Much of the information regarding interventions for fatigue relates either to healthy subjects or to persons in whom muscle fatigue is the primary etiology of the problem or fatigue is secondary to treatment-related anemia.[1,2][Level of evidence: II];[3,4] Without a determination of the causative mechanisms of fatigue in oncology patients, interventions must be directed to symptom management and emotional support. Although some recommendations for the management of fatigue in oncology patients have been made, these are theoretical or anecdotal in nature and in general have not been the focus of scientific evaluation.
Since the etiology and mechanisms regarding fatigue/asthenia in cancer patients are indeterminate, there is considerable variation in practice patterns regarding the management of this symptom. The focus of medical management is often directed at identifying specific and potentially reversible correlated symptoms, as in the following examples:
- Patients with fatigue and pain may have titration of pain medications.
- Patients with fatigue and anemia may receive a transfusion of packed red blood cells, nutritional interventions including iron-rich foods, supplemental iron or vitamins to correct an underlying deficiency, or injections of epoetin alfa.
- Patients with depressed mood and fatigue may be treated with antidepressants or psychostimulants.
It is often helpful to consider discontinuation of drugs that may be safely withheld. There is no agreed-upon approach for the evaluation and treatment of fatigue, but an increasing number of clinical trials are designed to address this issue in cancer patients.Psychostimulants
One of the most popular categories of pharmacologic interventions evaluated for cancer-related fatigue (CRF) is psychostimulants (see Table 2). 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. Psychostimulants on the market include the following:
- Nonprescription caffeine.
Initial support for the hypothesis that psychostimulants may improve CRF arises largely from clinical anecdotal experiences. These medications are not approved by the U.S. Food and Drug Administration (FDA) for the treatment of CRF. However, preliminary evidence from randomized controlled studies [5-7] suggests that these medications might be helpful in a subpopulation of patients experiencing more severe fatigue. There are at least seven published randomized clinical trials evaluating psychostimulants for CRF: six with methylphenidate and one with modafinil. Only one of these randomized trials  has shown significant differences between the placebo group and methylphenidate group with respect to the outcome of fatigue.
The one study 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. 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 participants on this trial withdrew because of adverse events, compared with 1% in the placebo arm. Conversely, an equally large randomized controlled trial randomly assigned patients with early and advanced disease, both on and off 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.[Level of evidence: I] There were significant differences between groups for nervousness and appetite loss, with the methylphenidate arm scoring worse on both of those side effects.
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. Modafinil and armodafinil are approved by the FDA for narcolepsy, obstructive sleep apnea, and shift-work disorders. Neither of these agents is approved by the FDA 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 a couple of promising open-label pilot trials,[11,12] a large randomized controlled trial evaluated modafinil for CRF using 200 mg versus placebo in more than 850 patients 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, this study failed to show significant differences between arms. Because armodafinil is newer to the marketplace, research on its possible role in CRF has not yet been published. More research is needed to identify whether modafinil and armodafinil can ameliorate fatigue and which populations of cancer survivors can benefit most from them.
With both methylphenidate and modafinil, there have been exploratory data suggesting that patients with more severe fatigue or more advanced disease may receive more benefit from these drugs.[7,8] A small (n = 13), randomized, placebo-controlled study  using methylphenidate (titrated up to 30 mg/day) 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 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 evaluating 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.
The side effects most commonly described with psychostimulants include insomnia, euphoria, headache, nausea, anxiety, and mood lability.[5,7,8,13,14] High doses and long-term use may produce anorexia, nightmares, insomnia, euphoria, paranoia, and possible cardiovascular complications. Patients with cancer carry a higher risk of cardiovascular complications, depending on the type of cancer and cancer treatment (e.g., cardiotoxic chemotherapy regimens). Cardiovascular complications with psychostimulants can arise even in patients without any significant risk factors. In the study using methylphenidate as an intervention for the treatment of CRF in patients with prostate cancer, 6 subjects (27%) out of a total of 16 subjects in the methylphenidate group were discontinued because of increased blood pressure and tachycardia. It is important to note that none of these subjects were being treated with known cardiotoxic chemotherapeutic regimens such as anthracyclines. Careful and continuous monitoring of certain cardiovascular parameters (mainly blood pressure and heart rate) is critical when psychostimulants are used to treat CRF. In certain complex cases, consulting with cardiology services may be considered. Cardiovascular issues are thought to be less of a risk with modafinil and armodafinil. It is important to consider risk-benefit ratio and to evaluate patients for response and side effects when these agents are used to treat CRF.
