Psychostimulants
Treatment of Anemia
Exercise
Cognitive Behavior Therapy
Activity and Rest
Patient Education

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.[1-4] Without a determination of the 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. For example, 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; and 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 there are an increasing number of clinical trials that are designed to address this issue in cancer patients.

Although fatigue is one of the most prevalent symptoms in cancer, to date few trials are published on the use of psychostimulants as a treatment for fatigue in people with cancer.[5] The support for their use arises largely from clinical anecdotal experience.[6] Psychostimulants (caffeine, methylphenidate, modafinil, and dextroamphetamine) given in low doses are useful for patients who are suffering from depressed mood, apathy, decreased energy, poor concentration, and weakness.[5] Extensive clinical experience with cancer patients indicates that psychostimulants promote a sense of well-being, decreased fatigue, and increased appetite. Psychostimulants are also helpful in countering the sedating effects of morphine, and compared with other antidepressants, their effect is rapidly produced. The side effects most commonly described with psychostimulants include insomnia, euphoria, and mood lability. High doses and long-term use may produce anorexia, nightmares, insomnia, euphoria, paranoia, and possible cardiac complications. These drugs (see Table 2 below) should be given in two divided doses at 8 a.m. and noon; they can be used as analgesic adjuvants and also to counter sedation by opiates. Methylphenidate and dextroamphetamine dosages are started at 2.5 to 5.0 mg at 8 a.m. and noon to avoid nighttime arousal. Modafinil is a centrally acting, nonamphetamine, central nervous system stimulant approved by the U.S. Food and Drug Administration for the treatment of narcolepsy. The exact mechanism of action is not known. Although not yet empirically studied for cancer-related fatigue or sedation (i.e., opioid-induced sedation), anecdotal experience has shown it to be useful for these problems. Modafinil is started at 50 to 100 mg in the morning and can be escalated to 200 mg by mouth every morning. In the fatigued cancer patient who also has depression, these medications may be started in conjunction with another nonstimulant antidepressant; discontinuation may be considered when the antidepressant takes effect.[7,8] Buproprion is a stimulating antidepressant with a primarily dopaminergic and noradrenergic mechanism of action. (Refer to the table on Antidepressant Medications for Ambulatory Adult Patients 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 buproprion has potential as an effective therapeutic agent for treating cancer-related fatigue with or without comorbid depressive symptoms.[9] Seizure, a rare but serious side effect of this agent, did not occur in this study (the maximum dose of buproprion SR used in this study was 300 mg).

On the basis of limited experience, it is reasonable to consider a psychostimulant such as methylphenidate or a corticosteroid for the treatment of severe fatigue. Long-term steroid therapy is generally reserved for patients with advanced disease.

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.[10]

Several large, community-based studies have examined the effectiveness of epoetin alfa in the treatment of cancer-related anemia in patients undergoing chemotherapy.[4,11,12] Each study 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. The dose employed in these studies was 10,000 units subcutaneously 3 times per week. Use of once-weekly dosing at 40,000 units has become common in both academic and community oncology settings.[13] If after 4 weeks the hemoglobin increases by less than 1 g/dL, the dose should be increased to 60,000 units every week. Treatment should be halted if hemoglobin rises above 12 g/dL or if the hemoglobin rises by more than 1.3 g/dL in any 2-week period. Excessive rise in hemoglobin level increases the risk of venous thromboembolism. Although baseline characteristics seem to have little value in predicting a patient’s response to recombinant human epoetin alfa treatment, serum ferritin levels early in treatment may be helpful. Retrospective studies of epoetin alfa treatment have suggested that patients with reduced baseline serum ferritin levels (<400 ng/mL) are likely to respond to treatment with epoetin alfa, while patients with baseline serum ferritin levels higher than 400 ng/mL may not respond.[14] One study retrospectively evaluated baseline characteristics among 2,289 patients to identify predictors of response to epoetin-alfa therapy. In this study, no differences were found among tumor types or if a patient had received prior chemotherapy.[11] Independent experts from two professional societies reviewed an extensive collection of evidence compiled by a national insurance company evaluation center and published guidelines.[15] Major aspects of these guidelines are summarized below:

• Evidence favors epoetin alfa use for chemotherapy-induced anemia (Hgb <10 g/dL). This recommendation is based on improvements in hemoglobin concentration (range, 1.6–3.1 g/dL) and lower transfusion requirements.



