Clinical Review

Clinical Assessment and Management of Cancer-Related Fatigue

Journal of Clinical Outcomes Management. 2017 May;24(5)

References

1. Scherber RM, Kosiorek HE, Senyak Z, et al. Comprehensively understanding fatigue in patients with myeloproliferative neoplasms. Cancer 2016;122:477–85.

2. Neefjes EC, van der Vorst MJ, Blauwhoff-Buskermolen S, Verheul HM. Aiming for a better understanding and management of cancer-related fatigue. Oncologist 2013;18:1135–43.

3. Radbruch L, Strasser F, Elsner F, et al. Fatigue in palliative care patients -- an EAPC approach. Palliat Med 2008;22:13–32.

4. Capuron L, Pagnoni G, Demetrashvili MF, et al. Basal ganglia hypermetabolism and symptoms of fatigue during interferon-alpha therapy. Neuropsychopharmacology 2007;32:2384–92.

5. Kisiel-Sajewicz K, Siemionow V, Seyidova-Khoshknabi D, et al. Myoelectrical manifestation of fatigue less prominent in patients with cancer related fatigue. PLoS One 2013;8:e83636.

6. Bower JE, Ganz PA, Aziz N. Altered cortisol response to psychologic stress in breast cancer survivors with persistent fatigue. Psychosom Med 2005;67:277–80.

7. Barsevick A, Frost M, Zwinderman A, et al. I’m so tired: biological and genetic mechanisms of cancer-related fatigue. Qual Life Res 2010;19:1419–27.

8. Morrow GR, Hickok JT, Roscoe JA, et al. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. J Clin Oncol 2003;21:4635–41.

9. Fontes-Oliveira CC, Busquets S, Toledo M, et al. Mitochondrial and sarcoplasmic reticulum abnormalities in cancer cachexia: altered energetic efficiency? Biochim Biophys Acta 2013;1830:2770–8.

10. Agteresch HJ, Dagnelie PC, van der Gaast A, et al. Randomized clinical trial of adenosine 5’-triphosphate in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2000;92:321–8.

11. Beijer S, Hupperets PS, van den Borne BE, et al. Randomized clinical trial on the effects of adenosine 5’-triphosphate infusions on quality of life, functional status, and fatigue in preterminal cancer patients. J Pain Symptom Manage 2010;40:520–30.

12. Kisiel-Sajewicz K, Davis MP, Siemionow V, et al. Lack of muscle contractile property changes at the time of perceived physical exhaustion suggests central mechanisms contributing to early motor task failure in patients with cancer-related fatigue. J Pain Symptom Manage 2012;44:351–61.

13. Ryan JL, Carroll JK, Ryan EP, et al. Mechanisms of cancer-related fatigue. Oncologist 2007;12 Suppl 1:22–34.

14. Seruga B, Zhang H, Bernstein LJ, Tannock IF. Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer 2008;8:887–99.

15. Wang XS, Giralt SA, Mendoza TR, et al. Clinical factors associated with cancer-related fatigue in patients being treated for leukemia and non-Hodgkin’s lymphoma. J Clin Oncol 2002;20:1319–28.

16. Collado-Hidalgo A, Bower JE, Ganz PA, et al. Inflammatory biomarkers for persistent fatigue in breast cancer survivors. Clin Cancer Res 2006;12:2759–66.

17. Wang XS, Shi Q, Williams LA, et al. Serum interleukin-6 predicts the development of multiple symptoms at nadir of allogeneic hematopoietic stem cell transplantation. Cancer 2008;113:2102–9.

18. Inagaki M, Isono M, Okuyama T, et al. Plasma interleukin-6 and fatigue in terminally ill cancer patients. J Pain Symptom Manage 2008;35:153–61.

19. Laird BJ, McMillan DC, Fayers P, et al. The systemic inflammatory response and its relationship to pain and other symptoms in advanced cancer. Oncologist 2013;18:1050–5.

20. Bower JE, Ganz PA, Irwin MR, et al. Inflammation and behavioral symptoms after breast cancer treatment: do fatigue, depression, and sleep disturbance share a common underlying mechanism? J Clin Oncol 2011;29:3517–22.

21. Whistler T, Taylor R, Craddock RC, et al. Gene expression correlates of unexplained fatigue. Pharmacogenomics 2006;7:395–405.

22. Fagundes CP, Bennett JM, Alfano CM, et al. Social support and socioeconomic status interact to predict Epstein-Barr virus latency in women awaiting diagnosis or newly diagnosed with breast cancer. Health Psychol 2012;31:11–19.

