRF are much the same. Benzein and Berg24 looked at the relationship between hope, hopelessness, and fatigue in 40 patients receiving palliative care, along with 45 family members. Results showed that family members actually had less hope than the patients did, and patients found this very difficult to deal with while dying. Authors suggest that if patients experience hope as hoping for something (eg, cure), fatigue poses a bigger obstacle to hope than if the patient is living in hope (reconciliation with life and death) because hopelessness is seen as loss of control.24,30 A sense of hopelessness-feelings of no control to change a situation-is common among both populations experiencing profound fatigue.

ASSESSMENT OF CRF

Given that fatigue is a subjective experience, the patient's self-report using the 0 (no fatigue) to 10 (severe fatigue) scale is suggested by the National Comprehensive Cancer Network (NCCN).1 However, patient, professional, and system barriers exist that hinder effective fatigue assessment and management. Studies have revealed that patients do not report fatigue for several reasons, including a belief that fatigue is inevitable, untreatable, and unimportant.31 Patients fear that CRF can negatively affect medical treatment if reported, such as needing to reduce or stop treatment, or the belief that fatigue means that the disease is not responding to treatment and/or getting worse.32 Professional barriers include a lack of knowledge about the underlying causes of fatigue; lack of assessment, leading to underreporting, underdiagnosing, and undertreatment; an unwillingness to initiate discussion if unaware of available treatment; or a belief that little can be done to manage the symptom.1,32,33 Documentation of fatigue in the medical record is not common practice nor required by the Joint Commission, thus creating a systems barrier. As a result, CRF assessment and management are not viewed as priorities, and clinicians are not reminded to document its occurrence.34,35 Obtaining a referral to physical or occupational therapy can be burdensome, thus preventing some patients from being referred.36 Unfortunately, interventions are provided to patients when the fatigue is already severe and thus less likely to implement or benefit from them.36 Type of health care coverage/reimbursement for medications/treatment/therapies can also be a barrier.34,36,37

In addition to the patient's self-report, using a multidimensional approach to elicit more information will enable the clinician to better manage the fatigue. Descriptors beyond severity, such as onset, duration, interference in daily activities, exacerbating and palliative factors, and treatments tried, are helpful. In addition, there are several single-item, multi-item, and multidimensional tools that have been developed to measure fatigue, and they have been reviewed by Piper and colleagues34 (Table 2). Some of these measures include single-item tools such as the NCCN Intensity Scale,38 Fatigue Intensity Scale,36 and the Visual Analogue Scale.39,40 Multi-item tools include the Brief Fatigue Inventory41 and the Cancer-Related Fatigue Distress Scale.42-44 Multidimensional measures include the Cancer Fatigue Scale,44,45 Fatigue Assessment Questionnaire,44,46 and the Revised Piper Fatigue Scale.47-49 Single- and multi-item measures embedded in other scales include the Profile of Mood States Fatigue and Vigor subscales,50 the Symptom Distress Scale,41,51 and the Edmonton Symptom Assessment System.52,53 These tools can be used both in research and in the clinical area.

TABLE 2 Sample Fatigue Assessment Tools

MANAGEMENT OF FATIGUE

General education should be provided to the patient with regard to treatment-related fatigue from chemotherapy and radiation therapy. General strategies include conserving energy; balancing rest and activity; optimizing nutrition; preventing weight loss; and using distraction such as listening to music, reading, enjoying nature, and taking 1-hour naps if needed.1,10,54 Teaching patients to use a diary to self-monitor their fatigue lets them see when their energy levels peak and diminish. It also provides the opportunity to plan their day accordingly.55 Other fatigue management interventions can be categorized into either nonpharmacologic (Table 3) or pharmacologic approaches. Nonpharmacologic interventions for CRF include patient education, exercise, energy conservation, proper nutrition and hydration, and complementary therapies such as acupuncture, cognitive behavior, and relaxation breathing.1,10,13,18,54 The NCCN guidelines organize the nonpharmacologic interventions into 3 categories: activity enhancement (eg, exercise), physical therapies (eg, massage), and psychosocial interventions (eg, cognitive behavioral therapy).1

