Understanding and Treating Cancer-Related Fatigue

Fatigue is the most common side effect of cancer and its treatment, and it frequently goes unrecognized and untreated. While the exact etiology of fatigue is unclear, numerous contributing factors that worsen fatigue can be clinically addressed. Substantial research supports physical exercise as an intervention for fatigue.

Cancer-related fatigue (fatigue) is the most common side effect of cancer and its treatment. An exact cause of this complex, subjective, multicausal, multidimensional side effect of cancer and its treatment has eluded researchers.[1]

Among patients on active treatment, the prevalence of fatigue ranges from 60%–96%.[2] While sometimes present at diagnosis, fatigue is commonly associated with treatment (radiation therapy, chemotherapy, surgery, and biotherapy) and with patients who have advanced disease.[2] Survivorship research has demonstrated that fatigue may persist for months and years following completion of treatment, with a prevalence ranging from 30%–45% of survivors.[3–7]

The fatigue experienced during and following treatment adversely affects quality of life. Some studies have reported that fatigue impairs quality of life more than pain and other symptoms, and that fatigue has a negative impact on the workplace, with one study reporting 75% of patients changing their work hours to accommodate fatigue.[8–11]

Pathophysiology

Fatigue is a pervasive, underdiagnosed, and poorly understood side effect. Treatment that focuses on the cause of fatigue is most effective; however, in the vast majority of cases, the etiology of fatigue is not clear. Patients often experience anemia, metabolic disturbances, infections, paraneoplastic syndromes, cachexia, pain, stress, and mood disturbances that may contribute to fatigue, but even when these conditions are corrected, fatigue persists. Proinflammatory cytokines (interleukin-1 (IL-1) beta, IL-6, tumor necrosis factor) are often implicated in the comorbid process.[12] These cytokines act on the central nervous system, causing fatigue and "sickness behaviors" (eg, sleep disturbance, depressed mood, and decreased activity). Reduced functional capacity and physical strength may also cause or be contributing factors to fatigue. As patients become more sedentary and inactive, they become debilitated, and the effort to perform routine tasks becomes fatiguing.[13,14]

Evaluation

NCCN Guidelines

The National Comprehensive Cancer Network (NCCN) has proposed a comprehensive, step-by-step approach to the evaluation and management of fatigue.[15] Seven factors are identified as frequent contributors to fatigue: pain, emotional distress, sleep disturbances, anemia, nutritional deficiencies, deconditioning, and comorbidities. NCCN guidelines recommend that these factors be evaluated and treated first.[16]

Ideally, fatigue would be monitored on a routine basis when the patient is seen in the clinical setting. A clinically relevant and easy measurement of fatigue is the 0-to-10 scale for fatigue assessment. The NCCN recommends that patients with a fatigue score of 1 through 3 receive education and ongoing assessment, and that patients with higher scores begin a formal screening for pain, distress, sleep disturbances, anemia, and hypothyroidism.[15]

The MID as an Intervention Benchmark

Determining when to intervene is most important. Several studies have examined the minimally important difference (MID) in fatigue; that is, the smallest amount of change between two scores that is subjectively meaningful to the patient.[13] The MID has been evaluated for several different scales, including the 0-to-10 scale. A change of 1 point on the 0-to-10 scale was found to be meaningful to patients. This finding suggests that patients with as little as a 1-point increase in fatigue should receive some intervention (eg, education or more thorough evaluation or referral to exercise).

Comprehensive Patient Review

A strong body of research supports the relationship between fatigue and anemia,[17] pain,[18,19] distress,[20] and deconditioning.[13,14] Therefore, a careful review of systems, evaluation of disease status, and review of medications is an important initial step in evaluating and treating fatigue. Unfortunately, in many cancer patients a clear cause of fatigue cannot be identified, and the management approach becomes more generalized.

