Purpose of This PDQ Summary
Overview
Pathogenesis of Fatigue
Contributing Factors

Cancer Treatment Anemia Nutrition Factors Psychologic Factors Cognitive Factors Sleep Disorders and Inactivity Medications

Assessment

Evaluation of Anemia

Intervention

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

Posttreatment Considerations
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Changes to This Summary (04/22/2009)
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Purpose of This PDQ Summary

This PDQ cancer information summary provides comprehensive, peer-reviewed information for health professionals about the pathophysiology and treatment of fatigue. This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board ¹.

Information about the following is included in this summary:

• Etiology.
• Assessment.
• Management.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for cancer patients during and after cancer treatment. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version ², which is written in less technical language, and in Spanish ³.

Overview

Fatigue is the most common side effect of cancer treatment with chemotherapy, radiation therapy, or selected biologic response modifiers. Cancer treatment–related fatigue generally improves after treatment is completed, but some level of fatigue may persist for months or years following treatment. Fatigue is also seen as a presenting symptom in cancers that produce problems such as anemia, endocrine changes, and respiratory obstruction and is common in people with advanced cancer who are not receiving active cancer treatment. Most of the research on fatigue in people with cancer has been conducted on samples of people undergoing cancer treatment, with a few studies focused on people receiving palliative care for terminal cancer and some research on samples of people after treatment is completed. Cancer treatment–related fatigue is reported in 14% to 96% of people undergoing cancer treatment.[1-7]

Fatigue, like pain, is viewed as a self-perceived state. Patients may describe fatigue as feeling tired, weak, exhausted, lazy, weary, worn-out, heavy, slow, or like they do not have any energy or any get-up-and-go. Health professionals have included fatigue within concepts such as asthenia, lassitude, malaise, prostration, exercise intolerance, lack of energy, and weakness. The research on fatigue in people with cancer focuses on fatigue as a self-preceived state; objective tests of variables such as muscle weakness, exercise performance, speed of task performance, and total daily movement have not been examined in relation to the sensation of fatigue.

The fatigue experienced as a side effect of cancer treatment is differentiated from the 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 and is not completely relieved by sleep and rest. Although the label chronic fatigue is accurate, using this label does not mean that people with cancer who experience fatigue have chronic fatigue syndrome. Using the phrase chronic fatigue 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 has a negative impact on all areas of function, including mood, physical function, work performance, social interaction, family care,[8] cognitive performance, school work, community activities, and sense of self.[9-12] The pattern of fatigue associated with cancer treatment varies according to type and schedule of treatment. For example, people treated with cyclic chemotherapy regimens generally exhibit peak fatigue in the days following treatment, then report lower levels of fatigue until the next treatment; however, those receiving external beam radiation therapy report gradually increasing fatigue over the course of treatment of the largest treatment field. Few studies of people receiving 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 that 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.[13,14]

Fatigue assessment in clinical practice takes many forms, most relying on a single-item fatigue intensity rating similar to that used for initial pain assessment. A number of multiple-item tools originally developed for fatigue research have also been used in clinical practice. Most of these tools include symptom dimensions other than fatigue intensity, such as the impact or consequences of fatigue, timing of fatigue, related symptoms, and self-care actions.[15-21] Basic recommendations for fatigue assessment in clinical practice include the following:

• Assessment should include self-report of fatigue intensity.



• The timeframe for the rating should have relevance to a patient’s current treatment status and the likely timing of fatigue if that patient is receiving treatment.



• The same approach to assessment should be used at each assessment point to detect changes in fatigue over time.

Recommendations for fatigue management focus on identifying factors that may be contributing to fatigue. Because the only causal mechanism demonstrated through research is chemotherapy-induced anemia, most clinical recommendations for managing fatigue caused by something other than chemotherapy-induced anemia rely on careful development of clinical hypotheses, as outlined in the National Comprehensive Cancer Network guidelines on fatigue.[22]

References

1. Fosså SD, Dahl AA, Loge JH: Fatigue, anxiety, and depression in long-term survivors of testicular cancer. J Clin Oncol 21 (7): 1249-54, 2003.  [PUBMED Abstract]
   
   
2. Miaskowski C, Portenoy RK: Update on the assessment and management of cancer-related fatigue. Principles and Practice of Supportive Oncology Updates 1 (2): 1-10, 1998. 
   
   
3. Irvine DM, Vincent L, Bubela N, et al.: A critical appraisal of the research literature investigating fatigue in the individual with cancer. Cancer Nurs 14 (4): 188-99, 1991.  [PUBMED Abstract]
   
   
4. Vogelzang NJ, Breitbart W, Cella D, et al.: Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. The Fatigue Coalition. Semin Hematol 34 (3 Suppl 2): 4-12, 1997.  [PUBMED Abstract]
   
   
5. Detmar SB, Aaronson NK, Wever LD, et al.: How are you feeling? Who wants to know? Patients' and oncologists' preferences for discussing health-related quality-of-life issues. J Clin Oncol 18 (18): 3295-301, 2000.  [PUBMED Abstract]
   
   
6. Costantini M, Mencaglia E, Giulio PD, et al.: Cancer patients as 'experts' in defining quality of life domains. A multicentre survey by the Italian Group for the Evaluation of Outcomes in Oncology (IGEO). Qual Life Res 9 (2): 151-9, 2000.  [PUBMED Abstract]
   
   
7. Cella D, Lai JS, Chang CH, et al.: Fatigue in cancer patients compared with fatigue in the general United States population. Cancer 94 (2): 528-38, 2002.  [PUBMED Abstract]
   
   
8. Passik SD, Kirsh KL: A pilot examination of the impact of cancer patients' fatigue on their spousal caregivers. Palliat Support Care 3 (4): 273-9, 2005.  [PUBMED Abstract]
   