The package inserts for all Schedule IV stimulant medications carry boxed warnings indicating risk of abuse potential and/or risk of psychological dependence. Additionally, boxed warnings for certain stimulant medications (methylphenidate and dexmethylphenidate products) indicate risk of psychotic episodes. Other stimulant medications (amphetamine, dextroamphetamine, lisdexamfetamine dimesylate, methamphetamine, and mixed salts of amphetamine products) carry boxed warnings alerting clinicians that misuse of these medications may cause serious cardiovascular adverse events, including sudden death.
Bupropion is a stimulating antidepressant with a primarily dopaminergic and noradrenergic mechanism of action. (Refer to Table 2 in the PDQ summary on Depression for more information.) Preliminary evidence from a small open-label study (n = 21) suggests that the sustained release (SR) form of bupropion has potential as an effective therapeutic agent for treating CRF with or without comorbid depressive symptoms.[Level of evidence: II] Seizure, a rare but serious side effect of this agent, did not occur in this study (the maximum dose of bupropion SR used in this study was 300 mg).Table 2. Centrally Acting Stimulants for Adult Cancer Patients
|Drug||Dosage||Comments/Primary Side Effects|
|AUC = area under the curve; MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin reuptake inhibitor.|
|Dextroamphetamine (Dexedrine)||2.5 mg/d (start)||Schedule II. Major potential interactions with citalopram and venlafaxine.|
|5–30 mg/d in 2 to 3 divided doses|
|Methylphenidate (Ritalin)||2.5 mg/d (start)||Schedule II. High-fat meals may increase AUC. Peak concentration 102 hours after ingestion. Do not use with MAOIs as it can precipitate hypertensive crisis. Antidepressants that increase norepinephrine can cause increased amphetamine side effects. Concomitant use with SSRI can result in increased SSRI concentrations.|
|Titrate up to 54 mg/d (27 mg D-isomer)|
|Modafinil (Provigil)||50–100 mg (start)||Schedule IV. Avoid driving/operation of machinery until effects are known. Do not take at bedtime. Peak concentration in 2–4 hours. Food slows absorption by about 1 hour but does not affect bioavailability. Decreases efficacy of birth control pills.|
|100–200 mg every morning|
|Armodafinil (Nuvigil)||50 mg (start)||Schedule IV. Avoid driving/operation of machinery until effects are known. Do not take at bedtime. Peak concentration in 2 hours if fasting, slowed to as many as 4 hours if fed, but food does not affect bioavailability. Decreases efficacy of birth control pills.|
|25–250 mg every morning|
On the basis of limited clinical experience and acknowledging a lack of evidence in randomized controlled trials, it might be reasonable to consider a psychostimulant such as methylphenidate or modafinil for the treatment of severe fatigue, particularly for short periods of time (a couple of weeks) in patients with advanced disease. When the use of these medications is being considered, it is important to obtain informed consent, with careful discussion of risks, benefits, and alternatives. Continuous monitoring of cardiovascular parameters is crucial when these medications are used, especially in patients with preexisting cardiovascular issues and in patients being treated with known cardiotoxic chemotherapeutic regimens (e.g., anthracyclines). In certain cases, consulting with cardiology services might be necessary. Longer-term psychostimulant therapy is not advisable at this time because there is limited information about its potential negative effects and longer-term benefits.Treatment of Anemia
Anemia in patients with cancer is best managed by treatment of the underlying cause. When the cause is obscure or there is no specific remedy, then treatment is supportive. Nutritional interventions, including the intake of nutrient-rich foods and supplements should be considered in addition to other treatment modalities. Transfusion of packed red blood cells is the most widely used and most rapid way to alleviate symptoms in cancer patients with symptomatic anemia. The likelihood of success in raising the level of hemoglobin is very high with transfusion, and the risks of complications are low. Nevertheless, repeated transfusions can be cumbersome, and the risks of blood-borne infection can be worrisome for patients. Other risks include an acute transfusion reaction, transfusion-associated graft-versus-host disease, subtle immune modulation that occurs with transfusion, and iron overload for those with repeated transfusions.
