Fatigue (PDQ®)

References

1. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue. Version 2.2024. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2024. Available online with registration. Last accessed July 17, 2024.
2. Prue G, Rankin J, Allen J, et al.: Cancer-related fatigue: A critical appraisal. Eur J Cancer 42 (7): 846-63, 2006. [PubMed: 16460928]
3. Mo J, Darke AK, Guthrie KA, et al.: Association of Fatigue and Outcomes in Advanced Cancer: An Analysis of Four SWOG Treatment Trials. JCO Oncol Pract 17 (8): e1246-e1257, 2021. [PMC free article: PMC8360454] [PubMed: 34255538]
4. Aapro M, Scotte F, Bouillet T, et al.: A Practical Approach to Fatigue Management in Colorectal Cancer. Clin Colorectal Cancer 16 (4): 275-285, 2017. [PubMed: 29066018]
5. Henry DH, Viswanathan HN, Elkin EP, et al.: Symptoms and treatment burden associated with cancer treatment: results from a cross-sectional national survey in the U.S. Support Care Cancer 16 (7): 791-801, 2008. [PubMed: 18204940]
6. 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: 16400678]
7. Di Meglio A, Havas J, Soldato D, et al.: Development and Validation of a Predictive Model of Severe Fatigue After Breast Cancer Diagnosis: Toward a Personalized Framework in Survivorship Care. J Clin Oncol 40 (10): 1111-1123, 2022. [PMC free article: PMC8966972] [PubMed: 35061509]
8. Vaz-Luis I, Di Meglio A, Havas J, et al.: Long-Term Longitudinal Patterns of Patient-Reported Fatigue After Breast Cancer: A Group-Based Trajectory Analysis. J Clin Oncol 40 (19): 2148-2162, 2022. [PMC free article: PMC9242405] [PubMed: 35290073]
9. 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: 12663711]
10. Saligan LN, Olson K, Filler K, et al.: The biology of cancer-related fatigue: a review of the literature. Support Care Cancer 23 (8): 2461-78, 2015. [PMC free article: PMC4484308] [PubMed: 25975676]
11. 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: 10986063]
12. 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: 10983479]
13. 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: 11900238]
14. Stone PC, Minton O: Cancer-related fatigue. Eur J Cancer 44 (8): 1097-104, 2008. [PubMed: 18381237]
15. Berger AM, Abernethy AP, Atkinson A, et al.: Cancer-related fatigue. J Natl Compr Canc Netw 8 (8): 904-31, 2010. [PubMed: 20870636]
16. Barsevick AM, Whitmer K, Walker L: In their own words: using the common sense model to analyze patient descriptions of cancer-related fatigue. Oncol Nurs Forum 28 (9): 1363-9, 2001. [PubMed: 11683307]
17. Bower JE, Wiley J, Petersen L, et al.: Fatigue after breast cancer treatment: Biobehavioral predictors of fatigue trajectories. Health Psychol 37 (11): 1025-1034, 2018. [PMC free article: PMC6372460] [PubMed: 30321021]
18. Glaus A: Assessment of fatigue in cancer and non-cancer patients and in healthy individuals. Support Care Cancer 1 (6): 305-15, 1993. [PubMed: 8156248]
19. 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: 12096292]
20. Curt GA: The impact of fatigue on patients with cancer: overview of FATIGUE 1 and 2. Oncologist 5 (Suppl 2): 9-12, 2000. [PubMed: 10896323]
21. Bower JE: Cancer-related fatigue--mechanisms, risk factors, and treatments. Nat Rev Clin Oncol 11 (10): 597-609, 2014. [PMC free article: PMC4664449] [PubMed: 25113839]
22. 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: 17039982]
23. Rao AV, Cohen HJ: Fatigue in older cancer patients: etiology, assessment, and treatment. Semin Oncol 35 (6): 633-42, 2008. [PubMed: 19027467]
24. 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. [PMC free article: PMC1599708] [PubMed: 16010529]

References

1. Bower JE: Cancer-related fatigue--mechanisms, risk factors, and treatments. Nat Rev Clin Oncol 11 (10): 597-609, 2014. [PMC free article: PMC4664449] [PubMed: 25113839]
2. Bower JE, Ganz PA, Aziz N, et al.: Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosom Med 64 (4): 604-11, 2002 Jul-Aug. [PubMed: 12140350]
3. Evans WJ, Lambert CP: Physiological basis of fatigue. Am J Phys Med Rehabil 86 (1 Suppl): S29-46, 2007. [PubMed: 17370370]
4. Bower JE, Ganz PA, Tao ML, et al.: Inflammatory biomarkers and fatigue during radiation therapy for breast and prostate cancer. Clin Cancer Res 15 (17): 5534-40, 2009. [PMC free article: PMC2884979] [PubMed: 19706826]
5. Bower JE, Wiley J, Petersen L, et al.: Fatigue after breast cancer treatment: Biobehavioral predictors of fatigue trajectories. Health Psychol 37 (11): 1025-1034, 2018. [PMC free article: PMC6372460] [PubMed: 30321021]
6. Bower JE, Ganz PA, Aziz N: Altered cortisol response to psychologic stress in breast cancer survivors with persistent fatigue. Psychosom Med 67 (2): 277-80, 2005 Mar-Apr. [PubMed: 15784794]
7. Bower JE, Ganz PA, Dickerson SS, et al.: Diurnal cortisol rhythm and fatigue in breast cancer survivors. Psychoneuroendocrinology 30 (1): 92-100, 2005. [PubMed: 15358446]
8. Jager A, Sleijfer S, van der Rijt CC: The pathogenesis of cancer related fatigue: could increased activity of pro-inflammatory cytokines be the common denominator? Eur J Cancer 44 (2): 175-81, 2008. [PubMed: 18162394]
9. Morrow GR, Andrews PL, Hickok JT, et al.: Fatigue associated with cancer and its treatment. Support Care Cancer 10 (5): 389-98, 2002. [PubMed: 12136222]

Cancer Treatment

The association of fatigue with the major cancer treatment modalities of surgery, chemotherapy, radiation therapy, endocrine 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-alpha and the finding of elevated levels of proinflammatory cytokines in people experiencing persistent fatigue after cancer treatment.[9,10] In longitudinal studies of patients undergoing radiation therapy, polymorphisms in tumor necrosis factor-alpha and interleukin-6 were associated with elevated fatigue before, during, and for 4 months after completion of treatment.[11,12]

Many people with cancer undergo surgery for diagnosis or treatment. Despite the high incidence of postoperative fatigue observed in these patients in clinical practice, few investigators have examined its causes and correlates. It is clear, however, that fatigue postsurgery improves with time and is compounded by fatigue caused by other cancer treatments.[13,14]