23. Landmark-Hoyvik H, Reinertsen KV, Loge JH, et al. Alterations of gene expression in blood cells associated with chronic fatigue in breast cancer survivors. Pharmacogenomics J 2009;9:333–40.

24. Smith AK, Conneely KN, Pace TW, et al. Epigenetic changes associated with inflammation in breast cancer patients treated with chemotherapy. Brain Behav Immun 2014;38:227–36.

25. Kim S, Miller BJ, Stefanek ME, Miller AH. Inflammation-induced activation of the indoleamine 2,3-dioxygenase pathway: Relevance to cancer-related fatigue. Cancer 2015;121:2129–36.

26. Mills PJ, Parker B, Dimsdale JE, et al. The relationship between fatigue and quality of life and inflammation during anthracycline-based chemotherapy in breast cancer. Biol Psychol 2005;69:85–96.

27. Jean-Pierre P, Figueroa-Moseley CD, Kohli S, et al. Assessment of cancer-related fatigue: implications for clinical diagnosis and treatment. Oncologist 2007;12 Suppl 1:11–21.

28. Wang XS, Zhao F, Fisch MJ, et al. Prevalence and characteristics of moderate to severe fatigue: a multicenter study in cancer patients and survivors. Cancer 2014;120:425–32.

29. Mendoza TR, Wang XS, Cleeland CS, et al. The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer 1999;85:1186–96.

30. Mendoza ME, Capafons A, Gralow JR, et al. Randomized controlled trial of the Valencia model of waking hypnosis plus CBT for pain, fatigue, and sleep management in patients with cancer and cancer survivors. Psychooncology 2016 Jul 28.

31. Glaus A. Assessment of fatigue in cancer and non-cancer patients and in healthy individuals. Support Care Cancer 1993;1:305–15.

32. Seyidova-Khoshknabi D, Davis MP, Walsh D. A systematic review of cancer-related fatigue measurement questionnaires. Am J Hosp Palliat Care 2011;28:119–29.

33. Holzner B, Kemmler G, Greil R, et al. The impact of hemoglobin levels on fatigue and quality of life in cancer patients. Ann Oncol 2002;13:965–73.

34. Stein KD, Jacobsen PB, Blanchard CM, Thors C. Further validation of the multidimensional fatigue symptom inventory-short form. J Pain Symptom Manage 2004;27:14–23.

35. Hwang SS, Chang VT, Rue M, Kasimis B. Multidimensional independent predictors of cancer-related fatigue. J Pain Symptom Manage 2003;26:604–14.

36. Peterspm DR. Scope and generality of verbally defined personality factors. Psychol Rev 1965;72:48–59.

37. Berger AM, Abernethy AP, Atkinson A, et al. NCCN Clinical Practice Guidelines Cancer-related fatigue. J Natl Compr Canc Netw 2010;8:904–31.

38. Crawford J, Cella D, Cleeland CS, et al. Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer 2002;95:888–95.

39. Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev 2012;12:CD003407.

40. Rizzo JD, Brouwers M, Hurley P, et al. American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood 2010;116:4045–59.

41. Preston NJ, Hurlow A, Brine J, Bennett MI. Blood transfusions for anaemia in patients with advanced cancer. Cochrane Database Syst Rev 2012(2):CD009007.

42. Minton O, Stone PC. A comparison of cognitive function, sleep and activity levels in disease-free breast cancer patients with or without cancer-related fatigue syndrome. BMJ Support Palliat Care 2012;2:231–8.

43. Heckler CE, Garland SN, Peoples AR, et al. Cognitive behavioral therapy for insomnia, but not armodafinil, improves fatigue in cancer survivors with insomnia: a randomized placebo-controlled trial. Support Care Cancer 2016;24:2059–66.

44. Howell D, Oliver TK, Keller-Olaman S, et al. Sleep disturbance in adults with cancer: a systematic review of evidence for best practices in assessment and management for clinical practice. Ann Oncol 2014;25:791–800.

45. Wilt TJ, MacDonald R, Brasure M, et al. Pharmacologic treatment of insomnia disorder: an evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med 2016;165:103–12.

46. Kuriyama A, Honda M, Hayashino Y. Ramelteon for the treatment of insomnia in adults: a systematic review and meta-analysis. Sleep Med 2014;15:385–92.

