Fatigue

Recommended for Practice

Interventions for which effectiveness has been demonstrated by strong evidence from rigorously designed studies, meta-analyses, or systematic reviews, and for which expectation of harm is small compared with benefit

Exercise

Two meta-analyses and five systematic reviews ^1-7 support the benefits of exercise in the management of fatigue during and following cancer treatment in patients with breast cancer and solid tumors, as well as those undergoing hematopoietic stem cell transplantation. Although positive results for the outcome of fatigue have not been observed consistently across studies, the general pattern of results in 34 controlled trials (including 27 randomized trials) indicates that exercise can be effective in reducing fatigue in patients during and following cancer treatment. Various exercise modalities have been applied, differing in content (walking, cycling, swimming, resistive exercise, or combined exercise), frequency (ranging from two times per week to two times per day), intensity (with most programs at 50%–90% of the estimated maximal rate of oxygen consumption or VO₂ max), degree of supervision (fully supervised group versus self-directed exercise), and duration (from two weeks to much as one year). In some studies, intervention groups were compared to groups that received some form of physical training of a lesser intensity, frequency, or duration; in other studies, comparison groups were on a waiting list, participated in a crossover arm, or did not receive any exercise program or advice. The specific beneficial effects of physical exercise may vary as a function of the stage of disease, the nature of the medical treatment, and the current lifestyle of the patient. More research is needed to systematically assess the safety of exercise (both aerobic exercise and strength training) ⁷⁸ and to tailor the type, intensity, frequency, and duration of physical exercise to different tumor types and stages of the disease and treatment process. Most of the studies reviewed suffer from methodologic shortcomings, and further research using larger samples and attentional control groups, blinding the outcome assessor, and controlling for motivation, exercise preferences, and adherence of the participants in an exercise program is needed.

Likely to Be Effective

Interventions for which the evidence is less well established than for those listed under “Interventions Recommended for Practice”

Screening for potential etiologic factors and management as appropriate

•  Based on lower level evidence, including clinical experience, the National Comprehensive Cancer Network consensus panel⁸ has recommended that patients with fatigue be screened for treatable etiologic factors such as hypothyroidism, hypogonadism, cardiomyopathy, adrenal insufficiency, pulmonary dysfunction, anemia, sleep disturbance, fluid and electrolyte imbalances, emotional distress; concurrent distressing symptoms such as pain, nausea, and depression; sedation secondary to specific classes of medications (e.g., opiates, antidepressants, antiemetics, antihistamines); or drug-drug interactions, and managed as indicated.

Energy conservation and activity management

•  A nurse-delivered intervention focused on energy conservation and activity management was found to have a modest but significant effect in a large, multisite, randomized clinical trial with patients (mostly those with breast cancer) initiating chemotherapy or radiation.⁹A pilot study by the same investigators showed a trend for energy conservation and activity management to be superior to that of a historic control group.⁷⁹

Education and information provision

•  Four randomized, controlled trials and two nonrandomized pilot studies suggested that educational interventions may have a role in supporting positive coping in patients with fatigue. A randomized trial evaluating a supportive intervention delivered by nurses tailored to managing pain and fatigue during chemotherapy was found to be effective in reducing the symptoms, as well as total symptoms.¹⁰ The trial was conducted in a sample of 113 patients with mixed diagnoses, and the intervention included teaching, counseling, support, coordination, and communication. Women commencing adjuvant chemotherapy and radiotherapy for stage I or II breast cancer (N = 109) participated in a multicenter, randomized, controlled trial of a tailored psychoeducational intervention to improve knowledge and skills relative to self-care behaviors for fatigue that was delivered in a clinic and by phone in four weekly sessions.¹¹ Women who received the intervention experienced significantly less fatigue (p = 0.01) and less interference from fatigue over the treatment cycle (p = 0.01) when evaluated one to two weeks after completing the intervention. However, the reduction in fatigue and fatigue interference was not sustained at the 6- and 10-week follow-up. In a randomized, controlled trial of a psychoeducational intervention comprised of education, stress management, and coping skills training in patients who were newly diagnosed with stage I or II melanoma, the treatment group reported statistically significant decreases in fatigue as well as several other outcomes^{. 12} In another randomized, controlled trial (N = 152), patients undergoing radiation therapy for prostate cancer were provided with an informational intervention at the first and fifth radiation treatment.¹³ The intervention was based on self-regulation theory and provided patients with specific, objective information regarding what to expect during their radiation treatments. The control group received general information at the same two time points. At the time of the last radiation treatment, patients in the informational intervention showed a trend toward less fatigue when compared to the control group; however, the result was only marginally significant (p < 0.10). The effects of a psychoeducational intervention (i.e., coping skills training designed to enhance personal control and promote emotional and instrumental coping responses) delivered to patients with head and neck cancer (N = 49) was assessed in a pilot study. ¹⁴ Participants reported improvements in fatigue as a result of the intervention. In the second study, a four-component, tailored intervention (assessment/monitoring, education, coaching in the management of fatigue, and provision of emotional support) was implemented in a case series of eight patients and was found to decrease self-reported fatigue. ¹⁵ These two studies, together with the results of another small randomized trial of an informational audiotape, 80 also support the conclusion that patients welcome psychoeducational interventions related to fatigue and that they will apply the skills they learn in their daily lives to the management of fatigue. In addition, the National Comprehensive Cancer Network's consensus panel guidelines have recommended that patients and families be provided with anticipatory guidance about patterns of fatigue and recommendations for self-management, especially when beginning fatigue-inducing treatments.⁸