An assessment of fatigue is not complete without a medication review. Polypharmacy is common in cancer patients, and many drugs, alone and in combination, cause fatigue. Sedation is associated with some of the older antidepressants, especially tricyclic antidepressants. Selective serotonin reuptake inhibitors (SSRIs) and the atypical antidepressants cause less sedation and are a better choice for these patients. Antiemetics (eg, promethazine, prochlorperazine, trimethobenzamide) and benzodiazepines also cause sedation. Sedation may be reduced by prescribing less-sedating antiemetics (dolasetron, palonosetron [Aloxi], aprepitant [Emend], granisetron [Kytril], ondansetron) or reserving sedating medications for use on an as-needed basis.

Opioids commonly cause sedation, but patients often develop tolerance to their sedative effect. While pain relief is an important goal, it is also important to regularly evaluate pain and assess the possibility of decreasing the opioid dose. Though it is not reasonable to expect to withdraw a patient from a needed medication, a realistic approach is to assess the type of drug being used and consider the availability of alternative, less-sedating medications.

Other comorbid conditions are known to contribute to fatigue. Electrolyte disturbances, anemia, dehydration, hypothyroidism, pain, hypocortisolism, new or worsening cardiac disease, infection, and hypoxia should all be evaluated as potential causes of fatigue. Identifiable and modifiable causes of fatigue need to be ruled out or treated. Unfortunately, the cause of fatigue for many cancer patients is not easily elucidated, or well understood.

Treatment

Interventions for fatigue can be categorized as pharmacologic and nonpharmacologic. Pharmacologic therapy includes erythropoietin for chemotherapy-induced anemia, antidepressants when fatigue is related to depression, and psychostimulants to give patients more energy to overcome their fatigue.

Pharmacologic Interventions

The benefit of erythropoietic agents in ameliorating fatigue in cancer patients with chemotherapy-induced anemia is under debate. Trials that have assessed fatigue as a secondary endpoint noted improvements in fatigue across different types of cancer, types of treatment, and measurement scales.[21–24] These studies concluded that patients who responded to erythropoietic agents reported increased energy and activity levels, and improved overall quality of life.[22–24] In earlier investigations, researchers reported that recombinant erythropoietin at dosages of 150 U/kg three times a week, 10,000 U/kg three times a week, or 40,000 U/kg weekly and darbepoetin alfa at dosages of 500 mg every 3 weeks appeared to effectively increase hemoglobin and improve quality of life in patients with chemotherapy-induced anemia.[21–25] However, correcting anemia frequently does not ameliorate fatigue, and many fatigued cancer patients are not anemic.[26]

Notably, in March 2007, the US Food and Drug Administration issued a product labeling alert to provide new safety information for erythropoietin-stimulating agents (ESAs), based on analysis of four new studies of their use in patients with cancer. Also, based on the newer study data, the FDA recommended that, "Physicians who prescribe ESAs should ... understand that in patients with cancer whose anemia is caused by chemotherapy ... there are no data to support claims of improvement in health-related quality of life, including effects on fatigue, energy, or strength. (See http://www.fda.gov.cder/drug/advisory/RHE2007.htm)

Fatigue is common in depression, and one might assume that antidepressant therapy may be a logical approach to managing cancer-related fatigue. Paroxetine (Paxil) was used in one study and demonstrated no effect on fatigue.[27] Because many antidepressants cause sedation and have a delayed onset of action, they do not appear to play a role in the management of fatigue, and their use should be limited to patients diagnosed with depression.

Limited research has examined the effects of psychostimulants on fatigue. Methylphenidate appears to improve fatigue and concentration and to reduce sedation.[28,29] Doses of methylphenidate used in these studies ranged from 5 mg to 10 mg quick-release formula administered at 8 am and 12 pm, and 20 mg extended release administered at 8 am. Early trials with dextromethylphenidate, the racemic form of methylphenidate, have demonstrated safety and efficacy, as well as decreased fatigue and improved memory.[30] These studies are intriguing; trials with larger sample sizes and more diverse populations are needed to determine the efficacy of these drugs on fatigue.

