CANCER-RELATED FATIGUE

Cancer-related fatigue (CRF) is 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. Fatigue is the most common side effect of cancer treatment with chemotherapy, radiation therapy, bone marrow transplantation, or selected biologic response modifiers. Clinically significant levels of fatigue may also negatively impact survival. The specific mechanisms underlying a common pathophysiology for CRF are unknown.

Cancer treatment–related fatigue is a commonly reported symptom, with 80% of patients reporting fatigue while receiving chemotherapy or radiation therapy.[4] The condition generally improves after therapy is completed, but some level of fatigue may persist for months or years after treatment. For a subset of patients, fatigue may be a significant issue long into survivorship.[5,6] For example, a longitudinal study assessed fatigue in individuals with stage I to stage III breast cancer over three time points postdiagnosis (1 year, n = 5,640; 2 years, n = 5,000; 4 years, n = 3,400). The study found that over 30% of patients at each time point experienced severe global fatigue. Physical fatigue (35%) occurred more often than emotional fatigue (25%) or cognitive fatigue (13%). Fatigue is also seen as a presenting symptom in cancers that cause complications such as anemia, endocrine dysfunction, neuromuscular complications, psychological distress, and end-organ dysfunction (e.g., renal, pulmonary, or cardiac dysfunction). Fatigue is common in people with advanced cancer who are not undergoing active cancer treatment. Cancer treatment–related fatigue has been reported in 39% to more than 90% of patients undergoing cancer treatment and in 19% to 82% of patients posttreatment.

Fatigue experienced as a side effect of cancer treatment is differentiated from fatigue experienced by healthy people in their daily lives. Healthy fatigue is frequently described as acute fatigue that is eventually relieved by sleep and rest; cancer treatment–related fatigue is categorized as chronic fatigue because it is present over a long period of time, interferes with functioning, and is not completely relieved by sleep and rest. Also, the level of CRF is often disproportionate to the level of activity or energy exerted. Although the label chronic fatigue is accurate, it does not mean that people with cancer who experience fatigue have chronic fatigue syndrome. Using this phrase can be confusing to both patients and health professionals. Terms such as cancer fatigue, cancer-related fatigue, and cancer treatment–related fatigue have all been used in the clinical literature, research literature, and educational materials for patients and the public.

Fatigue, like pain, is a self-perceived state and patient-reported outcome. Patients may describe fatigue as feeling:

Tired.
Weak.
Exhausted.
Lazy.
Weary.
Worn-out.
Heavy.
Slow.
Like they have no energy or get-up-and-go.

Health professionals have included fatigue within concepts such as:

Asthenia.
Lassitude.
Malaise.
Prostration.
Exercise intolerance.
Lack of energy.
Weakness.

Studies of women with breast cancer have attempted to define specific fatigue trajectories. For example, some patients experience a high degree of fatigue during treatment and recovery, while others deteriorate over time. In contrast, some patients suffer from little fatigue throughout treatment. Suggested fatigue trajectories include the following:[8,17]

Very low fatigue.
Low fatigue.
Late or deteriorating fatigue (initially low symptoms that increase over time).
Recovery (initially high symptoms that decrease over time).
High fatigue.

Research on fatigue in people with cancer has included primarily self-reports of fatigue, with increasing data exploring biological or physiological correlates. Such correlates have included measures of muscle weakness, maximal oxygen uptake, cytokines, cortisol, and genetic biomarkers.

Fatigue has a negative impact on all areas of function, including the following:

Mood.
Physical function.
Work performance.
Social interaction.
Family care.
Cognitive performance.
School work.
Community activities.
Sense of self.
Activities of daily living in older cancer survivors.

The pattern of fatigue associated with cancer treatment varies according to the type and schedule of treatment. For example, people treated with cyclic chemotherapy regimens generally exhibit peak fatigue in the days following treatment, then lower levels of fatigue until the next treatment. However, patients undergoing external-beam radiation therapy report gradually increasing fatigue over the course of therapy of the largest treatment field. Few studies of people undergoing cancer treatment have addressed the issue of fatigue as a result of the emotional distress associated with undergoing a diagnostic evaluation for cancer and the effects of medical and surgical procedures used for evaluation and for initial treatment. Because most adults enter the cancer care system following at least one surgical procedure, and because surgery and emotional distress are both associated with fatigue, it is likely that most people beginning nonsurgical treatment are experiencing fatigue at the beginning of treatment.