47. Strasser F, Palmer JL, Schover LR, et al. The impact of hypogonadism and autonomic dysfunction on fatigue, emotional function, and sexual desire in male patients with advanced cancer: a pilot study. Cancer 2006;107:2949–57.

48. Agasi-Idenburg SC, Thong MS, Punt CJ, et al. Comparison of symptom clusters associated with fatigue in older and younger survivors of colorectal cancer. Support Care Cancer 2017;25:625–32.

49. Miaskowski C, Aouizerat BE. Is there a biological basis for the clustering of symptoms? Semin Oncol Nurs 2007;23:99–105.

50. de Raaf PJ, de Klerk C, Timman R, et al. Systematic monitoring and treatment of physical symptoms to alleviate fatigue in patients with advanced cancer: a randomized controlled trial. J Clin Oncol 2013;31:716–23.

51. Barsevick AM, Whitmer K, Sweeney C, Nail LM. A pilot study examining energy conservation for cancer treatment-related fatigue. Cancer Nurs 2002;25:333–41.

52. Barsevick AM, Dudley W, Beck S, et a;. A randomized clinical trial of energy conservation for patients with cancer-related fatigue. Cancer 2004;100:1302–10.

53. Luciani A, Jacobsen PB, Extermann M, et al. Fatigue and functional dependence in older cancer patients. Am J Clin Oncol 2008;31:424–30.

54. Abrahams HJ, Gielissen MF, Goedendorp MM, et al. A randomized controlled trial of web-based cognitive behavioral therapy for severely fatigued breast cancer survivors (CHANGE-study): study protocol. BMC Cancer 2015;15:765.

55. Quesnel C, Savard J, Simard S, et al. Efficacy of cognitive-behavioral therapy for insomnia in women treated for nonmetastatic breast cancer. J Consult Clin Psychol 2003;71:189–200.

56. Goedendorp MM, Gielissen MF, Verhagen CA, Bleijenberg G. Psychosocial interventions for reducing fatigue during cancer treatment in adults. Cochrane Database Syst Rev 2009(1):CD006953.

57. Greiwe JS, Cheng B, Rubin DC, et al. Resistance exercise decreases skeletal muscle tumor necrosis factor alpha in frail elderly humans. FASEB J 2001;15:475–82.

58. Furmaniak AC, Menig M, Markes MH. Exercise for women receiving adjuvant therapy for breast cancer. Cochrane Database Syst Rev 2016;(9):CD005001.

59. Cramp F, Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev 2012;(11):CD006145.

60. Brown JC, Huedo-Medina TB, Pescatello LS, et al. Efficacy of exercise interventions in modulating cancer-related fatigue among adult cancer survivors: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2011;20:123–33.

61. Steindorf K, Schmidt ME, Klassen O, et al. Randomized, controlled trial of resistance training in breast cancer patients receiving adjuvant radiotherapy: results on cancer-related fatigue and quality of life. Ann Oncol 2014;25:2237–43.

62. Bower JE, Bak K, Berger A, et al. Screening, assessment, and management of fatigue in adult survivors of cancer: an American Society of Clinical oncology clinical practice guideline adaptation. J Clin Oncol 2014;32:1840–50.

63. Kenjale AA, Hornsby WE, Crowgey T, et al. Pre-exercise participation cardiovascular screening in a heterogeneous cohort of adult cancer patients. Oncologist 2014;19:999–1005.

64. Oldervoll LM, Loge JH, Paltiel H, et al. The effect of a physical exercise program in palliative care: A phase II study. J Pain Symptom Manage 2006;31:421–30.

65. Porock D, Kristjanson LJ, Tinnelly K, et al. An exercise intervention for advanced cancer patients experiencing fatigue: a pilot study. J Palliat Care 2000;16:30–6.

66. Lengacher CA, Kip KE, Reich RR, et al. A cost-effective mindfulness stress reduction program: a randomized control trial for breast cancer survivors. Nursing Econ 2015;33:210–8, 32.

67. Lengacher CA, Reich RR, Post-White J, et al. Mindfulness based stress reduction in post-treatment breast cancer patients: an examination of symptoms and symptom clusters. J Behav Med 2012;35:86–94.

68. Sprod LK, Fernandez ID, Janelsins MC, et al. Effects of yoga on cancer-related fatigue and global side-effect burden in older cancer survivors. J Geriatr Oncol 2015;6:8–14.

69. Wang G, Wang S, Jiang P, Zeng C. [Effect of Yoga on cancer related fatigue in breast cancer patients with chemotherapy]. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2014;39:1077–82.