Complementary alternative therapies with herbal supplements have been systematically studied, to a limited degree. Lectin-standardized mistletoe extract, levocarnitine supplements, and ginkgo biloba have demonstrated positive effects on cancer-related fatigue.[31–33] Although current data are insufficient to warrant recommendation of these agents, additional studies are being conducted to further understand the effects of these products.

Nonpharmacologic Interventions

Nonpharmacologic approaches to cancer-related fatigue have been tested more extensively than most of the pharmacologic approaches and many have demonstrated efficacy. Strong evidence from clinical trials supports exercise, and the NCCN recommends exercise as an intervention to reduce fatigue.[13,14,29,33–37] Both aerobic and resistance exercise have consistently demonstrated a powerful effect on reducing fatigue, with declines in fatigue levels of 40% to 50% among exercising subjects. Exercise is beneficial both during and following cancer treatment, and exerts its effect by improving aerobic capacity and muscle strength so that patients are able to pursue activities they find meaningful and important. The effects of exercise not only improve fatigue, but also improve quality of life.[38,39] Exercise for patients with advanced cancer also appears to reduce fatigue.[40] Exercise prescriptions in these studies ranged from low to moderate intensity, 10 to 30 minutes in duration, and from 3 days a week to every day. While some of these studies examined fatigue at different points in treatment or survivorship, it is clear that early intervention, before fatigue becomes too debilitating, is important to maintaining functional ability and quality of life.

Compelling evidence suggests psychosocial interventions that include education, energy conservation, stress management, and individual counseling and support groups improve energy and reduce fatigue. Energy conservation teaches patients to limit their energy by doing such things as delegating responsibilities so they are able to perform more valued activities.[41,42]

Knowledge is a powerful tool. Knowing that fatigue is a common side effect of cancer and its treatment can help patients feel less worried and less afraid of the significance of their fatigue. Educating patients about sleep hygiene, maintaining a normal sleep/wake cycle at night, and refraining from caffeine and stimulating activities several hours before bed can help to normalize sleep. Individual counseling and support groups can be helpful to reassure patients know that they are not alone in their experience, and to teach coping, stress management, and distraction techniques.[43–45]

Nursing Interventions

Fatigue is a side effect of cancer and its treatment that offers nurses an important opportunity to suggest an exercise routine for fatigued patients, to refer them to an exercise rehabilitation program, to educate them about fatigue and strategies that can address it (eg, sleep hygiene, energy conservation, stress management), and to recommend support groups for further education and counseling.

Implications for Nursing Practice

Nurses are at the forefront of patient care and should become advocates for patients. Nurses are positioned to identify patients who are struggling with fatigue early in the cancer-treatment process, before the fatigue becomes severe. Administering a simple 0-to-10 scale and recording changes over time will quickly alert a nurse to fatigue changes that need intervention. Regular review of the patient's record for physiologic causes of fatigue and time spent educating patients about the nonpharmacologic interventions for fatigue management (eg, exercise, education, etc) will improve patient care, reduce fatigue, and perhaps improve a patient's clinical outcome.

Summary

Fatigue is, without a doubt, one of the most debated, discussed, and researched topics in oncology in recent years. Despite efforts to determine the cause(s) and optimal treatment(s), we are still left with many questions. In appropriate patients, exercise intervention is strongly encouraged. The NCCN practice guidelines are a useful tool to assess and manage cancer-related fatigue. Nurses should strive to take a leadership role in addressing cancer-related fatigue in their patients.

References:

1. Nail, LM: Fatigue in patients with cancer. Oncol Nurs Forum 29(3):537–544, 2002.

2. Wagner IJ, Cella D: Fatigue and cancer: Causes, prevalence and treatment approaches. Br J Cancer 91(5):822–828, 2004.

3. Ganz PA, Moinpour CM, Pauler DK, et al: Health status and quality of life in patients with early-stage Hodgkin's disease treated on Southwest Oncology Group Study 9133. J Clin Oncol 21(18):3512–3519, 2003.