Fatigue management focuses on identifying and treating the underlying factors that may be contributing to fatigue. Most clinical recommendations for managing the symptoms of fatigue caused by something other than chemotherapy-induced anemia rely on careful development of clinical hypotheses, as outlined in the National Comprehensive Cancer Network (NCCN) guidelines on fatigue.

NCCN category 1 interventions for CRF include the following:

Physical activities (e.g., yoga).
Massage therapy.
Psychosocial interventions (e.g., cognitive behavioral therapy/behavioral therapy, supportive expressive therapies, and psychoeducational therapies).

For more information, see the Interventions section.

Although much progress has been made, further research is needed to better define fatigue and its trajectory, understand its physiology, and determine the best ways to prevent and treat it.

In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.

Assessment

The first step in the assessment of fatigue is screening. Patients can be screened for fatigue at the initial visit, at the beginning and end of primary cancer treatments, and at least annually (or as clinically indicated) during follow-up care. Evidence indicates that brief, self-report, quantitative, and single-item assessments with empirically established cut-off scores can measure fatigue levels in an expedited manner. These tools include assessments such as the National Comprehensive Cancer Network (NCCN) intensity tool [2] and the visual analog scale (VAS),[3] which are 0-to-10 numeric rating scales (0 = no fatigue; 10 = worst fatigue imaginable). Ratings are categorized as none to mild (score, 0–3), moderate (score, 4–6), and severe (score, 7–10). Fatigue is considered clinically significant when rated in the moderate-to-severe range (score, 4–10).

Patients with moderate-to-severe levels of fatigue require further evaluation. One study of ambulatory outpatients with solid tumors (n = 148) evaluated the usefulness of single-item screening for symptoms such as fatigue and pain.[5] Investigators found that the single-item assessment can help identify patients who require comprehensive assessments of their symptoms. Patients identified through single-item screening tools undergo comprehensive assessments to detect clinically relevant symptomatology.

Cancer-related fatigue (CRF) is multifactorial. The purpose of an in-depth evaluation is to assess diverse factors that can cause or contribute to fatigue. Such an evaluation may identify factors that can be reversed or treated (e.g., hypothyroidism, sleep disturbances, or depression). In addition, fatigue can be part of a symptom cluster.

A comprehensive assessment of a fatigued patient starts with carefully obtaining a history to fully characterize the patient’s fatigue pattern and to identify all factors that contribute to its development. An in-depth evaluation of fatigue includes the following:

Status of cancer and cancer treatments: recurrence or progression of disease, type and length of cancer treatments, and capacity of treatments to induce fatigue.
Review of systems to assess impact of cancer and cancer treatments on other organs and systems.
Comprehensive physical examination, including gait, posture, and range of motion.
Assessment of causative or contributing factors:
- Anemia.
- Hypothyroidism.
- Fluid/electrolyte imbalance.
- Weight/caloric intake.
- Sleep disturbances (e.g., insomnia, hypersomnia, sleep apnea, and restless legs syndrome).
- Emotional disturbances (depression or anxiety), including psychiatric history and adversity during childhood.
- Pain.
- Other treatment-related side effects (e.g., neuropathy or hot flashes).
- Review of medication effects and effects caused by drug interactions (e.g., exacerbation of fatigue due to sedation or insomnia, worsening of depression, and cardiovascular effects).
- Assessment of other comorbidities (e.g., alcohol and drug misuse and illicit substance use, cardiovascular or pulmonary diseases, endocrine dysfunction, neurological disorders, renal or hepatic dysfunction, infections, and gastrointestinal dysfunction).
- Assessment of social, economic, and spiritual factors that can directly or indirectly exacerbate fatigue levels (by worsening emotional distress).
- Assessment of functional status: physical activity levels and deconditioning.

An in-depth fatigue evaluation also includes an assessment of specific aspects of fatigue based on patient self-report:

Onset.
Duration.
Pattern.
Change in intensity and frequency over time.
Exacerbating or alleviating factors.
Associated patient distress.
Interference with functioning.

Although there is no universally accepted standard for the measurement of fatigue, a variety of instruments can assess fatigue and related sequelae. These instruments range from single-item instruments screening tools to multi-item, multidimensional instruments used to conduct in-depth evaluations of fatigue. These instruments can be generally divided into three major categories:

Very brief, single-item instruments that can be used for fatigue screening and longitudinal monitoring of fatigue (e.g., the VAS).
Brief, multi-item but unidimensional instruments (e.g., the Brief Fatigue Inventory [BFI]).
Comprehensive, multi-item, and multidimensional instruments (e.g., the Multidimensional Fatigue Inventory).