Measures to optimize sleep quality

•  Five studies (two feasibility studies, ^16,17 two small [N = 14 18 and N =10 19 ] single-arm trials, and one randomized controlled trial [N = 57 20 ]) provided preliminary support that a multicomponent cognitive-behavioral intervention designed to optimize sleep quality also may improve fatigue. The cognitive-behavioral intervention generally included relaxation training, along with sleep consolidation strategies (e.g., avoid long or late-afternoon naps, limit time in bed to actual sleep time), stimulus control therapy (e.g., go to bed only when sleepy, use bed or bedroom for sleep and sexual activities only, lie down and get up at consistent times, avoid caffeine and stimulating activity in the evening), and strategies to reduce cognitive-emotional arousal (e.g., relax for at least an hour before going to bed, establish a presleep routine to be used every night). Results support the feasibility of this intervention approach delivered individually or in a group setting to women undergoing adjuvant chemotherapy primarily for breast cancer. Study results also indicate that cognitive-behavioral interventions for insomnia may have a beneficial effect in terms of stabilizing fatigue during and following chemotherapy treatment (i.e., a time when it may be anticipated that fatigue would intensify in the absence of an intervention). In a single-arm trial of a mindfulness-based stress reduction intervention, participants reported improvements in sleep quality, as well as statistically significant reductions in stress, mood disturbance, and fatigue. ⁸¹

Relaxation

•  In a small (N = 34) randomized study of progressive muscle relaxation training delivered in six group sessions and coupled with supportive therapy and home practice of muscle relaxation exercises, participants in the intervention group reported significantly less fatigue than participants in the control group. ²¹ In another small (N = 35) randomized trial of an intervention that consisted of 30 minutes of relaxation breathing and yoga-like positioning that was administered daily for a six-week period, control group participants received usual post-transplant clinical care. Although conclusions are limited by the absence of an attentional control, the group that received the breathing and positioning intervention reported significantly lower fatigue scores (p < 0.05) on all subscales of the Piper Fatigue Scale. ²²

Massage and healing touch

•  A large, multisite, randomized trial with a crossover found that weekly healing touch had a significant effect on fatigue (p = 0.02) 23 and weekly Swedish massage with aromatherapy had a borderline significant effect (p = 0.06) compared to a control and presence condition in patients with multiple diagnoses receiving high-dose chemotherapy.²⁴ The interventions also included centering, breathing, and relaxing music. The effect of the diverse components in the programs could not be disentangled. In a pilot study with patients undergoing high-dose chemotherapy, upper-body Swedish massage as much as three times per week was associated with a significant decrease in fatigue pretransplant and prior to discharge but not during the acute post-bone marrow transplant phase ²⁴ . Data from an uncontrolled clinical analysis of a massage treatment program found a 40.7% reduction in fatigue in a large inpatient and outpatient population. ²⁵ A controlled pilot study demonstrated efficacy of polarity therapy (i.e., an intervention hypothesized to promote healing, relaxation, and well-being by unblocking and balancing energy flow and reestablishing homeostasis in the human energy field) in a small sample of 15 women receiving radiation therapy for breast cancer. ²⁶

Benefits Balanced With Harms

Interventions for which clinicians and patients should weigh the beneficial and harmful effects according to individual circumstances and priorities