4. Dow KH, Ferrell BR, Leigh S, et al: An evaluation of the quality of life among long-term survivors of breast cancer. Breast Cancer Res Treat 39(3):261–273, 1996.

5. Jacobsen PB, Stein K: Is fatigue a long-term side effect of breast cancer treatment? Cancer Control 6(3):256–263, 1999.

6. Ganz PA, Bower JE: Cancer related fatigue: A focus on breast cancer and Hodgkin's disease survivors. Acta Oncol 46(4):474–479, 2007.

7. Meeske K, Smith AW, Alfano CM, et al: Fatigue in breast cancer survivors two to five years postdiagnosis: A HEAL Study report. Qual Life Res 16(6):947–960, 2007.

8. Bower JE, Ganz PA, Desmond KA, et al: Fatigue in long-term breast carcinoma survivors: A longitudinal investigation. Cancer 106(4):751–758, 2006.

9. Mitchell SA, Berger AM: Cancer-related fatigue: The evidence base for assessment and management. Cancer J 12(5):374–387, 2006.

10. Andrykowski MA, Schmidt JE, Salsman JM, et al: Use of a case definition approach to identify cancer-related fatigue in women undergoing adjuvant therapy for breast cancer. J Clin Oncol 23:6613-6622, 2005.

11. 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.

12. Stone P, Hardy J, Broadley K, et al: Fatigue in advanced cancer: A prospective controlled cross-sectional study. Br J Cancer 79(9-10):1479–1486, 1999.

13. Schwartz AL, Mori M, Gao R, et al: Exercise reduces daily fatigue in women with breast cancer receiving chemotherapy. Med Sci Sports Exerc 33(5):718–723, 2001.

14. Courneya KS, Mackey JR, Bell GJ, et al: Randomized controlled trial of exercise training in post-menopausal breast cancer survivors: Cardiopulmonary and quality of life outcomes. J Clin Oncol 21:1660–1668, 2003.

15. National Comprehensive Cancer Network: Practice guidelines. Cancer-related fatigue panel 2007 Guidelines, version 3.2007, August 28, 2007. Rockledge, Pennsylvania. Available at: http://www.nccn.org/professionals/physician_gls/PDF/fatigue.pdf. Accessed September 10, 2007.

16. Mock V, Atkinson A, Barsevick A, et al: Cancer-related fatigue clinical practice guidelines in oncology. J Natl Comp Cancer Network 1:308–331, 2003.

17. Turner R, Anglin P, Burkes R, et al: Epoetin alfa in cancer patients: Evidence-based guidelines. J Pain Symptom Manage 22(5):954–965, 2001.

18. Blesch K, Paice J, Wickham R, et al: Correlates of fatigue in people with breast and lung cancer. Oncol Nurs Forum 18(1):81–87, 1991.

19. Bower JE, Ganz PA, Desmond KA, et al: Fatigue in breast cancer survivors: Occurrence, correlates, and impact on quality of life. J Clin Oncol 18(4):743–753, 2000.

20. Jacobson P, Hann D, Azzarello L, et al: Fatigue in women receiving adjuvant chemotherapy for breast cancer: Characteristics, course, and correlates. J Pain Symptom Manage 18:233–242, 1999.

21. 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):1218–1234, 2001.

22. Demetri GD, Kris M, Wade J, et al: Quality of life benefit of 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):3412–3425, 1998.

23. Gabrilove JL, Cleeland CS, Livingston RB, et al: Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: Improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 19(11):2875–2882, 2001.

24. Vansteenkiste J, Pirker R, Massuti B, et al: Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 94:1211–1220, 2002.