   
9. Pickard-Holley S: Fatigue in cancer patients. A descriptive study. Cancer Nurs 14 (1): 13-9, 1991.  [PUBMED Abstract]
   
   
10. Glaus A: Assessment of fatigue in cancer and non-cancer patients and in healthy individuals. Support Care Cancer 1 (6): 305-15, 1993.  [PUBMED Abstract]
    
    
11. 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]
    
    
12. Curt GA: The impact of fatigue on patients with cancer: overview of FATIGUE 1 and 2. Oncologist 5 (Suppl 2): 9-12, 2000.  [PUBMED Abstract]
    
    
13. Ancoli-Israel S, Liu L, Marler MR, et al.: Fatigue, sleep, and circadian rhythms prior to chemotherapy for breast cancer. Support Care Cancer 14 (3): 201-9, 2006.  [PUBMED Abstract]
    
    
14. Jacobsen PB, Hann DM, Azzarello LM, et al.: Fatigue in women receiving adjuvant chemotherapy for breast cancer: characteristics, course, and correlates. J Pain Symptom Manage 18 (4): 233-42, 1999.  [PUBMED Abstract]
    
    
15. Yellen SB, Cella DF, Webster K, et al.: Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 13 (2): 63-74, 1997.  [PUBMED Abstract]
    
    
16. Piper BF, Dibble SL, Dodd MJ, et al.: The revised Piper Fatigue Scale: psychometric evaluation in women with breast cancer. Oncol Nurs Forum 25 (4): 677-84, 1998.  [PUBMED Abstract]
    
    
17. Schwartz AL: The Schwartz Cancer Fatigue Scale: testing reliability and validity. Oncol Nurs Forum 25 (4): 711-7, 1998.  [PUBMED Abstract]
    
    
18. Hann DM, Jacobsen PB, Azzarello LM, et al.: Measurement of fatigue in cancer patients: development and validation of the Fatigue Symptom Inventory. Qual Life Res 7 (4): 301-10, 1998.  [PUBMED Abstract]
    
    
19. Aaronson LS, Teel CS, Cassmeyer V, et al.: Defining and measuring fatigue. Image J Nurs Sch 31 (1): 45-50, 1999.  [PUBMED Abstract]
    
    
20. Mendoza TR, Wang XS, Cleeland CS, et al.: The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer 85 (5): 1186-96, 1999.  [PUBMED Abstract]
    
    
21. Okuyama T, Akechi T, Kugaya A, et al.: Development and validation of the cancer fatigue scale: a brief, three-dimensional, self-rating scale for assessment of fatigue in cancer patients. J Pain Symptom Manage 19 (1): 5-14, 2000.  [PUBMED Abstract]
    
    
22. National Comprehensive Cancer Network.: NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue. Version 1.2008. Rockledge, Pa: National Comprehensive Cancer Network, 2008. Available online ⁴. Last accessed May 7, 2009. 
    
    

Pathogenesis of Fatigue

Except for chemotherapy-induced anemia, the mechanisms responsible for fatigue in people with cancer are not known. Understanding the causes of fatigue in people with cancer is especially challenging because each individual is likely to experience multiple possible causes of fatigue simultaneously. This multifactorial etiologic hypothesis is apparent in the various models that have been proposed for the study of fatigue.[1,2] Energy balance, stress, life demands, sleep, neurophysiologic changes, disruption of circadian rhythms, and neuroimmunologic changes are generally incorporated in these models, based on the rationale that these factors are associated with fatigue in contexts other than cancer.[3]The cancer literature supports some of these variables. Sleep disruption was associated with fatigue in women receiving adjuvant chemotherapy for breast cancer, one study demonstrated variations in energy requirements in people with cancer, and proinflammatory cytokines are elevated in some studies of people experiencing persistent fatigue following cancer treatment.[4,5] In addition, concurrent medications such as analgesics, hypnotics, antidepressants, antiemetics, steroids, or anticonvulsants, many of which act on the central nervous system, can significantly compound the problem of fatigue.

References

1. Miaskowski C, Portenoy RK: Update on the assessment and management of cancer-related fatigue. Principles and Practice of Supportive Oncology Updates 1 (2): 1-10, 1998. 
   
   
2. Morrow GR, Andrews PL, Hickok JT, et al.: Fatigue associated with cancer and its treatment. Support Care Cancer 10 (5): 389-98, 2002.  [PUBMED Abstract]
   
   
3. Aistars J: Fatigue in the cancer patient: a conceptual approach to a clinical problem. Oncol Nurs Forum 14 (6): 25-30, 1987 Nov-Dec.  [PUBMED Abstract]
   
   
4. Kaempfer SH, Lindsey AM: Energy expenditure in cancer: a review. Cancer Nurs 9 (4): 194-199, 1986. 
   
   
5. Ancoli-Israel S, Liu L, Marler MR, et al.: Fatigue, sleep, and circadian rhythms prior to chemotherapy for breast cancer. Support Care Cancer 14 (3): 201-9, 2006.  [PUBMED Abstract]
   
   

Contributing Factors

Although fatigue is clearly prevalent in patients with cancer, it has been difficult to identify consistent correlates of fatigue in this patient population. The factors most often implicated have been the following:[1-9]

• Cancer treatment.
• Anemia.
• Medications.
• Cachexia/anorexia.
• Metabolic disturbances.
• Hormone deficiency or excess.
• Psychological distress.
• Physical deconditioning.
• Sleep disturbances.
• Excessive inactivity.
• Pulmonary impairment.
• Neuromuscular dysfunction.
• Pain and other symptoms.
• Proinflammatory cytokines.
• Nutritional deficiencies.
• Dehydration.
• Infection.
• Concomitant medical illness.