• Transfusion of red blood cells is also an option.



• For patients with multiple myeloma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia, the hematologic outcome should be observed before deciding to start epoetin alfa.



• Symptomatic improvement with epoetin alfa use has not been established and requires further study. The existing quality-of-life data have shown inconsistent results, variable methodologic quality, and dropout rates of 10% to 40%.

The U.S. Food and Drug Administration has reviewed information on the use of erythropoiesis-stimulating agents (ESAs) for chemotherapy-induced anemia in cancer patients and has revised the safety data. The agency has mandated the following label changes for the ESAs epoetin alfa and darbepoetin alfa:

• ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated treatment outcome is cure. ESAs are still indicated when myelosuppressive chemotherapy is intended for palliation.



• ESAs should not be initiated at hemoglobin levels ≥10 g/dL.

Preliminary studies [16-23]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). A novel, small study (n = 21) randomly assigned patients with prostate cancer to receive radiation therapy plus aerobic exercise 3 times per week for 8 weeks, versus a control group that received radiation therapy without exercise. Fatigue and other adjustment indicators improved substantially in the exercise group versus controls.[24] The majority of trials of exercise programs have focused on women with breast cancer, and the validity of generalizing the findings to other cancer sites is unknown. These studies have many methodologic difficulties, including selection biases and nonrepresentative samples, recruitment of patients into randomized trials, poor adherence to exercise interventions, and highly varied assessments of research variables and outcome measures.[25] Conclusions based on these studies must be considered preliminary. A study of patients undergoing peripheral blood stem cell transplantation found symptomatic benefits and improvements in mood for patients who participated in the interval-training program versus the control group.[26,27] Supervised aerobic group exercise provided functional and quality-of-life benefits for women during treatment for breast cancer.[28] Exercise improved function in patients treated for breast cancer.[29,30] 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 activites after cancer.[31]

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.[32] 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.[33]

Cognitive behavior therapy (CBT) has long been used to treat a variety of psychological 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.[34] The CBT focused on each participant's unique pattern of 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, and 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.

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.

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),[35] a shift in responsibility for control of side effects from the health care professional to the individual is important.[36] It is imperative that individuals with cancer are educated to develop the self-care abilities necessary to cope with 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.[37]

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.[38,39] These intriguing results need to be further explored in patient populations other than women with breast or gynecologic malignancies.

References

1. Gibson H, Edwards RH: Muscular exercise and fatigue. Sports Med 2 (2): 120-32, 1985 Mar-Apr.  [PUBMED Abstract]
   
   
2. Hart LK: Fatigue in the patient with multiple sclerosis. Res Nurs Health 1 (4): 147-57, 1978. 
   
   
3. Arendt J, Borbely AA, Franey C, et al.: The effects of chronic, small doses of melatonin given in the late afternoon on fatigue in man: a preliminary study. Neurosci Lett 45 (3): 317-21, 1984.  [PUBMED Abstract]
   
   
4. Glaspy J, Bukowski R, Steinberg D, et al.: Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol 15 (3): 1218-34, 1997.  [PUBMED Abstract]
   
   
5. Bruera E, Valero V, Driver L, et al.: Patient-controlled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol 24 (13): 2073-8, 2006.  [PUBMED Abstract]
   
   
6. Breitbart W, Passik S, Payne D: Psychological and psychiatric interventions in pain control. In: Doyle D, Hanks GW, MacDonald N, eds.: Oxford Textbook of Palliative Medicine. 2nd ed. New York, NY: Oxford University Press, 1998, pp 437-54. 
   