TABLE 3 Nonpharmacologic Interventions

Activity Enhancement

Research has shown exercise to be the most effective approach for managing CRF.18,55-59 Based on the patient's performance status and preference, there are several exercise activities that may be beneficial, such as walking, swimming, biking, resistive exercise, aerobics, or a combination of exercises. Although studies on exercise range in frequency, intensity, and duration, empirical evidence is lacking for guidelines.10 Exercise should be tailored to the patient's needs to maximize its benefits. McMillan and Newhouse59 conducted a meta-analysis to look at the effects of exercise interventions on CRF as well as to shed light on prescriptive exercise guidelines. Electronic databases, journals, and articles were systematically searched, resulting in 16 studies representing 1426 participants (exercise = 759; control = 667). Study eligibility criteria included subjects 18 years or older, diagnosis of or treatment for cancer, exercise used to treat CRF, quantitative evaluation of the intervention, and adequate statistical data. Results showed that exercise significantly reduced CRF (P < .001). The subgroup analysis on different types of exercise demonstrated that aerobic, resistance, and mixed training interventions improved CRF, with aerobic exercise having the most significant effects (P < .001). Furthermore, exercise conducted in a supervised setting showed significant reduction in CRF as compared with unsupervised settings.

Puetz and Herring60 also conducted a meta-analysis to look at the effects of exercise on CRF in patients both during and after treatment to assess how much the effect is differentiated over the time of treatment and recovery. Electronic databases were systematically searched, resulting in 70 randomized control trials (43 active treatment; 27 posttreatment). Study eligibility criteria included cancer patients in active treatment or posttreatment, randomized to an exercise or nonexercise evaluation, and CRF outcome measured before, during, and/or after exercise training. Results support other studies that exercise reduces CRF in patients both during and after treatment. The overall mean effect was similar to the effects of exercise on other cancer-related outcomes such as QOL, depression, and anxiety; individual/group therapy; and pharmacotherapy. Over time during active treatment, CRF improvement varied based on the patient's baseline fatigue scores and adherence to the exercise regimen. Those with a higher adherence to exercise experienced the most improvement, even when baseline fatigue scores were low. For posttreatment, the effects of exercise on CRF were greater when the interval between the end of treatment and starting an exercise program was longer, when the exercise program was shorter in length, and when trials used a wait-list comparison. Results revealed that CRF for posttreatment patients was a predictor of exercise adherence and was more restorative, whereas for patients in active treatment, exercise was more palliative. All exercise interventions should be tailored to the patient's need, accounting for performance and physical status, and modified over the disease trajectory.

Physical therapy consultations are warranted when patients have comorbidites (eg, heart disease and chronic obstructive pulmonary disease), recent major surgery, functional/anatomic deficits, or substantial deconditioning.1^(pMS-9) Use caution with patients who have bone metastasis, low platelets, anemia, fever/infection, or limitations due to metastasis or other illnesses.1^(pMS-9) Occupational therapists (OTs) can be invaluable in assessing and analyzing functional problems. Specific to CRF, OTs can provide practical advice concerning energy conservation and lifestyle management.61,62 Some of the most common interventions include assessing and addressing educational needs, mobility, self-care skills, home management skills, need for assistive devices, and upper extremity strength and function.61-63 As CRF affects the patient's functional capacity, OTs can facilitate adapting activities that are meaningful yet in line with patient's current capabilities. Making sure that they have the proper equipment helps to increase the patient's independence, which, in turn, empowers them to continue making their own health care decisions and preserves their dignity as they cope with CRF.61,62