The association of fatigue with the major cancer treatment modalities of surgery, chemotherapy, radiation therapy, and biologic response modifier therapy caused speculation that fatigue resulted from tissue damage or accumulation of the products of cell death. Interest in the effects of cancer treatment on the production of proinflammatory cytokines is based on recognition of the strong fatigue-inducing effect of some biologic response modifiers such as interferon alfa and the finding of elevated levels of proinflammatory cytokines in people experiencing persistent fatigue following cancer treatment.[10,11]

Fatigue has long been associated with radiation exposure. The phenomenon of fatigue accompanying radiation therapy, however, is not well understood.[12] A number of research studies document the existence of a fatigue syndrome that is not specific to the disease type or to the radiation site, and that demonstrates a gradual decline in fatigue in the patient after treatment is completed.[13-17] Some of these studies suggest, however, that not all patients return to pretreatment energy levels. Specific etiologic factors and correlates of fatigue associated with radiation therapy have not been identified.[12] Risk factors for persistent low energy in cancer patients include older age, advanced disease, and combination-modality therapy.[18]

Fatigue is a dose-limiting toxicity of treatment with a variety of biotherapeutic agents. Biotherapy exposes patients with cancer to exogenous and endogenous cytokines.[19] Biotherapy-related fatigue usually occurs as part of a constellation of symptoms called flulike syndrome. This syndrome includes fatigue, fever, chills, myalgias, headache, and malaise.[20] Mental fatigue and cognitive deficits have also been identified as biotherapy side effects.[21] The type of biotherapeutic agent used may influence the type and pattern of fatigue experienced.

Many people with cancer undergo surgery for diagnosis or treatment. Despite the high incidence of postoperative fatigue observed in clinical practice, little research exists that examines causes and correlates of postoperative fatigue in people with cancer.[12] It is clear, however, that fatigue is a problem following surgery that improves with time and is compounded by fatigue experienced from other cancer treatments.[12]

Evidence suggests that anemia may be a major factor in cancer-related fatigue (CRF) and quality of life in cancer patients.[22-24] Anemia can be related to the disease itself or caused by the therapy. Occasionally, anemia is simply a co-occurring medical finding that is related to neither the disease nor the therapy. Anemia is often a significant contributor to symptoms in persons with cancer. For individual patients, it can be difficult to discern the actual impact of anemia, for there are often other problems that confound the ability to weigh the specific impact of anemia. The impact of anemia varies depending on factors such as the rapidity of onset, patient age, plasma-volume status, and the number and severity of comorbidities.[25] A retrospective review was conducted to understand the problem of anemia in patients receiving radiation therapy. Anemia was prevalent in 48% of the patients initially, and increased to 57% of the patients during therapy. It was more common in women than men (64% vs. 51%); however, men with prostate cancer experienced the greatest increase in anemia during radiation therapy.[26] In certain cancers, such as cancer of the cervix and cancer of the head and neck, anemia has been found to be a predictor of poor survival and diminished quality of life in patients undergoing radiation therapy.[27-30]

Fatigue often occurs when the energy requirements of the body exceed the supply of energy sources.[31,32] In people with cancer, three major mechanisms may be involved: alteration in the body’s ability to process nutrients efficiently, increase in the body’s energy requirements, and decrease in intake of energy sources. Causes of nutritional alterations are listed in Table 1.

Numerous factors related to the moods, beliefs, attitudes, and reactions to stressors of people with cancer are thought to contribute to the development of chronic fatigue. Nonorganic causes comprise approximately 40% to 60% of the cases of fatigue in general medical populations, with anxiety and depression being the most common psychiatric disorders.[33]

Depression can be a comorbid, disabling syndrome that affects approximately 15% to 25% of persons with cancer.[34] The presence of depression, as manifested by loss of interest, difficulty concentrating, lethargy, and feelings of hopelessness, can compound the physical causes for fatigue in these individuals and persist long past the time when physical causes have resolved.[35] Anxiety and fear associated with a cancer diagnosis, as well as its impact on the person’s physical, psychosocial, and financial well-being, are sources of emotional stress. Distress associated with the diagnosis of cancer alone may trigger fatigue. A study of 74 early-stage breast cancer patients with no history of affective disorder, assessed various symptoms of adjustment approximately 2 weeks after diagnosis; about 45% noted moderate or high levels of fatigue. This fatigue may have been secondary to the increased cognitive strain of dealing with the diagnosis or to insomnia, reported as moderate-to-severe by about 60% of the patients. Fatigue may, therefore, begin before treatment as a result of worry or other cognitive factors, both primary and secondary to insomnia. Various forms of treatment may compound this fatigue.[36] Fatigue may also be increased in cancer survivors above that seen in the general population.[37,38] In testicular cancer survivors, anxiety and depression were predictive of fatigue, suggesting a possible role for psychiatric intervention in fatigue management.[39] (Refer to the PDQ summaries on Depression ⁶ and Anxiety Disorder ⁷ for more information.)

Impairment in cognitive functioning, including decreased attention span and impaired perception and thinking, is commonly associated with fatigue.[40,41] Although fatigue and cognitive impairments are linked, the mechanism underlying this association is unclear. Mental demands inherent in the diagnosis and treatment of cancer have been well documented, but little is known about the concomitant problem of attention fatigue in people with cancer. Attention problems are common during and after cancer treatment. Some of the reported attention problems may be caused by the fatigue of directed attention.[42,43] Attention fatigue may be relieved by activities that promote rest and recovery of directed attention. Although sleep is necessary for relieving attention fatigue and restoring attention, it is insufficient when attention demands are high. Empirical literature suggests that the natural environment contains the properties for restoring directed attention and relieving attention fatigue.