25. Kotasek D, Albertsson M, Mackey J, et al: Randomized, double-blind, placebo-controlled dose-finding study of darbepoetin alfa administered once every 3 (Q3W) or 4 (Q4W) weeks in patients with solid tumors (abstract). Proc Am Soc Clin Oncol 21:1421, 2002.

26. Irvine D, Vincent L, Graydon JE, et al: The prevalence and correlates of fatigue inpatients receiving treatment with chemotherapy and radiotherapy: A comparison with the fatigue experienced by healthy individuals. Cancer Nurs 17:367–378, 1994.

27. Burkes TF: New agents for the treatment of cancer-related fatigue. Cancer 92(suppl 6):1714–1718, 2001.

28. Sarhill N, Walsh S, Nelson KA, et al: Methylphenidate for fatigue in advanced cancer: A prospective open label pilot study. Am J Hosp Palliat Care 18(3):187–192, 2001.

29. Schwartz AL, Thompson JA, Masood N: Interferon-induced fatigue in patients with melanoma: A pilot study of exercise and methylphenidate. Oncol Nurs Forum 29(7):E85–E90, 2002.

30. Lower E, Fleishman S, Cooper A, et al: A phase III, randomized placebo-controlled trial of the safety and efficacy of d-MPH as new treatment of fatigue and "chemobrain" in adult cancer patients (abstract). J Clin Oncol 23(16S):8000, 2005.

31. Schumacher K, Schneider B, Reich G, et al: Influence of post-operative complementary treatment with lectin-standardized mistletoe extract on breast cancer patients. A controlled epidemiological multicentric retrolective cohort study. Anticancer Res 23(6D):5081–5087, 2003.

32. Graziano F, Bisonni R, Catalano V, et al: Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients. Br J Cancer 86(12):1854–1857, 2002.

33. 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):357–374, 2003.

34. Segal RJ, Reid RD, Courneya KS, et al: Resistance exercise in men receiving androgen deprivation therapy for prostate cancer. J Clin Oncol 21:1653–1639, 2003.

35. Mock V, Dow KH, Meares C, et al: Effects of exercise on fatigue, physical functioning and emotional distress during radiation therapy for breast cancer. Oncol Nurs Forum 24(6):991–1000, 1997.

36. 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): 2273–2277, 1999.

37. Schwartz AL, Bagley J, Holub J, et al: Results of a 12-month randomized exercise trial for newly diagnosed cancer patients. Presented at the Annual Meeting of the Oncology Nursing Society, 2004; Anaheim, California.

38. Schwartz AL: Fatigue mediates the effect of exercise on quality of life. Qual Life Res 8(6):529–538, 1999.

39. Courneya KS, Freidenreich CM: Physical exercise and quality of life following cancer diagnosis: A literature review. Ann Behav Med 21(2):171–179, 1999.

40. Porock D, Kristjanson LJ, Tinnelly K, et al: An exercise intervention for advanced cancer patients experiencing fatigue: a pilot study. J Palliat Care 16(3):30–36, 2000.

41. Barsevick AM, Whitmer K, Sweeney C, et al. A pilot study examining energy conservation for cancer treatment-related fatigue. Cancer Nurs 25:333–349, 2002.

42. Barsevick AM, Dudley W, Beck S, et al: A randomized clinical trial of energy conservation for cancer-related fatigue. Cancer 100(6):1302–1310, 2004.

43. Spiegel D, Bloom JR, Yalom I: Group support for patients with metastatic cancer. A randomized outcome study. Arch Gen Psychiatry 38(5):527–533, 1981.

44. Jacobsen PB, Meade CD, Stein K, et al: Efficacy and costs of two forms of stress management training for cancer patients undergoing chemotherapy. J Clin Oncol 20(12): 2851–2862, 2002.

45. Stanton AL, Ganz PA, Kwan L, et al: Outcomes from the Moving Beyond Cancer psychoeducational, randomized, controlled trial with breast cancer patients. J Clin Oncol 23(25):6009–6018, 2005.