Correction of anemia

•  Data from four systematic reviews ^27-30 suggest that patients receiving recombinant human erythropoietin to correct anemia less than 10 g/dl may experience increased vigor and diminished fatigue. Evidence is limited that erythropoietin improves fatigue when anemia is less severe. Data suggest that a target hemoglobin level of 11 –12 g/dl will produce the greatest gains in fatigue and other quality-of-life outcomes. ³¹ Overall, better quality evidence is needed to unequivocally support the use of recombinant human erythropoietin solely as an intervention to improve patient-reported outcomes such as fatigue. ^82,83 Although epoetin and darbepoetin generally are well tolerated, the use of these agents specifically for the management of fatigue must be considered in light of safety issues, including a small increased risk of thrombotic events, hypertension, and theoretic concerns that epoetin may support or extend tumor growth in certain disease sites. ^31-33,84

Effectiveness Not Established

Interventions for which data currently are insufficient or of inadequate quality

Individual and group psychotherapy

•  A multicenter, randomized, controlled trial of supportive group psychotherapy in women with metastatic breast cancer (N = 158)³⁴ and a small randomized trial of a tailored cognitive-behavioral treatment (N = 28)⁸⁵ did not show positive benefit relative to the outcome of fatigue, although a benefit of psychotherapy was noted in terms of psychological symptoms, pain, and symptom interference. By contrast, patients with stage I and II melanoma who were treated with surgery (N = 131³⁵ and N = 38⁸⁶ ) participated in one of two randomized trials of six weekly group psychotherapy sessions and reported significantly less fatigue two months postintervention than a control group that did not receive such treatment. Psychotherapy also was found to have some benefit in alleviating fatigue in a small case series of women with metastatic breast cancer (N = 6).³⁶ The effects of a multicomponent supportive care intervention (i.e., physical exercise, relaxation training, qi-gong, and art therapy with peer support and information about cancer and its psychological effects and coping strategies) on fatigue delivered in a six-day residential rehabilitation program to individuals with mixed tumor types who were six months to three years post-treatment were studied in a single-arm trial (N = 59).⁸⁷ The intervention produced statistically significant improvements in fatigue immediately following the intervention; however, the improvements were not sustained at the three- and six-month follow-up. The addition of exercise to a group psychotherapy intervention (i.e., stress management and relaxation training or expressive-supportive psychotherapy) was found to improve outcomes related to fatigue when compared to the group psychotherapy intervention alone or a comparison group.³⁷ The effect of the diverse components in the programs cannot be disentangled.

Expressive Writing

•  A pilot study compared a group of patients with newly diagnosed stage IV metastatic renal cell carcinoma who participated in an expressive writing intervention (i.e., four weekly sessions in which participants wrote about their deepest thoughts and feelings) with a group who participated in a writing intervention where they wrote about neutral issues related to health. No differences in fatigue were found between the two groups; however, at postintervention, the group that had received the expressive writing intervention reported greater vigor.³⁸

Paroxetine

•  Four trials have examined the effectiveness of paroxetine in treating fatigue during and following cancer treatment, with mixed findings. In two large, multicenter, randomized, double-blinded placebo-controlled trials with more than 400 patients with solid tumors receiving cyclic chemotherapy (not concurrent with radiotherapy or interferon) 88 and 94 patients with breast cancer receiving at least four cycles of chemotherapy, 89 paroxetine 20 mg by mouth daily did not have an effect on fatigue, although improvements in depression and overall mood were noted in the paroxetine treatment group. However, two small trials have shown a trend toward a possible benefit for paroxetine in treating fatigue in women with hot flashes (N = 13)³⁹ and patients receiving interferon alpha (N = 18). ⁴⁰

Methylphenidate

•  Five prospective, open-label, single-arm trials with small samples have examined the use of methylphenidate in reducing fatigue. One study administered immediate-release methylphenidate using patient-controlled dosing (N = 30)⁹⁰ , and three studies used 5 mg in the morning and at noon (N = 11)⁴¹ , (N = 37)⁹¹, (N = 16)⁹², titrating the dose to as much as 20–30 mg per day to achieve effect. In patients receiving interferon (N = 8), methylphenidate was combined with exercise in a nonrandomized open-label trial.⁹³ All five studies reported improvements in fatigue in most of the participants as a result of the methylphenidate intervention; however, in one study, 41 more than half of the patients experienced side effects such as insomnia, agitation, anorexia, nausea and vomiting, or dry mouth, and in another study, ⁹¹ 19% of the patients withdrew from the trial because of the adverse events experienced. All adverse events were classified by the investigators as National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v.3) grade 1.