Disrupted sleep, poor sleep hygiene, decreased nighttime sleep or excessive daytime sleep, and inactivity may be causative or contributing factors in CRF. Patients with less daytime activity and more nighttime awakenings were noted to consistently report higher levels of CRF. Those with lower peak-activity scores, as measured by wristwatch activity monitors, experienced higher levels of fatigue.[6]

Medications other than chemotherapy may contribute to the overall sense of fatigue. Opioids used in the treatment of cancer-related pain are often associated with sedation, though the degree of sedation varies between individuals. Other medications including tricyclic antidepressants, neuroleptics, beta blockers, benzodiazepines, and antihistamines may produce side effects of sedation. The coadministration of multiple drugs with varying side effects may compound fatigue symptoms.

References

1. Blesch KS, Paice JA, Wickham R, et al.: Correlates of fatigue in people with breast or lung cancer. Oncol Nurs Forum 18 (1): 81-7, 1991 Jan-Feb.  [PUBMED Abstract]
   
   
2. Groopman JE: Fatigue in cancer and HIV/AIDS. Oncology (Huntingt) 12 (3): 335-44; discussion 345-6, 351, 1998.  [PUBMED Abstract]
   
   
3. Irvine DM, Vincent L, Bubela N, et al.: A critical appraisal of the research literature investigating fatigue in the individual with cancer. Cancer Nurs 14 (4): 188-99, 1991.  [PUBMED Abstract]
   
   
4. Hickok JT, Morrow GR, McDonald S, et al.: Frequency and correlates of fatigue in lung cancer patients receiving radiation therapy: implications for management. J Pain Symptom Manage 11 (6): 370-7, 1996.  [PUBMED Abstract]
   
   
5. Von Hoff D: Asthenia: incidence, etiology, pathophysiology, and treatment. Cancer Therapeutics 1: 184-197, 1998. 
   
   
6. Berger AM, Farr L: The influence of daytime inactivity and nighttime restlessness on cancer-related fatigue. Oncol Nurs Forum 26 (10): 1663-71, 1999 Nov-Dec.  [PUBMED Abstract]
   
   
7. Engstrom CA, Strohl RA, Rose L, et al.: Sleep alterations in cancer patients. Cancer Nurs 22 (2): 143-8, 1999.  [PUBMED Abstract]
   
   
8. Dimsdale JE, Ancoli-Israel S, Ayalon L, et al.: Taking fatigue seriously, II: variability in fatigue levels in cancer patients. Psychosomatics 48 (3): 247-52, 2007 May-Jun.  [PUBMED Abstract]
   
   
9. Jacobsen PB, Donovan KA, Small BJ, et al.: Fatigue after treatment for early stage breast cancer: a controlled comparison. Cancer 110 (8): 1851-9, 2007.  [PUBMED Abstract]
   
   
10. Collado-Hidalgo A, Bower JE, Ganz PA, et al.: Inflammatory biomarkers for persistent fatigue in breast cancer survivors. Clin Cancer Res 12 (9): 2759-66, 2006.  [PUBMED Abstract]
    
    
11. Wood LJ, Nail LM, Gilster A, et al.: Cancer chemotherapy-related symptoms: evidence to suggest a role for proinflammatory cytokines. Oncol Nurs Forum 33 (3): 535-42, 2006.  [PUBMED Abstract]
    
    
12. 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]
    
    
13. Haylock PJ, Hart LK: Fatigue in patients receiving localized radiation. Cancer Nurs 2 (6): 461-7, 1979.  [PUBMED Abstract]
    
    
14. King KB, Nail LM, Kreamer K, et al.: Patients' descriptions of the experience of receiving radiation therapy. Oncol Nurs Forum 12 (4): 55-61, 1985 Jul-Aug.  [PUBMED Abstract]
    
    
15. Greenberg DB, Sawicka J, Eisenthal S, et al.: Fatigue syndrome due to localized radiation. J Pain Symptom Manage 7 (1): 38-45, 1992.  [PUBMED Abstract]
    
    
16. Nail LM: Coping with intracavitary radiation treatment for gynecologic cancer. Cancer Pract 1 (3): 218-24, 1993. 
    
    
17. Larson PJ, Lindsey AM, Dodd MJ, et al.: Influence of age on problems experienced by patients with lung cancer undergoing radiation therapy. Oncol Nurs Forum 20 (3): 473-80, 1993.  [PUBMED Abstract]
    
    
18. Fobair P, Hoppe RT, Bloom J, et al.: Psychosocial problems among survivors of Hodgkin's disease. J Clin Oncol 4 (5): 805-14, 1986.  [PUBMED Abstract]
    
    
19. Piper BF, Rieger PT, Brophy L, et al.: Recent advances in the management of biotherapy-related side effects: fatigue. Oncol Nurs Forum 16 (6 Suppl): 27-34, 1989 Nov-Dec.  [PUBMED Abstract]
    
    
20. Haeuber D: Recent advances in the management of biotherapy-related side effects: flu-like syndrome. Oncol Nurs Forum 16 (6 Suppl): 35-41, 1989 Nov-Dec.  [PUBMED Abstract]
    
    
21. Mattson K, Niiranen A, Iivanainen M, et al.: Neurotoxicity of interferon. Cancer Treat Rep 67 (10): 958-61, 1983.  [PUBMED Abstract]
    
    
22. 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]
    
    
23. Vogelzang NJ, Breitbart W, Cella D, et al.: Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. The Fatigue Coalition. Semin Hematol 34 (3 Suppl 2): 4-12, 1997.  [PUBMED Abstract]
    
    
24. 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]
    
    
25. Johnston E, Crawford J: The hematologic support of the cancer patient. In: Berger A, Portenoy RK, Weissman DE, eds.: Principles and Practice of Supportive Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 1998, pp 549-69. 
    