Fatigue has long been associated with radiation exposure and is reportedly one of the most common and activity-limiting side effects of radiation therapy for cancer.[15,16] Up to 90% of patients undergoing radiation therapy experience fatigue during the course of their treatment.[17] Most of the research describing the fatigue trajectory during radiation therapy has been conducted in women with breast cancer and men with prostate cancer.[3,18]

Fatigue increases throughout radiation therapy, peaking around mid-course and remaining at this level until radiation therapy is completed. It then improves somewhat during the 2 months after treatment ends. A study that investigated the trajectory of fatigue in men who were undergoing radiation therapy for prostate cancer (N = 82) found significant interindividual variability.[3] The authors used hierarchical linear modeling, a highly sophisticated analytical method, to identify predictors for prolonged fatigue trajectories. Younger men with high levels of fatigue at the initiation of radiation therapy were at increased risk of developing higher levels of morning and evening fatigue during radiation therapy. In addition, the level of depression at the initiation of radiation therapy predicted the level of morning fatigue during radiation therapy.[3]

A second study of 73 women who were undergoing adjuvant radiation therapy for breast cancer found similar differences in the patterns and predictors of morning versus evening fatigue.[7] Participants were recruited to the study at their simulation visits and completed baseline questionnaires. Data were then collected on 2 subsequent days, in the morning and at bedtime, each week during radiation therapy; every 2 weeks for 2 months after radiation therapy; and once a month for 2 additional months thereafter. Fatigue was measured with the Lee Fatigue Scale. For the group as a whole, over the 25 weeks of data collection, morning fatigue decreased slightly during radiation therapy and was constant for 4 months afterwards, while evening fatigue increased through radiation therapy and then declined slightly after treatment. Evening fatigue was higher for those who:

• Were working.
• Had children at home.
• Had higher depression scores.

Morning fatigue was higher for those who:

• Had more trait anxiety.
• Were experiencing sleep disturbance.
• Were younger.
• Had lower body mass indices.

Advanced disease and comorbidities also added to the severity of morning fatigue.[7][Level of evidence: III]

Several research studies document a fatigue syndrome that is not specific to disease type or radiation site and that demonstrates a gradual decline in fatigue in the patient after treatment is completed.[19,20] Some of these studies suggest, however, that not all patients return to pretreatment energy levels. Risk factors for persistent low energy in cancer patients include pretreatment fatigue, psychological distress, high BMI, tumor location, advanced disease, and combination-modality therapy.[8,14,21]

Fatigue is a dose-limiting toxicity of treatment with a variety of biotherapeutic agents. Biotherapy exposes patients with cancer to exogenous and endogenous cytokines.[22] Biotherapy-related fatigue usually occurs as part of a constellation of symptoms called flulike syndrome.

Mental fatigue and cognitive deficits have also been identified as biotherapy side effects. The type of biotherapeutic agent used may influence the type and pattern of fatigue.[23,24]

Treatment with chemotherapy is a predictor of fatigue and can be exacerbated by the coexistence of pain, depression, and/or anxiety.[25][Level of evidence: II]; [26] A longitudinal, descriptive study reported the highest levels of fatigue at the midpoint of a patient’s chemotherapy cycles, with fatigue improving after treatment but not quite returning to baseline levels 30 days after the last treatment.[25] In another longitudinal study of women with stage 0 to stage II breast cancer who received chemotherapy with or without radiation therapy (n = 103) versus radiation therapy alone (n = 102) versus a control group (n = 193),[27] increases in fatigue were demonstrated 3 years posttreatment for the group that received chemotherapy with or without radiation therapy, compared with the two other groups. Mean scores for fatigue severity measured by the Fatigue Symptom Inventory (range, 0–10) increased over the 3 years.

A longitudinal, descriptive study of 78 women with gynecological cancer examined the daily and intraday changes and interrelationships among fatigue, depression, and disruptions in sleep and activity, before and after each individual chemotherapy treatment, for three treatments. Significant changes in symptoms were noted over time. Before infusions, fatigue was associated with depression; after infusions, fatigue was significantly associated with increased depression and sleep/wake irregularities (increases in minutes awake at night and decreases in daytime activity and sleep/wake activity).[28]

Aromatase inhibitors—the recommended first-line adjuvant endocrine therapy in postmenopausal women with hormone receptor–positive breast cancer—have been linked to cancer-related fatigue (CRF). In one study of survivors of stage 0 to III breast cancer who were receiving adjuvant aromatase inhibitor therapy at an outpatient breast oncology clinic, 616 of 1,103 participants (55.8%) had moderate to severe CRF.[29] In addition, breast cancer survivors who were younger (age ≤55 years), were college educated, had higher body mass indices, and reported more pain and insomnia were more likely to have moderate to severe CRF than were their counterparts.

Treatment with immune checkpoint inhibitors has been associated with clinically significant fatigue. Reviews of outcomes data demonstrated that fatigue is the most common adverse event incorporating anti–programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) agents. In the first phase I studies of nivolumab, 16% to 24% of patients had treatment-related fatigue, and 1% to 2% had grade 3 or 4 severity. Single-agent immune checkpoint studies have reported an incidence of 16% to 37% with anti–PD-1 agents, and 12% to 24% with anti–PD-L1 agents. Clinical studies that combined anti–PD-1/PD-L1 agents with other immune checkpoint inhibitors reported even higher rates of fatigue, in up to 71% of patients. The specific mechanism by which immune checkpoint inhibitors cause fatigue is not known; however, when fatigue symptoms occur during treatment, clinicians should be vigilant in assessing for early symptoms of endocrine dysfunction, such as hypothyroidism.[30-33]

Anemia

Evidence suggests that anemia may be a major factor in CRF and quality of life in cancer patients.[34-36] Anemia can be related to the disease itself or caused by therapy. Occasionally, anemia is simply a co-occurring medical finding that is related to neither disease nor therapy. Anemia is often a significant contributor to symptoms in people with cancer. For individual patients, it can be difficult to discern the actual impact of anemia because there are often other problems that confound the ability to weigh the specific impact of anemia.[37]

A retrospective review was conducted to understand anemia in patients undergoing radiation therapy. Anemia was found in 48% of the patients initially and increased to 57% during therapy. It was more common in women than in men (64% vs. 51%); however, men with prostate cancer experienced the greatest increase in anemia during radiation therapy.[38] In certain cancers, such as cancer of the cervix and cancer of the head and neck, anemia has been found to predict poor survival and diminished quality of life in patients undergoing radiation therapy.[39-41]

Nutrition Factors

Fatigue often occurs when the body's energy requirements exceed the supply of energy sources. 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.
• Decrease in intake of energy sources.