Physical Therapies

Physical therapies include interventions such as acupuncture and massage therapy.1 Several studies looking at the efficacy of acupuncture for CRF have demonstrated clinical significance, but more randomized control studies are needed with larger sample sizes to demonstrate statistical significance.64-67 A recent study conducted by Johnston et al65 looked at patient education with acupuncture for relief of CRF. This was a randomized controlled feasibility study. Thirteen participants (7 control, 6 treatment) were women, were considered free of breast cancer (after treatment), and had a fatigue rating of 4 or higher on the Brief Fatigue Inventory. Part 1 of the intervention entailed educating patients to improve self-care through exercise, nutrition, and cognitive behavioral techniques (4 weekly 50-minutesessions of stress management). In the second part of the intervention, patients received 8 weekly 50-minute acupuncture sessions. Results showed positive but not statistically significant results. Mean (SD) CRF scores at baseline were 6.33 (1.39) for the treatment group and 6.00 (1.09) for the control group. After 10 weeks of treatment, scores were 2.13 (1.23) and 4.38 (2.53) for the treatment and control groups, respectively. The treatment group experienced a 2.38-point decline (66%) in CRF as compared with the control group. Although the results of this study were not statistically significant, they were clinically significant.

Several massage studies show clinical significance, but similar to acupuncture, more large-scale randomized control trials are needed for statistical significance to confirm efficacy.10,68-70 One randomized control study (N = 86) looked at the efficacy of classical massage treatment for reducing symptoms related to breast cancer and improving mood.70 Women with primary breast cancer were randomized into either the massage group or the waiting list. The intervention group received biweekly 30-minute classical massages in the back and neck area twice a week for 5 weeks. The control group did not receive additional treatment beyond usual care. Each intervention participant completed questionnaires at baseline (T1), at the end of intervention (T2), and at 11 weeks follow-up (T3). Results showed a reduction in fatigue at the end of the intervention, which was sustained over time and was statistically significant compared with the control group at week 11. If massage can be proven in larger studies to be effective for reducing CRF, it could be used as an additional intervention to medication and physical activity.10

Psychosocial Therapy

Cognitive behavioral therapy teaches patients to understand how thoughts can influence their feelings and behavior. They are taught to recognize and identify thought patterns and behaviors when they occur and to use cognitive coping skills to modify them.71 Unlike cognitive behavioral therapy, which teaches patients to modify the meaning or content of negative thoughts, mindfulness-based cognitive therapy teaches patients to use a detached perspective to avoid the escalation of negative thought patterns.72 A recent study (N = 100) looked at the effectiveness of mindfulness-based cognitive therapy in reducing CRF in cancer survivors of mixed diagnoses.72 Patients were randomized to either the intervention (n = 59) or the wait-list (n = 24) group. Fatigue severity was determined using the subscale of the Checklist Individual Strength tool. Questionnaires were completed at baseline and at the end of the 9-week intervention. The intervention group received a 6-month follow-up. The intervention group received 9 weeks of a protocolized group therapy that included 8 weekly sessions lasing 2.5 hours, one 6-hour session, and one 2.5-hour follow-up session 2 months after the ninth session, for a total of 28.5 hours. Results revealed a positive effect on CRF as the primary outcome variable. The mean fatigue score at postmeasurement was significantly lower in the intervention group (95% confidence interval, 33.2-37.9) than in the wait-list group (95% confidence interval, 40.0-47.4), controlling for pretreatment fatigue levels. Kwekkeboom and colleagues71 found similar positive results in a review of 43 studies on mind-body interventions. Along with coping skills training and imagery/hypnosis, cognitive behavioral therapy has improved the cancer-related symptoms of pain, fatigue, and sleep disturbance.

Nutritional Consultation

Although several medications have been used to reduce CRF, larger randomized control trials are needed to rigorously evaluate their effectiveness in patients with CRF.10,54 The most commonly used medications in treating CRF are psychostimulants (methylphenidate and modafinil), antidepressants (paroxetine and bupropion), and cholinesterase inhibitors (donepezil).10,54 Less commonly used medications include corticosteroids and hematopoietic growth factors.13,73 Methylphenidate has been reported to improve QOL, reduce CRF, and along with exercise, increase functional capacity.21,10,74-76 Appropriate adult dosing for this drug is 10 to 60 mg daily in 2 to 3 divided doses preferably 30 to 45 minutes before meals. Maximum dose is 60 mg/d. Dose may be limited by adverse effects. Modafinil was originally approved for the treatment of narcolepsy and is currently the drug of choice for multiple sclerosis.76 It works in the central nervous system by facilitating release of the neurotransmitters dopamine, norepinephrine, and serotonin, promoting wakefulness.21 The starting dose of this drug for adults is 200 mg daily in the morning. The maximum dose is 400 mg/d.