   
7. Feighner JP, Boyer WF: Perspectives in Psychiatry. Volume 1. Selective Serotonin Re-uptake Inhibitors: The Clinical Use of Citalopram, Fluoxetine, Fluvoxamine, Paroxetine, and Sertraline. New York, NY: John Wiley & Sons Ltd, 1991. 
   
   
8. Fernandez F, Adams F, Holmes VF, et al.: Methylphenidate for depressive disorders in cancer patients. An alternative to standard antidepressants. Psychosomatics 28 (9): 455-61, 1987.  [PUBMED Abstract]
   
   
9. Moss EL, Simpson JS, Pelletier G, et al.: An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners. Psychooncology 15 (3): 259-67, 2006.  [PUBMED Abstract]
   
   
10. Armitage JO: Management of anemia in patients with cancer. Clinical Oncology Updates 1: 1-12, 1998. 
    
    
11. Demetri GD, Kris M, Wade J, et al.: Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. Procrit Study Group. J Clin Oncol 16 (10): 3412-25, 1998.  [PUBMED Abstract]
    
    
12. Osterborg A, Brandberg Y, Molostova V, et al.: Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies. J Clin Oncol 20 (10): 2486-94, 2002.  [PUBMED Abstract]
    
    
13. Shasha D, George MJ, Harrison LB: Once-weekly dosing of epoetin-alpha increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concomitantly or sequentially with chemotherapy. Cancer 98 (5): 1072-9, 2003.  [PUBMED Abstract]
    
    
14. Glaspy J, Cavill I: Role of iron in optimizing responses of anemic cancer patients to erythropoietin. Oncology (Huntingt) 13 (4): 461-73; discussion 477-8, 483-8, 1999.  [PUBMED Abstract]
    
    
15. Rizzo JD, Lichtin AE, Woolf SH, et al.: Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 20 (19): 4083-107, 2002.  [PUBMED Abstract]
    
    
16. Friendenreich CM, Courneya KS: Exercise as rehabilitation for cancer patients. Clin J Sport Med 6 (4): 237-44, 1996.  [PUBMED Abstract]
    
    
17. Winningham ML: Walking program for people with cancer. Getting started. Cancer Nurs 14 (5): 270-6, 1991.  [PUBMED Abstract]
    
    
18. Segal R, Evans W, Johnson D, et al.: Structured exercise improves physical functioning in women with stages I and II breast cancer: results of a randomized controlled trial. J Clin Oncol 19 (3): 657-65, 2001.  [PUBMED Abstract]
    
    
19. Galvão DA, Newton RU: Review of exercise intervention studies in cancer patients. J Clin Oncol 23 (4): 899-909, 2005.  [PUBMED Abstract]
    
    
20. Courneya KS, Friedenreich CM, Sela RA, et al.: The group psychotherapy and home-based physical exercise (group-hope) trial in cancer survivors: physical fitness and quality of life outcomes. Psychooncology 12 (4): 357-74, 2003.  [PUBMED Abstract]
    
    
21. Mustian KM, Griggs JJ, Morrow GR, et al.: Exercise and side effects among 749 patients during and after treatment for cancer: a University of Rochester Cancer Center Community Clinical Oncology Program Study. Support Care Cancer 14 (7): 732-41, 2006.  [PUBMED Abstract]
    
    
22. Schneider CM, Hsieh CC, Sprod LK, et al.: Effects of supervised exercise training on cardiopulmonary function and fatigue in breast cancer survivors during and after treatment. Cancer 110 (4): 918-25, 2007.  [PUBMED Abstract]
    
    
23. Milne HM, Wallman KE, Gordon S, et al.: Effects of a combined aerobic and resistance exercise program in breast cancer survivors: a randomized controlled trial. Breast Cancer Res Treat 108 (2): 279-88, 2008.  [PUBMED Abstract]
    