    
26. Bush RS: The significance of anemia in clinical radiation therapy. Int J Radiat Oncol Biol Phys 12 (11): 2047-50, 1986.  [PUBMED Abstract]
    
    
27. Fein DA, Lee WR, Hanlon AL, et al.: Pretreatment hemoglobin level influences local control and survival of T1-T2 squamous cell carcinomas of the glottic larynx. J Clin Oncol 13 (8): 2077-83, 1995.  [PUBMED Abstract]
    
    
28. Girinski T, Pejovic-Lenfant MH, Bourhis J, et al.: Prognostic value of hemoglobin concentrations and blood transfusions in advanced carcinoma of the cervix treated by radiation therapy: results of a retrospective study of 386 patients. Int J Radiat Oncol Biol Phys 16 (1): 37-42, 1989.  [PUBMED Abstract]
    
    
29. Dubray B, Mosseri V, Brunin F, et al.: Anemia is associated with lower local-regional control and survival after radiation therapy for head and neck cancer: a prospective study. Radiology 201 (2): 553-8, 1996.  [PUBMED Abstract]
    
    
30. Dunst J: Hemoglobin level and anemia in radiation oncology: prognostic impact and therapeutic implications. Semin Oncol 27 (2 Suppl 4): 4-8; discussion 16-7, 2000.  [PUBMED Abstract]
    
    
31. Watanabe S, Bruera E: Anorexia and cachexia, asthenia, and lethargy. Hematol Oncol Clin North Am 10 (1): 189-206, 1996.  [PUBMED Abstract]
    
    
32. MacDonald N, Alexander HR, Bruera E: Cachexia-anorexia-asthenia. J Pain Symptom Manage 10 (2): 151-5, 1995.  [PUBMED Abstract]
    
    
33. Reich SG: The tired patient: psychological versus organic causes. Hosp Med 22 (7): 142-54, 1986. 
    
    
34. Henriksson MM, Isometsä ET, Hietanen PS, et al.: Mental disorders in cancer suicides. J Affect Disord 36 (1-2): 11-20, 1995.  [PUBMED Abstract]
    
    
35. Cella D, Davis K, Breitbart W, et al.: Cancer-related fatigue: prevalence of proposed diagnostic criteria in a United States sample of cancer survivors. J Clin Oncol 19 (14): 3385-91, 2001.  [PUBMED Abstract]
    
    
36. Cimprich B: Pretreatment symptom distress in women newly diagnosed with breast cancer. Cancer Nurs 22 (3): 185-94; quiz 195, 1999.  [PUBMED Abstract]
    
    
37. Sugawara Y, Akechi T, Okuyama T, et al.: Occurrence of fatigue and associated factors in disease-free breast cancer patients without depression. Support Care Cancer 13 (8): 628-36, 2005.  [PUBMED Abstract]
    
    
38. Bower JE, Ganz PA, Desmond KA, et al.: Fatigue in long-term breast carcinoma survivors: a longitudinal investigation. Cancer 106 (4): 751-8, 2006.  [PUBMED Abstract]
    
    
39. Fosså SD, Dahl AA, Loge JH: Fatigue, anxiety, and depression in long-term survivors of testicular cancer. J Clin Oncol 21 (7): 1249-54, 2003.  [PUBMED Abstract]
    
    
40. Rhodes VA, Watson PM, Hanson BM: Patients' descriptions of the influence of tiredness and weakness on self-care abilities. Cancer Nurs 11 (3): 186-94, 1988.  [PUBMED Abstract]
    
    
41. Fan HG, Houédé-Tchen N, Yi QL, et al.: Fatigue, menopausal symptoms, and cognitive function in women after adjuvant chemotherapy for breast cancer: 1- and 2-year follow-up of a prospective controlled study. J Clin Oncol 23 (31): 8025-32, 2005.  [PUBMED Abstract]
    
    
42. Holmes S: Preliminary investigations of symptom distress in two cancer patient populations: evaluation of a measurement instrument. J Adv Nurs 16 (4): 439-46, 1991.  [PUBMED Abstract]
    
    
43. Oberst MT, James RH: Going home: patient and spouse adjustment following cancer surgery. Top Clin Nurs 7 (1): 46-57, 1985.  [PUBMED Abstract]
    
    

Assessment

Assessment of fatigue is multidimensional in nature.[1] Ambiguous literature and a previous lack of specific tools to measure fatigue have created difficulties in establishing assessment and management guidelines. Comprehensive assessment of the fatigued patient starts with obtaining a careful history to characterize the individual’s fatigue pattern and to identify all factors that contribute to its development. The following should be included in the initial assessment:

• Fatigue pattern, including onset, duration, and intensity, as well as aggravating and alleviating factors.
• Type and degree of disease and of treatment-related symptoms and/or side effects.
• Treatment history.
• Current medications.
• Sleep and/or rest patterns, relaxation habits, customs, and rituals.
• Nutrition intake and any appetite or weight changes.
• Effects of fatigue on activities of daily living and lifestyle.
• Psychiatric evaluation, including evaluation for depression.
• Complete physical examination, including gait, posture, and range of motion.
• Compliance with treatment.
• Job performance.
• Financial resources.
• Other contributing factors (e.g., anemia, dyspnea, muscle wasting).