Antidepressants such as paroxetine and sertraline (selective serotonin reuptake inhibitor) have not shown to be effective in relieving CRF.1,10,13,76 Bupropion is a norepinephrine dopamine reuptake inhibitor that may act as a stimulant and has provided significant improvement for depression and CRF.76 The starting dose for adults is 100 mg daily for 3 days, then the dose is increased to 100 mg 3 times daily at least 6 hours apart. Maximum dose is 450 mg/d in 3 divided doses. Donepezil, a reversible acetylcholinesterase inhibitor used in treating patients with Alzheimer disease, has shown promise for CRF.76 The half-life is prolonged at 70 hours with a plasma protein binding of 96%. Starting dose is 5 mg daily at bedtime, with dose increased to 10 mg daily after 4 to 6 weeks. Maximum dose is 23 mg daily after 3 months. Corticosteroids have been used to treat CRF and increase energy levels on a short-term basis.1,21,76 The NCCN1 also recommends using corticosteroids for patients at the end of life but only after ruling out other causes of CRF. Another medication that has been used for CRF is hematopoietic growth factors. However, due to the higher mortality rates and propensity for thromboembolic events, they are not frequently used and have been pulled from drug trials due to safety concerns.13 Other medications have been used to treat CRF without consistent efficacy, but the NCCN has now included the consideration of psychostimulants for CRF after other causes have been ruled out.1

CASE PRESENTATION

The health care providers were aggressive in assessing David's many symptoms because in this case, treating fatigue was complicated. The underlying etiologies and contributing factors to his fatigue, such as pain, nausea, and anemia, were treated. These factors have an even greater impact on fatigue toward the end of life.1 In addition to the Marinol, David was seen by the nutritionist regarding his lack of appetite and was educated on foods that would be of most benefit. He was asked to rate his fatigue on the 0-to-10 scale at every visit. Although David's fatigue levels never decreased to the point that he would have liked, it did improve from a 15 of 10 to a 4 of 10, allowing him to enjoy a somewhat better QOL for a short while. Maintaining effective pain control was key in alleviating one aspect of his fatigue. David was educated on the necessity to include some kind of exercise every day to the ability that he could and was encouraged to participate in as many family activities as possible. During this time, different family members would take him for rides to the beach, where he would take very short walks in the sand. Not only did David greatly enjoy these trips but they also provided positive memories for the family. David's lung cancer eventually progressed to the point where hospice was initiated. The entire health care team was vital to David's care. He presented with widely metastatic lung cancer and lived 4 months after diagnosis.

IMPLICATIONS FOR NURSING PRACTICE

Fatigue is one of the most common symptoms experienced by patients with cancer treated with chemotherapy and/or radiation. In fact, it is the most common symptom experienced by breast and lung cancer patients who are alive for more than 5 years.4,7-11,77 It is multidimensional and multicausal; therefore, clinicians need to assess and readjust the management of fatigue along the patient's cancer experience. Assessment needs to go beyond the 0-to-10 scale to include how fatigue is interfering with the patient's QOL and functional capacity. Patient and family education in the areas of pain control, proper nutrition and hydration, exercise, and energy conservation is crucial to empowering the patient with a sense of control over fatigue.

In addition to the many physical and functional issues related to CRF, it is vital for the health care team to remember that the patient is still a whole person. As shared in the case study, David's QOL was affected psychosocially and spiritually as well as physically. As the cancer progresses and symptoms increase, it is sometimes difficult to not fall prey to the "tyranny of the urgent," thereby objectifying the patient's experience to things that can be measured and fixed. Studies by Krishnasamy1,78 reported that fatigue produced significant regret, a sense of loss at gradually giving up things that are enjoyed, and sadness. It is important that patients feel heard and acknowledged when they share their feelings. Validating feelings is not a new intervention but can be easily overlooked when dealing with time constraints and multiple issues. Mystakidou and colleagues1,79 found that fatigue, pain, lack of appetite, and feeling sad were predictors for patient's desire for a hastened death. Cancer-related fatigue continues to present many challenges to helping patients maintain or improve their QOL.

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