Exercise

Studies suggest that exercise or physical activity has a beneficial effect on fatigue in patients during and after cancer treatment. The National Comprehensive Cancer Network (NCCN) guidelines identify physical activity as an intervention for patients during and after treatment (category 1 intervention). Researchers have noted reductions in fatigue of about 35% and improvements in vitality of 30% in randomized trials. Other documented benefits of exercise or physical activity include the following:

Improved physical energy.
Appetite stimulation.
Improved memory.
Enhanced functional capacity.
Enhanced psychosocial well-being (improved outlook, sense of well-being, and quality of life).

Initial trials of exercise programs focused on women with breast cancer, but subsequent studies included men with prostate cancer and patients with multiple myeloma, lung cancer, nasopharyngeal cancer, non-Hodgkin lymphoma, colorectal cancer, and advanced cancers.

CBT

CBT has long been used to treat a variety of psycho-physiological problems, with therapy focusing on the thoughts (cognition) and functional behaviors relevant to the presenting problems. While most of the CBT research for CRF has focused on the survivor period, CBT and CBT variants (e.g., CBT-I and mindfulness-based cognitive therapy) have been shown to be useful during both active treatment and the survivor period.

In the context of active treatment (e.g., chemotherapy, radiation therapy, surgery), CBT plus hypnosis may be effective for patients struggling with CRF. Significant decreases in fatigue were reported over a 6-week course of psychotherapy during radiation therapy, compared with a control group. At a 6-month follow-up, the CBT group continued to experience significantly improved fatigue, compared with the control group.

In a randomized clinical trial, 98 mixed-type cancer survivors (intervention group = 50, wait-list control = 48) experiencing severe fatigue not attributable to a specific somatic cause were provided individual CBT. The CBT focused on each participant's unique pattern of the following six possible factors that might perpetuate their post–cancer treatment fatigue:

Insufficient coping with the experience of cancer.
Fear of disease recurrence.
Dysfunctional cognition regarding fatigue.
Dysregulation of sleep.
Dysregulation of activity.
Low social support/negative social interactions.

Patient Education

Informing patients about the risk of fatigue and educating them about strategies to reduce fatigue are valuable adjuncts to other management strategies. However, a Cochrane review of educational interventions for CRF in adults cautions that educational interventions should be part of a more-comprehensive approach to managing fatigue.

Specific techniques for the management of fatigue include the following:

Differentiation of fatigue from depression.
Assessment for presence of correctable correlates or causes of fatigue (e.g., dehydration, electrolyte imbalance, dyspnea, anemia).
Evaluation of patterns of rest and activity during the day as well as over time.
Determination of the level of attention fatigue and encouragement of attention-restoring activities (e.g., walking, gardening, bird watching).
Providing anticipatory guidance regarding the likelihood of experiencing fatigue and the fatigue patterns associated with particular treatments.
Encouragement of activity/planned exercise programs within individual limitations; making goals realistic by keeping in mind the state of disease and treatment regimens.
Education of individuals and families about fatigue related to cancer and its treatment.
Helping people with cancer and their families identify fatigue-promoting activities and develop specific strategies to modify these activities.
Suggesting individualized environmental or activity changes that may offset fatigue.
Maintaining adequate hydration and nutrition.
Recommending physical therapy referral for people with specific neuromusculoskeletal deficits.
Recommending respiratory therapy referral for people with dyspnea that is a contributing factor to fatigue.
Scheduling important daily activities during times of least fatigue and eliminating nonessential, stress-producing activities.
Addressing the negative impact of psychological and social stressors and how to avoid or reduce them.
Evaluating the efficacy of fatigue interventions on a regular and systematic basis.

Psychostimulants

Psychostimulants are a common pharmacological intervention for cancer-related fatigue (CRF); however, the evidence for their efficacy is mixed. Psychostimulants are drugs that interact with neurotransmitters and receptors in the brain to increase cortical function. Different types of psychostimulants work through various mechanisms to produce activity in the brain consistent with short-term improvement in energy level and psychomotor activity. These medications may also improve mood, attention, and concentration in some populations.

Methylphenidate.
Dextroamphetamine.
Modafinil.
Armodafinil.

Psychostimulants are not approved by the U.S. Food and Drug Administration (FDA) for the treatment of CRF. However, preliminary evidence from randomized controlled studies suggests that these medications might be helpful in a subpopulation of patients experiencing moderate to severe fatigue. Of the psychostimulants, methylphenidate is the most studied pharmacological agent for fatigue, yet the evidence for its efficacy is mixed.