Specific attention should be paid to underlying factors that contribute to fatigue and may be correctable. These include anemia, depression, anxiety, pain, dehydration, nutritional deficiencies (e.g., protein, calories, vitamins), sedating medications (e.g., opioids, benzodiazepines), neurotoxic therapies, infection, fever, sleep disturbances, or immobility.[2,3]

Proposed criteria for cancer-related fatigue are listed below. These criteria have been adopted for inclusion in the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Clinical Modification (ICD-10-CM).[4] Defining cancer-related fatigue as a diagnostic syndrome has some potential advantages and disadvantages.[5] One of the possible advantages is that it would enable clinicians to document the presence or absence of fatigue in a reproducible fashion. It may also be useful in establishing appropriate reimbursement for management of this finding. The potential disadvantage of this approach is that it may deter management of fatigue that does not reach the threshold for ICD-10 diagnosis. The alternative to the syndrome-based approach is a symptom-based approach. The symptom-based approach is commonly used for phenomena such as pain and nausea. The syndrome-based approach is commonly used for depression. The utility of the ICD-10 criteria for cancer-related fatigue below has not been validated.

ICD-10 Criteria for Cancer-Related Fatigue

The following symptoms have been present every day or nearly every day during the same 2-week period in the past month:

1. Significant fatigue, diminished energy, or increased need to rest, disproportionate to any recent change in activity level, plus five or more of the following:
   1. Complaints of generalized weakness, limb heaviness.
   
   
   
   2. Diminished concentration or attention.
   
   
   
   3. Decreased motivation or interest to engage in usual activities.
   
   
   
   4. Insomnia or hypersomnia.
   
   
   
   5. Experience of sleep as unrefreshing or nonrestorative.
   
   
   
   6. Perceived need to struggle to overcome inactivity.
   
   
   
   7. Marked emotional reactivity (e.g., sadness, frustration, or irritability) to feeling fatigued.
   
   
   
   8. Difficulty completing daily tasks attributed to feeling fatigued.
   
   
   
   9. Perceived problems with short-term memory.
   
   
   
   10. Postexertional fatigue lasting several hours.
   
   
   



2. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.



3. There is evidence from the history, physical examination, or laboratory findings that the symptoms are a consequence of cancer or cancer therapy.



4. The symptoms are not primarily a consequence of comorbid psychiatric disorders such as major depression, somatization disorder, somatoform disorder, or delirium.

As with other purely subjective symptoms such as pain, it may be necessary to encourage the patient and other family members to report symptoms of fatigue to the medical staff. Information regarding the potential for fatigue due to the underlying disease or treatments, possible options for management, and the importance of reporting these symptoms should be given to all patients at the initiation of treatment.[2] Patients may not mention the fatigue they experience, unless prompted by a health professional. Several barriers hamper appropriate management of cancer-related fatigue. Some of these barriers were identified in phase 1 of an ongoing three-phase project related to the implementation of evidence-based (National Comprehensive Cancer Network) guidelines for fatigue management.[6] The most commonly identified barriers were the patient’s belief that the physician would introduce the subject of fatigue if it was important (patient barrier); lack of fatigue documentation (professional barrier); and lack of supportive care referrals (system barrier).[6,7]

Although there is no universally accepted standard for the measurement of fatigue, there are a variety of instruments that have been developed to assess fatigue.[8-16] Fatigue is also commonly assessed in multidimensional quality-of-life instruments. Selected instruments for assessing fatigue are listed below.

• Brief Fatigue Inventory.[14]



• The Functional Assessment of Cancer Therapy-Anemia.[8]



• The Functional Assessment of Cancer Therapy-Fatigue.[9]



• Piper Fatigue Self-Report Scale.[10]



• The Schwartz Cancer Fatigue Scale.[11]



• Fatigue Symptom Inventory.[16]



• The Profile of Mood States Fatigue/Inertia Subscale.[12]



• Lee’s Visual Analogue Scale for Fatigue.[13]



• Cancer Fatigue Scale.[15]

One study of ambulatory outpatients with solid tumors (N = 148) evaluated the usefulness of single-item screening for symptoms such as fatigue and pain.[17] Investigators found that the single-item assessment can assist as a first screening step to identify patients requiring comprehensive assessment of the symptoms. Patients identified using the single-item screens should undergo comprehensive assessments to detect clinically relevant symptomatology.[17,18]

The proper evaluation of anemia in cancer patients includes a careful history and physical examination, an evaluation of the complete blood count and red blood cell indices, and examination of the peripheral blood smear. In combination, the information from these investigations is often diagnostic.

One commonly used method for classifying anemia is to categorize the anemia by the size of the red blood cell as measured by the mean corpuscular volume (MCV). Microcytic anemias are associated with an MCV of 79 femtoliters or lower and include iron-deficiency anemia, thalassemia, and anemia of chronic disease. Macrocytic anemias are associated with an MCV higher than 101 femtoliters and include anemias related to vitamin B₁₂ or folate deficiency, myelodysplasia, and liver disease. Most anemias are normocytic, meaning that the MCV is in the normal range. This category includes myelophthisic anemia (i.e., anemia due to neoplastic replacement of the bone marrow), most chemotherapy-related anemias, anemia due to renal or hepatic dysfunction, hemolytic anemia, and aplastic anemia.[19] A mixed red blood cell population consisting of both microcytic and macrocytic cells (anisocytosis), however, may indicate a combined etiology, for example, chronic blood loss (microcytic) with resultant reticulocytosis (macrocytic). In this situation, the MCV may be in the normal range, but the red cell size distribution width would be elevated.

The peripheral blood smear examination, though often overlooked, remains an important step in the evaluation of anemia. For example, nucleated blood cells and teardrop-shaped red blood cells suggest myelophthisic anemia. Macro-ovalocytes and hypersegmented neutrophils often indicate megaloblastic anemia. Small target cells and basophilic stippling are associated with thalassemia.