Donepezil

•  Donepezil 5 mg every morning was evaluated in an uncontrolled, open-label trial in 27 patients with a variety of tumor sites who were receiving narcotics at a median oral morphine-equivalent daily dose of 180 mg per day (range = 30–600 mg). 42 Fatigue was significantly improved following a seven-day course of treatment. Seven of the initial 27 patients enrolled in the study were discontinued from participating because of side effects. Increased frequency of bowel movements was noted; however, this was seen as a beneficial side effect because many of the study participants were experiencing constipation at baseline. Five out of 20 participants experienced grade I diarrhea. At the conclusion of the study, 85% of the participants opted to continue treatment with donepezil. The study was limited by its single-arm design and small sample size, and the short length of treatment and minimal follow-up make it difficult to conclusively assess the anticipated incidence of donepezil side effects. Randomized, controlled trials in a larger sample are needed to evaluate the efficacy and toxicity profile of donepezil in limiting fatigue.

Modafinil

•  In a case report regarding the use of modafinil (at a dose of 100 mg once or twice a day), improvements in daytime wakefulness and normalization of the sleep-wake cycle were reported in two older adult patients with advanced cancer.⁴³ No side effects were reported. The use of modafinil (at a dose of 100–400 mg in a daily or divided dose) also is supported by an expert opinion report. ⁹⁴

Bupropion sustained-release

•  Bupropion sustained release at a dose of 100–300 mg per day has been evaluated in an uncontrolled, open-label trial in 15 patients with various cancer diagnoses who were experiencing fatigue or depression with marked fatigue ⁴⁴ and in a prospective open case series of 21 patients who mainly had primary brain tumors, breast cancer, or a hematologic malignancy. ⁴⁵ In the study by Cullum et al. ⁴⁴ the rating for fatigue improvement was made by a clinician not directly involved in the trial; however, whether the rater was blinded to the treatment condition was unclear. Thirteen of 15 participants reported improvement in fatigue, with eight participants indicating that their fatigue level was much improved ⁴⁴ . In all patients, the improvement occurred within two to four weeks. In the study by Moss et al. ⁴⁵ , statistically significant differences existed in self-reported fatigue (as measured by the Brief Fatigue Inventory) from pre- to post-treatment (p = 0.001). Controlled studies are necessary to establish the efficacy of this intervention in a more homogeneous sample of patients with cancer and to determine whether the effect of bupropion is separate from its action as an antidepressant.

Yoga

•  One small pilot study compared the effects of a seven-week yoga program to a wait-list control in 38 adults with lymphoma receiving cytoxan, adriamycin, vincristine, and prednisone (CHOP) or similar therapy, either during or within 12 months post-treatment. ⁴⁶ No significant differences in fatigue were found, but the effects of treatment were not controlled.

Acupuncture

•  One small, single-arm pilot study with no control found that traditional Chinese acupuncture decreased fatigue by an average of 31.9% in 37 adults at least three weeks post-treatment.⁴⁷ In a small randomized trial of 15 hospice patients, acupuncture-like transcutaneous electrical nerve stimulation did decrease fatigue, although not significantly, compared to a control group. ⁴⁸

Distraction - virtual reality immersion

•  A distractive intervention, virtual reality immersion, has been investigated in two randomized crossover trials ^49,50 ; a randomized, controlled trial ⁵¹ ; and a single-arm, unblinded pilot study. ⁵² Each study had small samples (i.e., 16–20 participants) consisting of patients with mostly solid tumors. When compared to treatment cycles in which no virtual reality immersion intervention was given, fatigue decreased statistically and significantly immediately following a chemotherapy treatment during which the subjects received the intervention. Two days after treatment, a trend toward lower fatigue scores existed, although the differences did not reach statistical significance.⁴⁹ In the second crossover study led by the same principal investigator, fatigue scores tended to be lower when participants received the virtual reality immersion intervention; however, the results did not achieve statistical significance.⁵⁰ In the only randomized, controlled trial, no significant differences were found between the intervention and control groups when the virtual reality immersion intervention was given for the first time. When the intervention was repeated with a subsequent cycle of chemotherapy, significant differences were observed between the intervention and control groups in their report of fatigue and tiredness. Whether the findings are attributable to carryover effects from the first virtual reality immersion intervention, as the authors conclude, or simply from differential effects of repeated testing is unknown.⁵¹