Causes of nutritional alterations are listed in Table 1.

Table

Table 1. Nutrition/Energy Factors in Cancer.

A randomized controlled trial compared a plant-based, high-protein diet to usual care in 103 patients with newly diagnosed breast cancer who were undergoing adjuvant chemotherapy.[42][Level of evidence: I] Patients were assessed over three time points (T0: baseline, T1: end of third chemotherapy infusion, T2: 3 weeks after last treatment). Fatigue was measured using the Fatigue Symptom Inventory, which has a clinically meaningful fatigue level threshold of more than 3. Patients in the control group (n = 51) had an increase in mean fatigue score from 4.2 + 1.64 to 5.37 + 1.87, while patients in the intervention group (n = 52) had a decrease in mean fatigue score from 4.2 + 1.94 to 2.47 + 1.31 (P < .001). Of note, the intervention group's fatigue level decreased to below a clinically meaningful level between T0 and T2, while the control group’s fatigue level stayed above the clinically meaningful threshold and slightly worsened. In addition, while both groups had a decrease in BMI (intervention group, 0.7 + 0.8 kg/m²; control group, 0.4 + 1.3 kg/m²), the control group had a decrease in muscle mass, and the intervention group had an increase in muscle mass and a decrease in fat mass (P < .001). A plant-based, high protein diet may be an effective approach to fatigue management.

Psychological Factors

Numerous factors related to the moods, beliefs, attitudes, and reactions to stressors of people with cancer can also contribute to the development of chronic fatigue. Anxiety and depression are the most common comorbid psychiatric disorders of CRF.[43][Level of evidence: II] Often, fatigue is the final common pathway for a range of physical and emotional etiologies.

Depression can be a comorbid, disabling syndrome that affects approximately 15% to 25% of people with cancer.[28,44] Multiple studies show that pretreatment depression increases fatigue during and after cancer treatment.[9,45,46] The presence of depression—manifested by loss of interest in normal activities, difficulty concentrating, lethargy, and feelings of hopelessness—can compound the physical causes of fatigue in these individuals and persist long past the time when physical causes have resolved.[47] A history of stressful experiences in childhood, including abuse and neglect, has also been associated with higher levels of fatigue in breast cancer survivors.[48]

The anxiety and fear associated with a cancer diagnosis—and the impact of that diagnosis on a person’s physical, psychosocial, and financial well-being—are sources of emotional stress. Distress associated with the cancer diagnosis 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% of participants 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 patients. Therefore, fatigue may 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.[49]

In cancer survivors, fatigue may also be above levels seen in the general population.[50,51] A Brazilian study found that in patients who had advanced cancer but were not undergoing therapy, those with anxiety and depression had higher fatigue levels.[51] A Dutch study found a correlation between anxiety, depression, and CRF.[52] Despite psychological care, those with poorer physical health and mood disturbances reported more fatigue. For more information, see Depression and Adjustment to Cancer: Anxiety and Distress.

Psychological and symptom distress have also been found to be significant predictors of fatigue.[53,54] In a study of 101 women about to undergo surgery for breast cancer, younger age, presurgery distress, and expectations about fatigue significantly predicted fatigue levels 1 week after surgery. In the regression model, age, distress, and expectancy each uniquely contributed to fatigue, with distress and expectancy accounting for 25% of the variance.[53][Level of evidence: III] In a longitudinal study with women who had gynecological cancer, symptom and psychological distress significantly predicted fatigue before, during, and after treatment with chemotherapy, explaining up to 80% of the variance in fatigue scores after chemotherapy treatment.[54] In another study, posttreatment colorectal cancer patients were found to have more fatigue when they had catastrophizing thoughts (rumination, magnification, and helplessness).[55] Factors similar to those seen in patients with early-stage cancer also contribute to fatigue in patients with advanced, incurable cancer.[56]

Cognitive Factors

Impairment in cognitive functioning, including decreased attention span and impaired perception and thinking, is commonly associated with fatigue.[57] Although fatigue and cognitive impairments are linked, the mechanism underlying this association is unclear. The 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.[57] Some of these problems may be caused by the fatigue of directed attention.[57,58] Attention fatigue may be relieved by activities that promote rest and restore directed attention.[58] Although sleep is necessary for relieving attention fatigue and restoring attention, it is insufficient when attention demands are high. Research in this area is limited and most commonly conducted in breast cancer patients, potentially limiting its application across diverse populations. Empirical literature suggests that exposure to the natural environment may help restore directed attention and relieve attention fatigue.

Sleep Disorders and Inactivity

Causative or contributing factors in CRF may be:

• Disrupted sleep.
• Poor sleep hygiene.
• Decreased nighttime sleep or excessive daytime sleep.
• Inactivity.
• Timing of therapy.[28]

Patients with less daytime activity, restless sleep, and obesity were noted to have consistently higher levels of CRF.[59]

Sleep disorders clearly contribute to fatigue [60] and may differentially affect fatigue ratings, depending on the time of the rating. A study that evaluated fatigue in women undergoing radiation therapy for breast cancer found that sleep had a greater influence on fatigue values in the morning than in the evening.[7] However, fatigue and sleep can also be distinct problems. One study found that the use of cognitive behavioral therapy resulted in significant improvement in sleep quality but did not significantly affect CRF.[61] For more information, see Sleep Disorders.

Other Medications That Contribute to Fatigue

Medications other than chemotherapy drugs may contribute to fatigue. Opioids used to treat cancer-related pain are often associated with sedation, though the degree varies among individuals. Opioids are known to alter the normal function of the hypothalamic secretion of gonadotropin-releasing hormone.[62] Hypogonadism may be found in patients with advanced cancer and can contribute to fatigue during cancer treatment.[63,64] One case-control study examined the effects of chronic oral opioid administration in survivors of cancer and, consistent with the research on intrathecal administration, found marked central hypogonadism among the opioid users with significant symptoms of sexual dysfunction, depression, and fatigue.[65] In patients with hypogonadism and symptoms of fatigue, testosterone replacement over a month had mixed results in clinical trials, with benefit for fatigue occurring around the 70-day mark, but with no improvement in quality of life.[66]

Other medications—including tricyclic antidepressants, neuroleptics, beta blockers, benzodiazepines, and antihistamines—may produce side effects of sedation. 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. The coadministration of multiple drugs with varying side effects may compound fatigue symptoms.