Additional studies that are sometimes required to characterize anemia in a given patient include testing of vitamin B₁₂ or folate levels; serum iron, transferrin, and ferritin levels; erythropoietin level, the direct and indirect Coombs test, and/or examination of a bone marrow aspirate and biopsy. In cancer patients, the underlying etiology is often multifactorial.

References

1. Portenoy RK, Miaskowski C: Assessment and management of cancer-related fatigue. In: Berger A, Portenoy RK, Weissman DE, eds.: Principles and Practice of Supportive Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 1998, pp 109-18. 
   
   
2. Cella D, Peterman A, Passik S, et al.: Progress toward guidelines for the management of fatigue. Oncology (Huntingt) 12 (11A): 369-77, 1998.  [PUBMED Abstract]
   
   
3. Groopman JE: Fatigue in cancer and HIV/AIDS. Oncology (Huntingt) 12 (3): 335-44; discussion 345-6, 351, 1998.  [PUBMED Abstract]
   
   
4. Portenoy RK, Itri LM: Cancer-related fatigue: guidelines for evaluation and management. Oncologist 4 (1): 1-10, 1999.  [PUBMED Abstract]
   
   
5. Sadler IJ, Jacobsen PB, Booth-Jones M, et al.: Preliminary evaluation of a clinical syndrome approach to assessing cancer-related fatigue. J Pain Symptom Manage 23 (5): 406-16, 2002.  [PUBMED Abstract]
   
   
6. Borneman T, Piper BF, Sun VC, et al.: Implementing the Fatigue Guidelines at one NCCN member institution: process and outcomes. J Natl Compr Canc Netw 5 (10): 1092-101, 2007.  [PUBMED Abstract]
   
   
7. Passik SD, Kirsh KL, Donaghy K, et al.: Patient-related barriers to fatigue communication: initial validation of the fatigue management barriers questionnaire. J Pain Symptom Manage 24 (5): 481-93, 2002.  [PUBMED Abstract]
   
   
8. Cella D: The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: a new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol 34 (3 Suppl 2): 13-9, 1997.  [PUBMED Abstract]
   
   
9. Cella D: Manual of the Functional Assessment of Chronic Illness Therapy (FACIT) Scales. Version 4. Evanston, Ill: Evanston Northwestern Healthcare, 1997. 
   
   
10. Piper BF, Dibble SL, Dodd MJ, et al.: The revised Piper Fatigue Scale: psychometric evaluation in women with breast cancer. Oncol Nurs Forum 25 (4): 677-84, 1998.  [PUBMED Abstract]
    
    
11. Schwartz AL: The Schwartz Cancer Fatigue Scale: testing reliability and validity. Oncol Nurs Forum 25 (4): 711-7, 1998.  [PUBMED Abstract]
    
    
12. McNair D, Lorr M, Droppelman L, et al.: Profile of Mood States. San Diego, Calif: Educational and Industrial Testing Service, 1971. 
    
    
13. Lee KA, Hicks G, Nino-Murcia G: Validity and reliability of a scale to assess fatigue. Psychiatry Res 36 (3): 291-8, 1991.  [PUBMED Abstract]
    
    
14. Mendoza TR, Wang XS, Cleeland CS, et al.: The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer 85 (5): 1186-96, 1999.  [PUBMED Abstract]
    
    
15. Okuyama T, Akechi T, Kugaya A, et al.: Development and validation of the cancer fatigue scale: a brief, three-dimensional, self-rating scale for assessment of fatigue in cancer patients. J Pain Symptom Manage 19 (1): 5-14, 2000.  [PUBMED Abstract]
    
    
16. Hann DM, Denniston MM, Baker F: Measurement of fatigue in cancer patients: further validation of the Fatigue Symptom Inventory. Qual Life Res 9 (7): 847-54, 2000.  [PUBMED Abstract]
    
    
17. Butt Z, Wagner LI, Beaumont JL, et al.: Use of a single-item screening tool to detect clinically significant fatigue, pain, distress, and anorexia in ambulatory cancer practice. J Pain Symptom Manage 35 (1): 20-30, 2008.  [PUBMED Abstract]
    
    
18. Kirsh KL, Passik S, Holtsclaw E, et al.: I get tired for no reason: a single item screening for cancer-related fatigue. J Pain Symptom Manage 22 (5): 931-7, 2001.  [PUBMED Abstract]
    
    
19. Armitage JO: Management of anemia in patients with cancer. Clinical Oncology Updates 1: 1-12, 1998. 
    
    

Intervention

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 ⁸ 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 ⁹ in the PDQ summary on Depression ⁶ 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 ¹¹ 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]
    
    

Posttreatment Considerations

This posttreatment section has been especially prepared for those individuals with cancer who have been off all antineoplastic therapy for at least 6 months. The rationale for creating a separate section is twofold. First, the etiology of problems is different for individuals receiving treatment versus those who are no longer receiving therapy. Second, intervention strategies and information can be better tailored so that there will be a greater likelihood of meeting the needs of these two distinct populations.

Fatigue is a separate and distinct problem for individuals after treatment is completed. Many theories have been proposed to explain the etiology of fatigue in the patient undergoing treatment and to explain the impact of that treatment on quality of life. Many of these theories, however, do not apply to the posttreatment population. Nonetheless, fatigue continues to be a major issue for individuals who are no longer receiving therapy and who are considered to be disease free.