Several large, community-based studies have examined the effectiveness of epoetin alfa and darbepoetin alfa [Level of evidence: I];[Level of evidence: I] in the treatment of cancer-related anemia in patients undergoing chemotherapy.[Level of evidence: II];[Level of evidence: III];[Level of evidence: I] A few of the studies of epoetin alfa employed an open-label, nonrandomized design and included objective endpoints (hemoglobin response, transfusion requirements) and subjective evaluation of fatigue and quality of life. In this setting, epoetin alfa has been effective at increasing hemoglobin levels and decreasing transfusion requirements. In addition, epoetin alfa was associated with improvement in functional status and quality of life, independent of tumor response. Several studies of epoetin alfa and darbepoetin alfa employed a randomized, controlled design. These studies varied in terms of dosing and frequency of medication administration. A review and meta-analysis of randomized and open-label studies concluded that these agents are effective in the management of CRF  but also raises serious concerns about safety data and adverse outcomes associated with these agents. The review concludes that these agents should not be used for the treatment of fatigue in patients with cancer. The authors argue that the risks associated with these agents outweigh their benefits for the treatment of CRF.
The FDA has conducted a comprehensive review of safety information from studies of these agents. The review showed that in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers, erythropoiesis-stimulating agents (ESAs) shortened overall survival and/or increased the risk of tumor progression or recurrence. The review also showed that ESAs increase the risk of serious cardiovascular and thromboembolic events when they are administered to target higher hemoglobin levels (13.5–14 g/dL).
On the basis of these findings, the FDA mandated revised ESA labeling to include an updated warning, a new boxed warning, and modifications to the indications and dosing instructions. The boxed warning includes information on the higher mortality risks due to cardiovascular/thromboembolic events and tumor progression or recurrence. The 2010 American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) guidelines recommend the following:
- In accordance with the FDA-approved label, the use of these agents should be restricted to the treatment of anemia (hemoglobin level <10 g/dL) due to concomitant palliative myelosuppressive chemotherapy and should be discontinued upon completion of a course of chemotherapy. (The above does not hold for low-risk myelodysplastic syndrome.)
- In accordance with the FDA-approved label, the lowest possible dose should be used, with the goal of avoiding red blood cell transfusions, because the higher doses increase the risk of cardiovascular and thromboembolic events.
- Initial dose and modification should follow FDA-approved labeling.[26,27] ESAs should be discontinued if there is no response after 6 to 8 weeks (<1–2 g/dL increase in hemoglobin or decrease in transfusion requirements).
- The FDA-approved label states that ESAs are not indicated for patients receiving curative myelosuppressive chemotherapy. However, the 2010 ASCO/ASH recommendations state that clinical judgment, goals of therapy, and patient preference should guide ESA use in the curative and palliative settings.
A Cochrane review concluded that ESAs provide a clinically significant reduction in fatigue for anemic patients receiving chemotherapy. However, on the basis of safety concerns raised by the FDA and in view of identified side effects, this review further concluded that ESAs should not be used in clinical practice for fatigue. Clinicians should initiate discussions with patients and family members about the risks and benefits of ESAs.