References

1. Campos MP, Hassan BJ, Riechelmann R, et al.: Cancer-related fatigue: a practical review. Ann Oncol 22 (6): 1273-9, 2011. [PubMed: 21325448]
2. Yennurajalingam S, Palmer JL, Zhang T, et al.: Association between fatigue and other cancer-related symptoms in patients with advanced cancer. Support Care Cancer 16 (10): 1125-30, 2008. [PubMed: 18504622]
3. Miaskowski C, Paul SM, Cooper BA, et al.: Trajectories of fatigue in men with prostate cancer before, during, and after radiation therapy. J Pain Symptom Manage 35 (6): 632-43, 2008. [PMC free article: PMC2491660] [PubMed: 18358683]
4. Vaz-Luis I, Di Meglio A, Havas J, et al.: Long-Term Longitudinal Patterns of Patient-Reported Fatigue After Breast Cancer: A Group-Based Trajectory Analysis. J Clin Oncol 40 (19): 2148-2162, 2022. [PMC free article: PMC9242405] [PubMed: 35290073]
5. Bortolon C, Krikorian A, Carayol M, et al.: Cancer-related fatigue in breast cancer patients after surgery: a multicomponent model using partial least squares-path modeling. Psychooncology 23 (4): 444-51, 2014. [PubMed: 24150929]
6. 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 120 (3): 425-32, 2014. [PMC free article: PMC3949157] [PubMed: 24436136]
7. Dhruva A, Dodd M, Paul SM, et al.: Trajectories of fatigue in patients with breast cancer before, during, and after radiation therapy. Cancer Nurs 33 (3): 201-12, 2010 May-Jun. [PMC free article: PMC2881569] [PubMed: 20357659]
8. Pertl MM, Hevey D, Boyle NT, et al.: C-reactive protein predicts fatigue independently of depression in breast cancer patients prior to chemotherapy. Brain Behav Immun 34: 108-19, 2013. [PubMed: 23928287]
9. Xiao C, Miller AH, Felger J, et al.: Depressive symptoms and inflammation are independent risk factors of fatigue in breast cancer survivors. Psychol Med 47 (10): 1733-1743, 2017. [PubMed: 28193310]
10. Wang XS, Williams LA, Krishnan S, et al.: Serum sTNF-R1, IL-6, and the development of fatigue in patients with gastrointestinal cancer undergoing chemoradiation therapy. Brain Behav Immun 26 (5): 699-705, 2012. [PMC free article: PMC3355215] [PubMed: 22251605]
11. Aouizerat BE, Dodd M, Lee K, et al.: Preliminary evidence of a genetic association between tumor necrosis factor alpha and the severity of sleep disturbance and morning fatigue. Biol Res Nurs 11 (1): 27-41, 2009. [PubMed: 19419979]
12. Miaskowski C, Dodd M, Lee K, et al.: Preliminary evidence of an association between a functional interleukin-6 polymorphism and fatigue and sleep disturbance in oncology patients and their family caregivers. J Pain Symptom Manage 40 (4): 531-44, 2010. [PMC free article: PMC2952712] [PubMed: 20570482]
13. Reinertsen KV, Engebraaten O, Loge JH, et al.: Fatigue During and After Breast Cancer Therapy-A Prospective Study. J Pain Symptom Manage 53 (3): 551-560, 2017. [PubMed: 28042070]
14. Kuhnt S, Szalai C, Erdmann-Reusch B, et al.: [Cancer Related Fatigue in Rehabilitation Care]. Rehabilitation (Stuttg) 56 (5): 337-343, 2017. [PubMed: 28437815]
15. Donovan KA, Jacobsen PB, Andrykowski MA, et al.: Course of fatigue in women receiving chemotherapy and/or radiotherapy for early stage breast cancer. J Pain Symptom Manage 28 (4): 373-80, 2004. [PMC free article: PMC2398710] [PubMed: 15471655]
16. 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: 8935141]
17. Hofman M, Ryan JL, Figueroa-Moseley CD, et al.: Cancer-related fatigue: the scale of the problem. Oncologist 12 (Suppl 1): 4-10, 2007. [PubMed: 17573451]
18. Kishan AU, Wang PC, Sharif J, et al.: Clinical Indicators of Psychosocial Distress Predict for Acute Radiation-Induced Fatigue in Patients Receiving Adjuvant Radiation Therapy for Breast Cancer: An Analysis of Patient-Reported Outcomes. Int J Radiat Oncol Biol Phys 95 (3): 946-955, 2016. [PubMed: 27105720]
19. Bower JE: Cancer-related fatigue--mechanisms, risk factors, and treatments. Nat Rev Clin Oncol 11 (10): 597-609, 2014. [PMC free article: PMC4664449] [PubMed: 25113839]
20. Hsiao CP, Daly B, Saligan LN: The Etiology and management of radiotherapy-induced fatigue. Expert Rev Qual Life Cancer Care 1 (4): 323-328, 2016. [PMC free article: PMC5891725] [PubMed: 29651466]
21. Goedendorp MM, Gielissen MF, Verhagen CA, et al.: Development of fatigue in cancer survivors: a prospective follow-up study from diagnosis into the year after treatment. J Pain Symptom Manage 45 (2): 213-22, 2013. [PubMed: 22926087]
22. Bower JE, Lamkin DM: Inflammation and cancer-related fatigue: mechanisms, contributing factors, and treatment implications. Brain Behav Immun 30 (Suppl): S48-57, 2013. [PMC free article: PMC3978020] [PubMed: 22776268]
23. Weber JS, Yang JC, Atkins MB, et al.: Toxicities of Immunotherapy for the Practitioner. J Clin Oncol 33 (18): 2092-9, 2015. [PMC free article: PMC4881375] [PubMed: 25918278]
24. Wick W, Hertenstein A, Platten M: Neurological sequelae of cancer immunotherapies and targeted therapies. Lancet Oncol 17 (12): e529-e541, 2016. [PubMed: 27924751]
25. Berger AM, Lockhart K, Agrawal S: Variability of patterns of fatigue and quality of life over time based on different breast cancer adjuvant chemotherapy regimens. Oncol Nurs Forum 36 (5): 563-70, 2009. [PubMed: 19726396]
26. So WK, Marsh G, Ling WM, et al.: The symptom cluster of fatigue, pain, anxiety, and depression and the effect on the quality of life of women receiving treatment for breast cancer: a multicenter study. Oncol Nurs Forum 36 (4): E205-14, 2009. [PubMed: 19581224]
27. Goedendorp MM, Andrykowski MA, Donovan KA, et al.: Prolonged impact of chemotherapy on fatigue in breast cancer survivors: a longitudinal comparison with radiotherapy-treated breast cancer survivors and noncancer controls. Cancer 118 (15): 3833-41, 2012. [PMC free article: PMC4007757] [PubMed: 22086766]
28. Jim HS, Small B, Faul LA, et al.: Fatigue, depression, sleep, and activity during chemotherapy: daily and intraday variation and relationships among symptom changes. Ann Behav Med 42 (3): 321-33, 2011. [PMC free article: PMC3432914] [PubMed: 21785899]
29. Mao H, Bao T, Shen X, et al.: Prevalence and risk factors for fatigue among breast cancer survivors on aromatase inhibitors. Eur J Cancer 101: 47-54, 2018. [PMC free article: PMC6148367] [PubMed: 30014974]
30. Topalian SL, Hodi FS, Brahmer JR, et al.: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366 (26): 2443-54, 2012. [PMC free article: PMC3544539] [PubMed: 22658127]