70. Stan DL, Croghan KA, Croghan IT, et al. Randomized pilot trial of yoga versus strengthening exercises in breast cancer survivors with cancer-related fatigue. Support Care Cancer 2016;24:4005–15.

71. Larkey LK, Roe DJ, Weihs KL, et al. Randomized controlled trial of Qigong/Tai Chi Easy on cancer-related fatigue in breast cancer survivors. Ann Behav Med 2015;49:165–76.

72. Molassiotis A, Bardy J, Finnegan-John J, et al. Acupuncture for cancer-related fatigue in patients with breast cancer: a pragmatic randomized controlled trial. J Clin Oncol 2012;30:4470–6.

73. Deng G, Chan Y, Sjoberg D, et al. Acupuncture for the treatment of post-chemotherapy chronic fatigue: a randomized, blinded, sham-controlled trial. Support Care Cancer 2013;21:1735–41.

74. Finnegan-John J, Molassiotis A, Richardson A, Ream E. A systematic review of complementary and alternative medicine interventions for the management of cancer-related fatigue. Integr Cancer Ther 2013;12:276–90.

75. Schwartz AL, Thompson JA, Masood N. Interferon-induced fatigue in patients with melanoma: a pilot study of exercise and methylphenidate. Oncol Nurs Forum 2002;29:E85–90.

76. Spathis A, Dhillan R, Booden D, et al. Modafinil for the treatment of fatigue in lung cancer: a pilot study. Palliat Med 2009;23:325–31.

77. Blackhall L, Petroni G, Shu J, et al. A pilot study evaluating the safety and efficacy of modafinal for cancer-related fatigue. J Palliat Med 2009;12:433–9.

78. Qu D, Zhang Z, Yu X, et al. Psychotropic drugs for the management of cancer-related fatigue: a systematic review and meta-analysis. Eur J Cancer Care (Engl) 2015;25:970–9.

79. Minton O, Richardson A, Sharpe M, et al. Drug therapy for the management of cancer-related fatigue. Cochrane Database Syst Rev 2010(7):CD006704.

80. Moraska AR, Sood A, Dakhil SR, et al. Phase III, randomized, double-blind, placebo-controlled study of long-acting methylphenidate for cancer-related fatigue: North Central Cancer Treatment Group NCCTG-N05C7 trial. J Clin Oncol 2010;28:3673–9.

81. Bruera E, Driver L, Barnes EA, et al. Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report. J Clin Oncol 2003;21:4439–43.

82. Kerr CW, Drake J, Milch RA, et al. Effects of methylphenidate on fatigue and depression: a randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage 2012;43:68–77.

83. Escalante CP, Meyers C, Reuben JM, et al. A randomized, double-blind, 2-period, placebo-controlled crossover trial of a sustained-release methylphenidate in the treatment of fatigue in cancer patients. Cancer J 2014;20:8–14.

84. Mar Fan HG, Clemons M, Xu W, et al. A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer. Support Care Cancer 2008;16:577–83.

85. Butler JM Jr, Case LD, Atkins J, et al. A phase III, double-blind, placebo-controlled prospective randomized clinical trial of d-threo-methylphenidate HCl in brain tumor patients receiving radiation therapy. Int J Radiat Oncol Biol Phys 2007;69:1496–501.

86. Hovey E, de Souza P, Marx G, et al. Phase III, randomized, double-blind, placebo-controlled study of modafinil for fatigue in patients treated with docetaxel-based chemotherapy. Support Care Cancer 2014;22:1233–42.

87. Spathis A, Fife K, Blackhall F, et al. Modafinil for the treatment of fatigue in lung cancer: results of a placebo-controlled, double-blind, randomized trial. J Clin Oncol 2014;32:1882–8.

88. Berenson JR, Yellin O, Shamasunder HK, et al. A phase 3 trial of armodafinil for the treatment of cancer-related fatigue for patients with multiple myeloma. Support Care Cancer 2015;23:1503–12.

89. Boele FW, Douw L, de Groot M, et al. The effect of modafinil on fatigue, cognitive functioning, and mood in primary brain tumor patients: a multicenter randomized controlled trial. Neuro Oncol 2013;15:1420–8.

90. Jean-Pierre P, Morrow GR, Roscoe JA, et al. A phase 3 randomized, placebo-controlled, double-blind, clinical trial of the effect of modafinil on cancer-related fatigue among 631 patients receiving chemotherapy: a University of Rochester Cancer Center Community Clinical Oncology Program Research base study. Cancer 2010;116:3513–20.