In February 2010, the FDA approved and mandated a risk management program to inform health care providers and their patients about the risk of ESAs.[23,28] This program includes a specific medication guide for patients that, along with the FDA public health advisory, states that ESAs are not approved or indicated for the treatment of fatigue in patients with cancer.Exercise
Preliminary studies [30-32][Level of evidence: I];[Level of evidence: II];[34,35][Level of evidence: III];[36,37][Level of evidence: IV] suggest that exercise (including light- to moderate-intensity walking programs) has potential benefits for people with cancer. The benefits shown in these studies and observed in clinical settings include improved physical energy, appetite stimulation, and/or enhanced functional capacity, with improvements in quality of life and in many aspects of psychologic state (e.g., improved outlook and sense of well-being, enhanced sense of commitment, and the ability to meet the challenges of cancer and cancer treatment).
Several reviews and National Comprehensive Cancer Network guidelines outline numerous studies that support the beneficial effects of exercise on fatigue.[38,39] Reductions in fatigue of about 35% and improvements in vitality of 30% have been shown in randomized trials, with stronger effects being shown during cancer therapy in some studies and after therapy in other studies.[38,40] Many initial trials of exercise programs focused on women with breast cancer, but later studies included men with prostate cancer, multiple myeloma, and colorectal cancer. Some studies have had methodologic weaknesses, including the following:[Level of evidence: I]
- Selection biases and nonrepresentative samples.
- Recruitment of patients into randomized trials.
- Poor adherence to exercise interventions.
- Highly varied assessments of research variables and outcome measures.
- Lack of adequate control groups.
Some examples of the breadth of trials evaluating exercise are discussed in the following paragraphs. One study of patients undergoing peripheral blood stem cell transplantation found symptomatic benefits and improvements in mood in patients who participated in the interval-training program versus the control group.[43,44][Level of evidence: I] Supervised aerobic group exercise provided functional and quality-of-life benefits for women during treatment for breast cancer.[Level of evidence: I] Exercise improved function in patients treated for breast cancer.[46,47][Level of evidence: I]
In a study of 545 breast cancer survivors who were, on average, 6 months postdiagnosis, increased physical activity was consistently related to both improved physical functioning and reduced fatigue and bodily pain. Prediagnosis physical activity was associated with better physical functioning at 39 months but generally unrelated to symptoms. Increased physical activity after cancer was related to less fatigue and pain and better physical functioning. Significant positive associations were found with moderate to vigorous recreational physical activity but not household activity. This study suggests that breast cancer survivors may be able to decrease fatigue and bodily pain and be better able to pursue daily activities by increasing their recreational physical activities after cancer.[Level of evidence: II]
Exercise for patients with advanced or terminal disease is difficult to study but may yield similar benefits. The ability of patients with advanced cancer who are in hospice care and on a physical therapy regimen to carry out activities of daily living has been reported to improve in one study.[Level of evidence: III] Improved satisfaction with the physical therapy regimen was reported when family involvement in the program increased. A randomized study suggested that exercise improved fatigue during breast cancer treatment.[Level of evidence: I]
When educating patients about activity with respect to CRF, one important goal to consider is inclusion of 3 to 5 hours per week of moderate activity. It is critical that:
- Patients choose a type of exercise they enjoy.
- Providers discuss specific implementation strategies (type of exercise, time of day, days of the week, location of activity) to enable patients to make frequent activity a reality.
Beginning with lighter activity for shorter periods of time and building in intensity and length of time may be required. Studies have confirmed this can be safely done both during active treatment and after treatment is completed.
Variations of exercise that have a mind-body component include complementary modalities such as qigong, tai chi, and yoga, popular interventions that are being studied for their effects on CRF. These modalities are unique in that they incorporate cognitive and spiritual elements with movement, stretching, and balance. One fairly large study evaluated medical qigong for CRF. This study reported significant improvements in fatigue and several other aspects of quality of life for the intervention group versus usual care. The major weakness limiting interpretation and integration of these results is that there was no attempt to control for attention or any of the social aspects of the intervention.