31. Brahmer JR, Tykodi SS, Chow LQ, et al.: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366 (26): 2455-65, 2012. [PMC free article: PMC3563263] [PubMed: 22658128]
32. Rizvi NA, Mazières J, Planchard D, et al.: Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 16 (3): 257-65, 2015. [PMC free article: PMC5726228] [PubMed: 25704439]
33. Naidoo J, Page DB, Li BT, et al.: Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol 26 (12): 2375-91, 2015. [PMC free article: PMC6267867] [PubMed: 26371282]
34. 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: 11900238]
35. Jacobsen PB, Garland LL, Booth-Jones M, et al.: Relationship of hemoglobin levels to fatigue and cognitive functioning among cancer patients receiving chemotherapy. J Pain Symptom Manage 28 (1): 7-18, 2004. [PubMed: 15223080]
36. Blair S, Bardwell WA, Podbelewicz-Schuller Y, et al.: Correlation between hemoglobin and fatigue in women undergoing adjuvant chemotherapy without erythropoietin-stimulating-agent support. Clin Breast Cancer 8 (6): 522-6, 2008. [PMC free article: PMC4689300] [PubMed: 19073508]
37. Jacobsen PB, Thors CL: Fatigue in the radiation therapy patient: current management and investigations. Semin Radiat Oncol 13 (3): 372-80, 2003. [PubMed: 12903024]
38. Bush RS: The significance of anemia in clinical radiation therapy. Int J Radiat Oncol Biol Phys 12 (11): 2047-50, 1986. [PubMed: 3771322]
39. 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: 2912956]
40. 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: 8888257]
41. 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: 10847301]
42. Sathiaraj E, Afshan K, R S, et al.: Effects of a Plant-Based High-Protein Diet on Fatigue in Breast Cancer Patients Undergoing Adjuvant Chemotherapy - a Randomized Controlled Trial. Nutr Cancer 75 (3): 846-856, 2023. [PubMed: 36546552]
43. Williams AM, Khan CP, Heckler CE, et al.: Fatigue, anxiety, and quality of life in breast cancer patients compared to non-cancer controls: a nationwide longitudinal analysis. Breast Cancer Res Treat 187 (1): 275-285, 2021. [PMC free article: PMC8080260] [PubMed: 33392843]
44. Krebber AM, Buffart LM, Kleijn G, et al.: Prevalence of depression in cancer patients: a meta-analysis of diagnostic interviews and self-report instruments. Psychooncology 23 (2): 121-30, 2014. [PMC free article: PMC4282549] [PubMed: 24105788]
45. Goldstein D, Bennett BK, Webber K, et al.: Cancer-related fatigue in women with breast cancer: outcomes of a 5-year prospective cohort study. J Clin Oncol 30 (15): 1805-12, 2012. [PubMed: 22508807]
46. Andrykowski MA, Donovan KA, Laronga C, et al.: Prevalence, predictors, and characteristics of off-treatment fatigue in breast cancer survivors. Cancer 116 (24): 5740-8, 2010. [PMC free article: PMC4048855] [PubMed: 20734399]
47. 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: 11454886]
48. Fagundes CP, Lindgren ME, Shapiro CL, et al.: Child maltreatment and breast cancer survivors: social support makes a difference for quality of life, fatigue and cancer stress. Eur J Cancer 48 (5): 728-36, 2012. [PMC free article: PMC3202655] [PubMed: 21752636]
49. Cimprich B: Pretreatment symptom distress in women newly diagnosed with breast cancer. Cancer Nurs 22 (3): 185-94; quiz 195, 1999. [PubMed: 10376379]
50. 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: 16400678]
51. Rodrigues AR, Trufelli DC, Fonseca F, et al.: Fatigue in Patients With Advanced Terminal Cancer Correlates With Inflammation, Poor Quality of Life and Sleep, and Anxiety/Depression. Am J Hosp Palliat Care 33 (10): 942-947, 2016. [PubMed: 26324072]
52. Zhu L, Ranchor AV, van der Lee M, et al.: Co-morbidity of depression, anxiety and fatigue in cancer patients receiving psychological care. Psychooncology 26 (4): 444-451, 2017. [PubMed: 27193933]
53. Montgomery GH, Schnur JB, Erblich J, et al.: Presurgery psychological factors predict pain, nausea, and fatigue one week after breast cancer surgery. J Pain Symptom Manage 39 (6): 1043-52, 2010. [PMC free article: PMC2918882] [PubMed: 20538186]
54. Prue G, Allen J, Gracey J, et al.: Fatigue in gynecological cancer patients during and after anticancer treatment. J Pain Symptom Manage 39 (2): 197-210, 2010. [PubMed: 19995675]
55. Müller F, Stephenson E, DeLongis A, et al.: The reciprocal relationship between daily fatigue and catastrophizing following cancer treatment: Affect and physical activity as potential mediators. Psychooncology 27 (3): 831-837, 2018. [PubMed: 29076568]
56. Peters ME, Goedendorp MM, Verhagen SA, et al.: Exploring the contribution of psychosocial factors to fatigue in patients with advanced incurable cancer. Psychooncology 23 (7): 773-9, 2014. [PubMed: 24458595]
57. 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 2 (3): 231-8, 2012. [PMC free article: PMC3621525] [PubMed: 23585925]
58. Von Ah D, Storey S, Crouch A, et al.: Relationship of Self-reported Attentional Fatigue to Perceived Work Ability in Breast Cancer Survivors. Cancer Nurs 40 (6): 464-470, 2017 Nov/Dec. [PubMed: 27782905]
59. Berger AM: Update on the state of the science: sleep-wake disturbances in adult patients with cancer. Oncol Nurs Forum 36 (4): E165-77, 2009. [PubMed: 19581220]
60. 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. [PMC free article: PMC1599708] [PubMed: 16010529]
61. Berger AM, Kuhn BR, Farr LA, et al.: One-year outcomes of a behavioral therapy intervention trial on sleep quality and cancer-related fatigue. J Clin Oncol 27 (35): 6033-40, 2009. [PMC free article: PMC2793045] [PubMed: 19884558]
62. Katz N, Mazer NA: The impact of opioids on the endocrine system. Clin J Pain 25 (2): 170-5, 2009. [PubMed: 19333165]
63. 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 107 (12): 2949-57, 2006. [PubMed: 17103445]
64. Dev R, Hui D, Del Fabbro E, et al.: Association between hypogonadism, symptom burden, and survival in male patients with advanced cancer. Cancer 120 (10): 1586-93, 2014. [PMC free article: PMC4046338] [PubMed: 24577665]
65. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, et al.: Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer 100 (4): 851-8, 2004. [PubMed: 14770444]
66. Del Fabbro E, Garcia JM, Dev R, et al.: Testosterone replacement for fatigue in hypogonadal ambulatory males with advanced cancer: a preliminary double-blind placebo-controlled trial. Support Care Cancer 21 (9): 2599-607, 2013. [PubMed: 23653013]