91. Conley CC, Kamen CS, Heckler CE, et al. Modafinil moderates the relationship between cancer-related fatigue and depression in 541 patients receiving chemotherapy. J Clin Psychopharmacol 2016;36:82–5.

92. Brattsand R, Linden M. Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies. Aliment Pharmacol Ther 1996;10 Suppl 2:81–90.

93. Yennurajalingam S, Frisbee-Hume S, Palmer JL, et al. Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-controlled trial in patients with advanced cancer. J Clin Oncol 2013;31:3076–82.

94. Bruera E, Roca E, Cedaro L, et al. Action of oral methylprednisolone in terminal cancer patients: a prospective randomized double-blind study. Cancer Treat Rep 1985;69:751–4.

95. Pulivarthi K, Dev R, Garcia J, et al. Testosterone replacement for fatigue in male hypogonadic patients with advanced cancer: A preliminary double-blind placebo-controlled trial. J Clin Oncol 2012;30 (suppl). Abstract e19643.

96. Palesh OG, Mustian KM, Peppone LJ, et al. Impact of paroxetine on sleep problems in 426 cancer patients receiving chemotherapy: a trial from the University of Rochester Cancer Center Community Clinical Oncology Program. Sleep Med 2012;13:1184–90.

97. Thekdi SM, Trinidad A, Roth A. Psychopharmacology in Cancer. Curr Psychiatry Rep 2014;17:529.

98. Lesser GJ. Case D, Stark N, et al. A randomized, double-blind, placebo-controlled study of oral coenzyme Q10 to relieve self-reported treatment-related fatigue in newly diagnosed patients with breast cancer. J Support Oncol 2013;11:31–42.

99. Barton DL, Liu H, Dakhil SR, et al. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst 2013;105:1230–8.

100. Yennurajalingam S, Reddy A, Tannir NM, et al. High-dose Asian ginseng (panax ginseng) for cancer-related fatigue: a preliminary report. Integr Cancer Ther 2015;14:419–27.

101. Howell D, Keller-Olaman S, Oliver TK, et al. A pan-Canadian practice guideline and algorithm: screening, assessment, and supportive care of adults with cancer-related fatigue. Curr Oncol 2013;20:e233–46.

The seed extract of the guarana plant ( Paullinia cupana ) traditionally has been used as a stimulant. An improvement in fatigue scores was seen with the use of oral guarana (100 mg daily) at the end of 21 days in breast cancer patients receiving chemotherapy [101]. Further studies are needed for these results to be generalized and to understand the adverse effects and interaction profile of guarana.

Re-evaluation

Patients who have completed cancer treatment must be monitored for fatigue over the long term, as fatigue may exist beyond the period of active treatment. Many studies have shown fatigue in breast cancer survivors, and fatigue has been demonstrated in survivors of colorectal, lung, and prostate cancers as well as myeloproliferative neoplasms [28]. Therefore, it is important to screen patients for fatigue during follow-up visits. There are currently no studies evaluating the long-term treatment of fatigue. In our experience, the timing of follow-up depends on the level of fatigue and interventions prescribed. Once fatigue is stabilized to a level with which the patient is able to cope, the time interval for follow up may be lengthened. Annual visits may suffice in patients with mild fatigue. Follow-up of patients with moderate to severe fatigue depends on the level of fatigue, the ability to cope, choice of treatment, and presence of contributing factors.

Conclusion

CRF is a complex condition that places a significant burden on patients and caregivers, resulting in emotional distress, poor functioning, and suffering. Fatigue can occur before, during, and long after cancer treatment. The approach to CRF begins with screening for and educating patients and their caregivers about the symptoms. Many screening scales are available that may be used to follow patients’ progress over time. The evaluation and management of contributing conditions may help improve fatigue. If the fatigue persists, an individualized approach with a combination of nonpharmacologic and pharmacologic approaches should be considered. More research is needed to understand brain signaling pathways, cytokine changes, and genomic changes in cancer patients with fatigue. Though many hypotheses have been proposed, to date there is no biological marker to assess this condition. Biomarker research needs to be advanced to help to identify patients at risk for fatigue. As cytokines have a major role in CRF, targeted therapy to block cytokine pathways may also be explored in the future.

Acknowledgment: Bryan Tutt provided editorial assistance.

Corresponding author: Carmelita P. Escalante, MD, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030, cescalan@mdanderson.org.

Financial disclosures: None.