Methylphenidate

Among all pharmacological treatment options for CRF, methylphenidate has the best evidence based on studies to date. The evidence for methylphenidate remains mixed, but it may play an important role in a subpopulation of cancer survivors.

One of the studies that demonstrated significant improvements over placebo for CRF used a mean dose of 27.7 mg of the D-isomer of methylphenidate as a study intervention.[8] The population that benefited was women who had completed chemotherapy for breast or ovarian cancer. The study design incorporated a titration to effect, so some patients who may have benefited may have received more than 27.7 mg of the drug. Furthermore, 11% of trial participants withdrew because of adverse events, compared with 1% in the placebo arm.

Conversely, an equally large randomized controlled trial assigned patients with early and advanced disease, who were either receiving treatment or not receiving treatment, to receive 54 mg of a long-acting methylphenidate preparation equaling 27 mg of the D-isomer or a placebo. This trial found no differences between the two groups in any of the fatigue outcomes. There were significant differences between groups for nervousness and appetite loss, with the methylphenidate arm scoring worse on both of those side effects.

Another large randomized placebo-controlled trial (n = 163) in patients with advanced cancer investigated immediate-release methylphenidate, starting at 5 mg twice daily.[The dose was titrated up to 20 mg three times daily over a 6-week period. Improvement in fatigue and depression was nominally higher in the methylphenidate group than in the placebo group, but the differences did not reach clinically meaningful levels. There were no differences in adverse events between the two groups, including side effects such as anxiety, insomnia, loss of appetite, or heart palpitations.

Methylphenidate continues to show mixed results as a treatment for fatigue in patients with cancer. Several factors may cause this situation, including high placebo response, differential formulation and dosing, and heterogeneity of patient-related factors (e.g., early stage versus advanced stage of cancer, heterogeneity of cancer, cancer treatments, co-morbidities, and concomitant medications). Based on the mixed trial results to date, methylphenidate may treat fatigue in specific subpopulations of cancer survivors. Immediate-release formulations with a shorter half-life appear to have a better safety and tolerability profile, with a lower risk of side effects, compared with longer-acting formulations.

Modafinil and armodafinil

The newer so-called wake-promoting agents, modafinil and armodafinil, are just beginning to be studied for CRF. Modafinil is a centrally acting, nonamphetamine central nervous system stimulant. Armodafinil is the R-enantiomer of modafinil and an alpha-1 adrenoceptor agonist. The FDA has approved modafinil and armodafinil for the treatment of narcolepsy, obstructive sleep apnea, and shift-work disorders but not for the treatment of CRF. These agents are also not indicated for use in children and adolescents.

The mechanism of action of modafinil and armodafinil is different from that of amphetamines, but the exact mechanisms by which these agents improve wakefulness are not known. On the basis of two promising open-label pilot trials, a large randomized controlled trial evaluated modafinil for the treatment of CRF using 200 mg versus placebo in more than 850 patients who were receiving chemotherapy. Patients had to have fatigue ratings of at least 2 out of 10 to be eligible for this study. During four cycles of chemotherapy, there were no significant differences between arms.

A randomized placebo-controlled trial (four-arm factorial study) comparing cognitive behavioral therapy (CBT) for insomnia (CBT-I) versus armodafinil (50 mg by mouth twice a day) found that CBT-I with and without armodafinil resulted in a clinically and statistically significant reduction of subjective daytime fatigue in cancer survivors with chronic insomnia.Armodafinil alone did not show a statistically significant effect on fatigue for cancer survivors.

For both methylphenidate and modafinil, exploratory data have suggested that patients with more severe fatigue or more advanced disease may benefit from these drugs. A small (N = 23), randomized, placebo-controlled study using methylphenidate (titrated up to 30 mg/d) as an intervention failed to show statistical difference on the primary outcome measure, the Brief Fatigue Inventory (BFI) total score, or activity interference subscale. However, the methylphenidate group showed significant reductions in the BFI severity subscale scores compared with the reductions seen in the placebo group. The mean severity score at baseline was 6.5 for the methylphenidate group and 5.7 for the placebo group, placing these patients in a more severe fatigue category. A secondary analysis of the phase III trial that evaluated modafinil versus placebo for CRF also revealed that patients with more severe fatigue may have benefited from modafinil. More research is needed to further evaluate whether psychostimulants are beneficial for patients experiencing more severe CRF.