Evaluation of Anemia

The proper evaluation of anemia in cancer patients includes the following:

• A careful history and physical examination.
• An evaluation of the complete blood count and red blood cell indices.
• An 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 fL or lower and include iron-deficiency anemia, thalassemia, and anemia of chronic disease.
• Macrocytic anemias are associated with an MCV higher than 101 fL 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 the following:[26]

• 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.
• Aplastic anemia.

However, a mixed red blood cell population consisting of both microcytic and macrocytic cells (anisocytosis) 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 blood 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 tests for the following:

• 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. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue. Version 2.2024. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2024. Available online with registration. Last accessed July 17, 2024.
2. Mock V, Atkinson A, Barsevick AM, et al.: Cancer-related fatigue. Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 5 (10): 1054-78, 2007. [PubMed: 18053429]
3. Glaus A: Assessment of fatigue in cancer and non-cancer patients and in healthy individuals. Support Care Cancer 1 (6): 305-15, 1993. [PubMed: 8156248]
4. Fabi A, Bhargava R, Fatigoni S, et al.: Cancer-related fatigue: ESMO Clinical Practice Guidelines for diagnosis and treatment. Ann Oncol 31 (6): 713-723, 2020. [PubMed: 32173483]
5. 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: 17959345]
6. 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: 11728796]
7. 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: 9095563]
8. Smets EM, Garssen B, Bonke B, et al.: The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 39 (3): 315-25, 1995. [PubMed: 7636775]
9. Weis J, Arraras JI, Conroy T, et al.: Development of an EORTC quality of life phase III module measuring cancer-related fatigue (EORTC QLQ-FA13). Psychooncology 22 (5): 1002-7, 2013. [PubMed: 22565359]
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: 9599351]
11. Bower JE, Wiley J, Petersen L, et al.: Fatigue after breast cancer treatment: Biobehavioral predictors of fatigue trajectories. Health Psychol 37 (11): 1025-1034, 2018. [PMC free article: PMC6372460] [PubMed: 30321021]
12. Lee KA, Hicks G, Nino-Murcia G: Validity and reliability of a scale to assess fatigue. Psychiatry Res 36 (3): 291-8, 1991. [PubMed: 2062970]
13. 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: 10091805]
14. 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: 10687321]
15. 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: 11297027]
16. 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: 9253779]
17. Cella D: Manual of the Functional Assessment of Chronic Illness Therapy (FACIT) Scales. Version 4. Evanston Northwestern Healthcare, 1997.
18. Schwartz AL: The Schwartz Cancer Fatigue Scale: testing reliability and validity. Oncol Nurs Forum 25 (4): 711-7, 1998. [PubMed: 9599354]
19. McNair D, Lorr M, Droppelman L, et al.: Profile of Mood States. Educational and Industrial Testing Service, 1971.
20. 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: 9610214]
21. Portenoy RK, Itri LM: Cancer-related fatigue: guidelines for evaluation and management. Oncologist 4 (1): 1-10, 1999. [PubMed: 10337366]
22. 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: 12007758]
23. Cella D, Peterman A, Passik S, et al.: Progress toward guidelines for the management of fatigue. Oncology (Huntingt) 12 (11A): 369-77, 1998. [PubMed: 10028520]
24. 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. [PMC free article: PMC2515169] [PubMed: 18053431]
25. 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: 12547048]
26. Bohlius J, Bohlke K, Castelli R, et al.: Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice Guideline Update. J Clin Oncol 37 (15): 1336-1351, 2019. [PubMed: 30969847]

Treatment of Anemia

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, are considered in addition to other treatment modalities.

The transfusion of packed RBCs is the most widely used and most rapid way to alleviate symptoms in cancer patients with symptomatic anemia. The likelihood of raising a patient's hemoglobin level is very high with transfusion, and the risks of complications are low. Nevertheless, repeated transfusions can be cumbersome, and the risk of blood-borne infection can be worrisome. Other risks include an acute transfusion reaction, transfusion-associated graft-versus-host disease, subtle immune modulation that occurs with transfusion, and iron overload in patients who receive repeated transfusions.[6]

The management of cancer-associated anemia using erythropoiesis-stimulating agents (ESAs) was established in the 2019 American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) guidelines, which recommended the following:[7]

• ESAs (including biosimilars) may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin levels have declined to lower than 10 g/dL. RBC transfusion is also an option.
• With the exception of selected patients with myelodysplastic syndromes, ESAs should not be offered to most patients with non–chemotherapy-associated anemia.
• During ESA treatment, hemoglobin may be increased to the lowest concentration needed to avoid transfusions.
• Iron replacement may be used to improve hemoglobin response and reduce RBC transfusions for patients with or without iron deficiency who are receiving ESAs.
• ESAs increase the risk of thromboembolism, and clinicians should carefully weigh the risks of thromboembolism and use caution and clinical judgment when considering the use of these agents.[7]

Psychostimulants

Psychostimulants are a common pharmacological intervention for cancer-related fatigue (CRF); however, the evidence for their efficacy is mixed. Psychostimulants are drugs that interact with neurotransmitters and receptors in the brain to increase cortical function. Different types of psychostimulants work through various mechanisms to produce activity in the brain consistent with short-term improvement in energy level and psychomotor activity. These medications may also improve mood, attention, and concentration in some populations. Psychostimulant clinical trials for the management of fatigue include the following therapies (for information about levels of evidence and dosing used in the clinical trials, see Table 3):

• Methylphenidate.
• Dextroamphetamine.
• Modafinil.
• Armodafinil.