The qigong intervention was delivered in 90-minute group sessions twice a week for 10 weeks, for 1,800 minutes of treatment. The usual-care group did not receive any group meetings or additional provider interaction. It is therefore difficult to say what qigong uniquely provided over and above nonspecific or group-interaction effects. It is also not known how much survivors would need to continue performing qigong to maintain benefits. There were no adverse events in this study, so other than time and resource expenditure, it is difficult to pinpoint a downside to encouraging patients to adopt such an activity. One important strength of the study evaluating qigong was the collection of serum to measure markers of inflammation. At the end of 10 weeks, the C-reactive protein of patients in the medical qigong group decreased 3.6 mg/L, while patients in the usual-care group experienced an increase in this marker of 19.57 mg/L. This was a statistically significant difference.Cognitive Behavior Therapy
Cognitive behavior therapy (CBT) has long been used to treat a variety of psychophysiological problems, with therapy focusing on the thoughts (cognitions) and functional behaviors relevant to the presenting problems. 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.[Level of evidence: I] The CBT focused on each participant's unique pattern of the following six possible factors that might serve to perpetuate their post–cancer treatment fatigue:
- Insufficient coping with the experience of cancer.
- Fear of disease recurrence.
- Dysfunctional cognitions regarding fatigue.
- Dysregulation of sleep.
- Dysregulation of activity.
- Low social support/negative social interactions.
The number of therapy sessions varied according to the number of perpetuating factors (range: 5–26 1-hour sessions; mean: 12.5 sessions); results showed a clinically significant decrease in fatigue severity and functional impairment.Activity and Rest
Health professionals can work with patients with cancer to develop an activity/rest program based on an assessment of the patient’s fatigue patterns that allows the best use of the individual’s energy. Any changes in daily routine require additional energy expenditure. Individuals with cancer should be advised about setting priorities and maintaining a reasonable schedule. Health professionals may assist patients by providing information on support services that are available to help with daily activities and responsibilities. An occupational therapy consultation can be of assistance in evaluating energy conservation methods. Sleep hygiene, including avoidance of lying in bed at times other than sleep, shortening naps to no more than 1 hour, avoiding distracting noise (e.g., television, radio) during sleep hours, and other measures may improve sleep and activity cycles.Patient Education
Much of the management of chronic fatigue in people with cancer involves promoting adaptation and adjustment to the condition. The possibility that fatigue may be a chronic disability should be discussed. Although fatigue is frequently an expected, temporary side effect of treatment, the problem may persist if other factors continue to be present.
An important goal of management is to facilitate self-care for the person with cancer. Since fatigue is documented as the most commonly reported symptom in individuals receiving outpatient chemotherapy (81% of cancer patients report fatigue), a shift in responsibility for control of side effects from the health care professional to the individual is important. It is imperative that individuals with cancer are educated about fatigue before it occurs and are taught about self-care strategies necessary to manage 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 attentional fatigue and encouragement of the planned use 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 psychologic and social stressors and how to avoid or modify them.
- Evaluating the efficacy of fatigue interventions on a regular and systematic basis.
In a controlled trial of patients who reported the symptom cluster of pain and fatigue while receiving chemotherapy, a nursing behavioral intervention produced improvements in quality of life and decreased symptom burden relative to usual care.[56,57][Level of evidence: I] These intriguing results need to be further explored in patient populations other than women with breast or gynecologic malignancies.
As researchers and practitioners learned with pain, misconceptions and a lack of knowledge may prove to be patient- and provider-related barriers to successful assessment and management. A quasi-experimental study tested a multisystem educational approach to improving both pain and fatigue management. The approach consisted of the following:
- Education and assessment of patients regarding the management of pain and fatigue, with phone calls every 2 weeks for 3 months.
- Education of providers about pain and fatigue assessment and management, including monthly newsletters.
- An effort to engage with an internal advisory board.
- Efforts aimed toward research nurses to refer earlier to supportive care services.
Over a 3-month period, the educational intervention resulted in increases in knowledge and a decrease in barriers related to management of pain and fatigue. Of note, important patient barriers related to fatigue management included the following beliefs:[Level of evidence: II]
- Fatigue is inevitable.
- Fatigue can indicate worsening of disease.
- Treating the cancer is more important than treating fatigue.
- Reporting fatigue will cause a patient to be perceived as a complainer.
Check NCI’s list of cancer clinical trials for U.S. supportive and palliative care trials about fatigue and anemia that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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