    
24. Monga U, Garber SL, Thornby J, et al.: Exercise prevents fatigue and improves quality of life in prostate cancer patients undergoing radiotherapy. Arch Phys Med Rehabil 88 (11): 1416-22, 2007.  [PUBMED Abstract]
    
    
25. Pickett M, Mock V, Ropka ME, et al.: Adherence to moderate-intensity exercise during breast cancer therapy. Cancer Pract 10 (6): 284-92, 2002 Nov-Dec.  [PUBMED Abstract]
    
    
26. Dimeo FC, Stieglitz RD, Novelli-Fischer U, et al.: Effects of physical activity on the fatigue and psychologic status of cancer patients during chemotherapy. Cancer 85 (10): 2273-7, 1999.  [PUBMED Abstract]
    
    
27. Mock V, Pickett M, Ropka ME, et al.: Fatigue and quality of life outcomes of exercise during cancer treatment. Cancer Pract 9 (3): 119-27, 2001 May-Jun.  [PUBMED Abstract]
    
    
28. Mutrie N, Campbell AM, Whyte F, et al.: Benefits of supervised group exercise programme for women being treated for early stage breast cancer: pragmatic randomised controlled trial. BMJ 334 (7592): 517, 2007.  [PUBMED Abstract]
    
    
29. Matthews CE, Wilcox S, Hanby CL, et al.: Evaluation of a 12-week home-based walking intervention for breast cancer survivors. Support Care Cancer 15 (2): 203-11, 2007.  [PUBMED Abstract]
    
    
30. Daley AJ, Crank H, Saxton JM, et al.: Randomized trial of exercise therapy in women treated for breast cancer. J Clin Oncol 25 (13): 1713-21, 2007.  [PUBMED Abstract]
    
    
31. Alfano CM, Smith AW, Irwin ML, et al.: Physical activity, long-term symptoms, and physical health-related quality of life among breast cancer survivors: a prospective analysis. J Cancer Surviv 1 (2): 116-28, 2007.  [PUBMED Abstract]
    
    
32. Yoshioka H: Rehabilitation for the terminal cancer patient. Am J Phys Med Rehabil 73 (3): 199-206, 1994.  [PUBMED Abstract]
    
    
33. Mock V, Frangakis C, Davidson NE, et al.: Exercise manages fatigue during breast cancer treatment: a randomized controlled trial. Psychooncology 14 (6): 464-77, 2005.  [PUBMED Abstract]
    
    
34. Gielissen MF, Verhagen S, Witjes F, et al.: Effects of cognitive behavior therapy in severely fatigued disease-free cancer patients compared with patients waiting for cognitive behavior therapy: a randomized controlled trial. J Clin Oncol 24 (30): 4882-7, 2006.  [PUBMED Abstract]
    
    
35. Nail LM, Jones LS, Greene D, et al.: Use and perceived efficacy of self-care activities in patients receiving chemotherapy. Oncol Nurs Forum 18 (5): 883-7, 1991.  [PUBMED Abstract]
    
    
36. Dy SM, Lorenz KA, Naeim A, et al.: Evidence-based recommendations for cancer fatigue, anorexia, depression, and dyspnea. J Clin Oncol 26 (23): 3886-95, 2008.  [PUBMED Abstract]
    
    
37. Winningham ML, Nail LM, Burke MB, et al.: Fatigue and the cancer experience: the state of the knowledge. Oncol Nurs Forum 21 (1): 23-36, 1994 Jan-Feb.  [PUBMED Abstract]
    
    
38. Given B, Given CW, McCorkle R, et al.: Pain and fatigue management: results of a nursing randomized clinical trial. Oncol Nurs Forum 29 (6): 949-56, 2002.  [PUBMED Abstract]
    
    
39. Ream E, Richardson A, Alexander-Dann C: Supportive intervention for fatigue in patients undergoing chemotherapy: a randomized controlled trial. J Pain Symptom Manage 31 (2): 148-61, 2006.  [PUBMED Abstract]
    
    

Back to Top

< Previous Section  |  Next Section >