Psychostimulants are not approved by the U.S. Food and Drug Administration (FDA) for the treatment of CRF. However, preliminary evidence from randomized controlled studies [8-10] suggests that these medications might be helpful in a subpopulation of patients experiencing moderate to severe fatigue. Of the psychostimulants, methylphenidate is the most studied pharmacological agent for fatigue, yet the evidence for its efficacy is mixed.[11]

Table

Table 3. Centrally Acting Stimulants for Adult Cancer Patients.

Other Pharmacological Interventions

Exercise

Studies suggest that exercise or physical activity has a beneficial effect on fatigue in patients during and after cancer treatment. The National Comprehensive Cancer Network (NCCN) guidelines [41] identify physical activity as an intervention for patients during and after treatment (category 1 intervention). Researchers have noted reductions in fatigue of about 35% and improvements in vitality of 30% in randomized trials.[42,43] Other documented benefits of exercise or physical activity include the following:

• Improved physical energy.
• Appetite stimulation.
• Improved memory.
• Enhanced functional capacity.
• Enhanced psychosocial well-being (improved outlook, sense of well-being, and quality of life).

Initial trials of exercise programs focused on women with breast cancer, but subsequent studies included men with prostate cancer and patients with multiple myeloma, lung cancer, nasopharyngeal cancer, non-Hodgkin lymphoma, colorectal cancer, and advanced cancers.[44-46]

Some studies had methodological weaknesses, including the following:[47][Level of evidence: I]; [48]

• Selection biases and nonrepresentative samples.
• Varied type (aerobic, anaerobic, or combined), dose (frequency and duration), and timing (during or after cancer treatment) of exercise prescription.
• Poor adherence to exercise interventions.
• Highly varied assessments of research variables and outcome measures.
• Lack of adequate control groups.

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 to better pursue daily activities by increasing their recreational physical activities after cancer.[49][Level of evidence: II]

A similar study of breast cancer survivors (N = 222) who were randomly assigned to a 3-month, multicomponent physical activity and behavior change intervention (Better Exercise Adherence after Treatment for Cancer [BEAT Cancer]) demonstrated reduced fatigue, depression, and anxiety symptomatology.[50]

A study of 1,033 patients with breast, gynecological, gastrointestinal, or lung cancer who had received chemotherapy in the past 2 weeks identified associations between level of exercise and fatigue and co-occurring sleep disturbance.[51][Level of evidence: II] Three subgroups of patients were classified: no exercise, less exercise (<150 minutes per week), and recreational exercise (≥150 minutes per week). The most common reported exercise was walking. Compared with the other two groups, the no-exercise group had higher levels of morning fatigue, lower levels of morning and evening energy, and higher levels of sleep disturbance. Patients in the no-exercise group had fewer years of education, were more likely to be non-White, and had a higher body mass index and more comorbidities.[51][Level of evidence: II] These findings suggest associations among patient characteristics, engagement in exercise, and risk for fatigue.

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 reportedly improved in one study.[52][Level of evidence: III] 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.[53][Level of evidence: I] An observational study of patients with advanced cancer found that fatigue was less severe in those who engaged in physical exercise.[54]

When educating patients about activity with respect to CRF, one important goal to consider is inclusion of 3 to 5 hours per week of moderate activity. It is critical that:

• Patients choose a type of exercise they enjoy.
• Providers discuss specific implementation strategies (type of exercise, time of day, days of the week, location of activity) to enable patients to make frequent activity a reality.

Beginning with lighter activity for shorter periods of time and building in intensity and length of time may be required. Studies have confirmed this can be safely done both during active treatment and after treatment is completed.[42]

CBT

CBT has long been used to treat a variety of psycho-physiological problems, with therapy focusing on the thoughts (cognition) and functional behaviors relevant to the presenting problems. While most of the CBT research for CRF has focused on the survivor period, CBT and CBT variants (e.g., CBT-I and mindfulness-based cognitive therapy) have been shown to be useful during both active treatment and the survivor period.[45]

In the context of active treatment (e.g., chemotherapy, radiation therapy, surgery), CBT plus hypnosis may be effective for patients struggling with CRF.[70] Significant decreases in fatigue were reported over a 6-week course of psychotherapy during radiation therapy, compared with a control group. At a 6-month follow-up, the CBT group continued to experience significantly improved fatigue, compared with the control group.

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.[71][Level of evidence: I] The CBT focused on each participant's unique pattern of the following six possible factors that might perpetuate their post–cancer treatment fatigue:

• Insufficient coping with the experience of cancer.
• Fear of disease recurrence.
• Dysfunctional cognition regarding fatigue.
• Dysregulation of sleep.
• Dysregulation of activity.
• Low social support/negative social interactions.

The number of therapy sessions varied according to the number of perpetuating factors (range, 5–26 one-hour sessions; mean: 12.5 sessions). Results showed a clinically significant decrease in fatigue severity and functional impairment.

Fatigue-related improvements that occur during CBT for CRF can be maintained for extremely long periods of time, even without periodic, long-term follow-up (booster) sessions that are usually a component of CBT. In a 10-year follow-up of 81 individuals who completed a CRF CBT protocol,[72] fatigue levels increased among cancer survivors over the 10-year follow-up period, compared with the initial post-CBT assessment. In addition, at the 10-year follow-up, fatigue levels continued to be higher among cancer survivors compared with general-population controls. However, more than half of the cancer survivors (52%) who recovered from severe fatigue at the time of the post-CBT assessment maintained their low fatigue levels at the 10-year follow-up. While levels of fatigue deteriorated over time, the strong maintenance gains for more than half of the study population suggest that CBT for CRF can help control fatigue over long periods of time.

While CBT and medication therapy may often work hand in hand, some studies show that CBT alone has a more powerful impact on fatigue than medication alone. In a 7-week, double-blind treatment study,[23] 96 cancer survivors with cancer-related insomnia and fatigue were randomly divided into four groups:

• CBT-I plus placebo (twice a day).
• CBT-I plus armodafinil (50 mg twice a day).
• Placebo alone (twice a day).
• Armodafinil alone (50 mg twice a day).

The study found a significant reduction of fatigue with CBT alone or with CBT plus armodafinil (though the drug provided limited additive benefit compared with CBT alone), and no improvement with armodafinil alone.[23] Furthermore, the armodafinil group showed significantly less improvement than did the placebo-alone group.

Patient Education

Informing patients about the risk of fatigue and educating them about strategies to reduce fatigue are valuable adjuncts to other management strategies. However, a Cochrane review of educational interventions for CRF in adults cautions that educational interventions should be part of a more-comprehensive approach to managing fatigue.[73]

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 attention fatigue and encouragement 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 psychological and social stressors and how to avoid or reduce them.
• Evaluating the efficacy of fatigue interventions on a regular and systematic basis.