Levocarnitine supplementation

•  Two small, open-label trials support the safety and potential efficacy of levocarnitine supplementation in treating fatigue in patients with cancer who have low serum carnitine levels. In a phase I study of 13 patients with a low serum carnitine level, researchers confirmed that an oral dose of 1,750 mg of levocarnitine per day is tolerated without adverse effects and produced statistically significant beneficial effects on fatigue after only one week of therapy.⁵³ A larger phase II study of levocarnitine supplementation was conducted in patients with lower serum carnitine levels and fatigue who were receiving ifosfamide and cisplatin palliative chemotherapy (a therapy known to cause urinary loss of carnitine).⁵⁴ Fifty nonanemic patients were supplemented with oral levocarnitine at a dose of 4,000 mg daily for seven days. Ninety percent of patients reported improvements in fatigue after just one week of levocarnitine, and the differences in fatigue scores from baseline to the first week of chemotherapy or levocarnitine treatment were statistically and significantly improved. The improvements were sustained for two additional weeks after discontinuing levocarnitine supplementation. Although interpretation of the results is limited by the small sample size, the open-label, nonrandomized design, and the absence of a double-blinded control group, the studies suggest that levocarnitine supplementation should be studied further as a possible intervention for fatigue in patients with cancer.

Adenosine 5' triphosphate infusion

•  A randomized, open-label study of 30-hour IV infusions of adenosine 5' triphosphate administered every two to four weeks for ten doses was conducted in 28 patients with advanced non-small cell lung cancer.⁵⁵ Researchers reported a significant effect on fatigue, as measured by single items on the Rotterdam Symptom checklist. Mild infusional side effects ( National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v.3) grade I–II toxicities were chest discomfort, 15%; an urge to take a deep breath, 10%; flushing, 5%; nausea, 5%; lightheadedness, 3%; dyspnea, 3%; headache, 2%; sweating, 2%; mood alteration—anxiety, 2%; and palpitations, 1%). The side effects always resolved by slowing the rate of 5' triphosphate infusion. Study results are limited by the open-label design, by the small sample size, and because the study procedures did not control for the concomitant administration of corticosteroids to manage other disease-related symptoms such as cerebral edema, nausea, and dyspnea. The impact for continuous infusion therapy on quality of life also is of potential concern.

Omega-3 fatty acid supplementation

•  A placebo-controlled, randomized trial of a 1,000 mg omega-3 fatty acid supplement (180 mg eicosapentaenoic acid, 120 mg docosahexaenoic acid, and 1 mg vitamin E) in 91 adult patients with locally recurrent or metastatic cancer showed a trend toward less fatigue; however, the therapy was not well tolerated. Only 30 of the 46 patients randomized to the fatty acid supplement were able to complete a course of treatment. ⁵⁶ Dosing required the consumption of more than 15 capsules per day and resulted in belching, dysgeusia, and oily diarrhea. A phase I trial to establish the maximum tolerated dose of omega-3 fatty acid supplementation in patients with satisfactory performance status and limited gastrointestinal symptoms at baseline may be indicated as an initial step in further development of this therapy.

Combination Therapy: Aromatherapy, foot soak, and reflexology

•  An open-label pilot study of a combination of an aromatherapy foot soak with lavender for three minutes and reflexology for 10 minutes with jojoba oil and lavender in 20 patients at the end of life found significant decreases in fatigue one and four hours after treatment. ⁵⁷ No control group was included.

Combination Therapy: Medroxyprogesterone, celecoxib, and enteral food supplementation

•  The effects on fatigue of medroxyprogesterone (500 mg twice per day), celecoxib (200 mg twice per day), and an enteral diet supplement (i.e., a supplement designed to provide maximal caloric load in the smallest volume and lowest osmolarity, with a carbohydrate, protein, and fat composition equivalent to 20% of the resting basal metabolic rate) was evaluated in a single-arm study of 15 adults with stage IIIb or IV adenocarcinoma of the lung.⁵⁸ A significant difference was found in pretreatment and post-treatment fatigue (p = .009), although the results are limited by the uncontrolled study design and small sample size.

Combination Therapy: Soy protein supplementation and nutrition counseling following discharge from hospital

Following elective colorectal surgery (69% for cancer), 32 patients (22 of whom were patients with cancer) were randomly assigned to four months of soy protein supplementation and nutritional counseling or usual post-discharge follow-up.⁵⁹ Although the intervention group consumed significantly more protein than the control group and gained weight and body mass, both groups had similar fatigue scores at hospital discharge and at the conclusion of the intervention follow-up period. Results suggest that, among patients with small to moderate weight loss associated with colorectal surgery, improvements in weight and body mass are not associated with corollary improvements in fatigue or functional status.