There is evidence that fatigue significantly affects the quality of life of cancer survivors. The experience of fatigue in cancer survivors is quite similar to the experience of patients with chronic fatigue syndrome in the general medical setting.[1] Few studies have been done that indicate the impact of fatigue on quality of life, but some examples follow:

• In cancer survivors who had bone marrow transplants, 50% of 29 survivors reported moderate-to-severe fatigue more than 1 year after transplant. Fatigue was one of the three most negative items studied and had an impact on quality of life more than any other physical problem.[2]



• In patients who had bone marrow transplants, 56% of 125 patients reported ongoing fatigue 6 to 18 years after transplant.[3]



• Of 687 posttreatment survivors of various forms of cancer evaluated for quality-of-life issues, fatigue was one of the three most negative items affecting quality of life.[4]



• Of 90 patients with a diagnosis of Hodgkin lymphoma or non-Hodgkin lymphoma, 30 reported a lack of energy at a median of 32 months after diagnosis.[5]



• Of 403 individuals with Hodgkin lymphoma, 37% reported their energy levels had not returned to levels that satisfied them even after a median of 9 years posttreatment.[6]



• In Hodgkin lymphoma survivors, 26% had persistent fatigue 6 months after treatment with 50% associated with psychological distress. Increasing age and no prior psychological symptoms predicted fatigue “caseness.”[7]



• Of 162 women treated with radiation for breast cancer and 173 women treated with chemotherapy for breast cancer, 75% and 61% respectively described decreased stamina 2 to 10 years after the completion of treatment.[8] In a separate cross-sectional survey of women who completed therapy for breast cancer by a mean of 29 months prior to the survey, 38% had severe fatigue compared with only 11% of matched controls.[9]



• Fatigue has been reported in women survivors of autologous bone marrow transplantation and high-dose chemotherapy treatment for lymphomas 4 to 10 years posttreatment.[10]

Although many studies document the incidence of fatigue in those who are no longer receiving cancer treatment, the specific mechanism of fatigue remains unknown. Because fatigue is a multifaceted problem, determining its etiology is difficult.

The information available regarding fatigue in survivors of childhood cancer is from the literature describing the physiologic and cognitive effects following treatment. In one study, cognitive outcomes were evaluated in children 3 to 4 years after diagnosis of brain tumors. Fatigue was a factor in poor school performance.[11]

In another study, survivors of acute lymphoblastic leukemia who were evaluated for cognitive deficits after treatment were noted to have a typical fatigue effect. This was thought to be a factor in the variability of their test scores.[12] Anecdotally, individuals who have received chest and total-body irradiation complain of fatigue, with an increased sleep requirement.

People who are successfully treated for cancer are at risk for a variety of organ-specific complications that are secondary to their treatment.[13] Fatigue in the posttreatment population underscores the importance of follow-up care. The persistence of fatigue following cancer treatment requires a thorough evaluation to rule out contributing physiologic conditions.

References

1. Servaes P, van der Werf S, Prins J, et al.: Fatigue in disease-free cancer patients compared with fatigue in patients with chronic fatigue syndrome. Support Care Cancer 9 (1): 11-7, 2001.  [PUBMED Abstract]
   
   
2. Whedon M, Stearns D, Mills LE: Quality of life of long-term adult survivors of autologous bone marrow transplantation. Oncol Nurs Forum 22 (10): 1527-35; discussion 1535-7, 1995 Nov-Dec.  [PUBMED Abstract]
   
   
3. Bush NE, Haberman M, Donaldson G, et al.: Quality of life of 125 adults surviving 6-18 years after bone marrow transplantation. Soc Sci Med 40 (4): 479-90, 1995.  [PUBMED Abstract]
   
   
4. Ferrell BR, Grant M, Dean GE, et al.: Bone tired: the experience of fatigue and its impact on quality of life. Oncol Nurs Forum 23 (10): 1539-47, 1996. 
   
   
5. Devlen J, Maguire P, Phillips P, et al.: Psychological problems associated with diagnosis and treatment of lymphomas. II: Prospective study. Br Med J (Clin Res Ed) 295 (6604): 955-7, 1987.  [PUBMED Abstract]
   
   
6. Fobair P, Hoppe RT, Bloom J, et al.: Psychosocial problems among survivors of Hodgkin's disease. J Clin Oncol 4 (5): 805-14, 1986.  [PUBMED Abstract]
   
   
7. Loge JH, Abrahamsen AF, Ekeberg, et al.: Fatigue and psychiatric morbidity among Hodgkin's disease survivors. J Pain Symptom Manage 19 (2): 91-9, 2000.  [PUBMED Abstract]
   
   
8. Berglund G, Bolund C, Fornander T, et al.: Late effects of adjuvant chemotherapy and postoperative radiotherapy on quality of life among breast cancer patients. Eur J Cancer 27 (9): 1075-81, 1991.  [PUBMED Abstract]
   
   
9. Servaes P, Verhagen S, Bleijenberg G: Determinants of chronic fatigue in disease-free breast cancer patients: a cross-sectional study. Ann Oncol 13 (4): 589-98, 2002.  [PUBMED Abstract]
   
   
10. Knobel H, Loge JH, Nordøy T, et al.: High level of fatigue in lymphoma patients treated with high dose therapy. J Pain Symptom Manage 19 (6): 446-56, 2000.  [PUBMED Abstract]
    
    
11. Radcliffe J, Packer RJ, Atkins TE, et al.: Three- and four-year cognitive outcome in children with noncortical brain tumors treated with whole-brain radiotherapy. Ann Neurol 32 (4): 551-4, 1992.  [PUBMED Abstract]
    
    
12. Brouwers P: Neuropsychological abilities of long-term survivors of childhood leukemia. In: Aaronsen NK, Beckmann J, eds.: The Quality of Life of Cancer Patients. New York: Raven Press, 1987, pp 153-65. 
    
    
13. Baker F, Denniston M, Smith T, et al.: Adult cancer survivors: how are they faring? Cancer 104 (11 Suppl): 2565-76, 2005.  [PUBMED Abstract]
    
    

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Contributing Factors ¹⁵

Added Jacobsen et al. as reference 9 ¹⁶.

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