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.[74,75][Level of evidence: I] These intriguing results need to be further explored in patient populations other than women with breast or gynecological malignancies.

As researchers and practitioners have learned with pain, misconceptions and a lack of knowledge may prove to be patient- and provider-related barriers to successful assessment and management. A quasi-experimental study tested a multisystem educational approach to improving both pain and fatigue management.[76] The approach consisted of the following:

• Education and assessment of patients regarding the management of pain and fatigue, with phone calls every 2 weeks for 3 months.
• Education of providers about pain and fatigue assessment and management, including monthly newsletters.
• An effort to engage with an internal advisory board.
• Efforts aimed toward research nurses to refer earlier to supportive care services.

Over a 3-month period, the educational intervention resulted in increases in knowledge and a decrease in barriers related to management of pain and fatigue. Of note, important patient barriers related to fatigue management included the following beliefs:[76][Level of evidence: II]

• Fatigue is inevitable.
• Fatigue can indicate worsening of disease.
• Treating the cancer is more important than treating fatigue.
• Reporting fatigue will cause a patient to be perceived as a complainer.

Providing patient education about strategies to reduce fatigue may help eliminate the barriers related to managing fatigue.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. 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: 6728321]
2. 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: 9060566]
3. Gibson H, Edwards RH: Muscular exercise and fatigue. Sports Med 2 (2): 120-32, 1985 Mar-Apr. [PubMed: 3847097]
4. Hart LK: Fatigue in the patient with multiple sclerosis. Res Nurs Health 1 (4): 147-57, 1978.
5. 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 31 (6): 716-23, 2013. [PubMed: 23284036]
6. Armitage JO: Management of anemia in patients with cancer. Clinical Oncology Updates 1: 1-12, 1998.
7. Bohlius J, Bohlke K, Castelli R, et al.: Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice Guideline Update. J Clin Oncol 37 (15): 1336-1351, 2019. [PubMed: 30969847]
8. Lower EE, Fleishman S, Cooper A, et al.: Efficacy of dexmethylphenidate for the treatment of fatigue after cancer chemotherapy: a randomized clinical trial. J Pain Symptom Manage 38 (5): 650-62, 2009. [PubMed: 19896571]
9. Roth AJ, Nelson C, Rosenfeld B, et al.: Methylphenidate for fatigue in ambulatory men with prostate cancer. Cancer 116 (21): 5102-10, 2010. [PMC free article: PMC3632439] [PubMed: 20665492]
10. 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 116 (14): 3513-20, 2010. [PMC free article: PMC2941794] [PubMed: 20564068]
11. Yennurajalingam S, Bruera E: Review of clinical trials of pharmacologic interventions for cancer-related fatigue: focus on psychostimulants and steroids. Cancer J 20 (5): 319-24, 2014 Sep-Oct. [PubMed: 25299141]
12. Auret KA, Schug SA, Bremner AP, et al.: A randomized, double-blind, placebo-controlled trial assessing the impact of dexamphetamine on fatigue in patients with advanced cancer. J Pain Symptom Manage 37 (4): 613-21, 2009. [PubMed: 18790598]
13. Breitbart W, Alici Y: Psychostimulants for cancer-related fatigue. J Natl Compr Canc Netw 8 (8): 933-42, 2010. [PubMed: 20870637]
14. 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 28 (23): 3673-9, 2010. [PMC free article: PMC2917307] [PubMed: 20625123]
15. 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 43 (1): 68-77, 2012. [PubMed: 22208450]
16. Bruera E, Yennurajalingam S, Palmer JL, et al.: Methylphenidate and/or a nursing telephone intervention for fatigue in patients with advanced cancer: a randomized, placebo-controlled, phase II trial. J Clin Oncol 31 (19): 2421-7, 2013. [PMC free article: PMC3691358] [PubMed: 23690414]
17. 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 20 (1): 8-14, 2014 Jan-Feb. [PMC free article: PMC4510946] [PubMed: 24445757]
18. Richard PO, Fleshner NE, Bhatt JR, et al.: Phase II, randomised, double-blind, placebo-controlled trial of methylphenidate for reduction of fatigue levels in patients with prostate cancer receiving LHRH-agonist therapy. BJU Int 116 (5): 744-52, 2015. [PubMed: 24684534]
19. Mitchell GK, Hardy JR, Nikles CJ, et al.: The Effect of Methylphenidate on Fatigue in Advanced Cancer: An Aggregated N-of-1 Trial. J Pain Symptom Manage 50 (3): 289-96, 2015. [PubMed: 25896104]
20. 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 15 (10): 1420-8, 2013. [PMC free article: PMC3779045] [PubMed: 23925452]
21. 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 22 (5): 1233-42, 2014. [PubMed: 24337761]
22. 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 32 (18): 1882-8, 2014. [PubMed: 24778393]
23. 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 24 (5): 2059-2066, 2016. [PMC free article: PMC4805518] [PubMed: 26542272]
24. 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 23 (6): 1503-12, 2015. [PubMed: 25370889]
25. Medication Guide: PROVIGIL (modafinil) Tablets. North Wales, Pa: Teva Pharmaceuticals USA, Inc., 2015. Available online. Last accessed July 17, 2024.
26. Medication Guide: NUVIGIL (armodafinil) Tablets. North Wales, Pa: Teva Pharmaceuticals USA, Inc., 2017. Available online. Last accessed July 17, 2024.
27. 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 12 (5): 433-9, 2009. [PubMed: 19416039]
28. Spathis A, Dhillan R, Booden D, et al.: Modafinil for the treatment of fatigue in lung cancer: a pilot study. Palliat Med 23 (4): 325-31, 2009. [PubMed: 19270033]
29. CONCERTA (methylphenidate HCl) Extended-release Tablets. Titusville, NJ: Janssen Pharmaceuticals, Inc., 2023. Available online. Last accessed July 17, 2024.
30. Prommer E: Modafinil: is it ready for prime time? J Opioid Manag 2 (3): 130-6, 2006 May-Jun. [PubMed: 17319446]
31. ADDERALL XR (mixed salts of a single-entity amphetamine product), Extended-release Capsules, for Oral Use, CII. Lexington, Mass: Takeda Pharmaceutical America, Inc., 2023. Available online. Last accessed July 17, 2024.
32. 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: 16041840]
33. Ashrafi F, Mousavi S, Karimi M: Potential Role of Bupropion Sustained Release for Cancer-Related Fatigue: a Double-Blind, Placebo-Controlled Study Asian Pac J Cancer Prev 19 (6): 1547-1551, 2018. [PMC free article: PMC6103561] [PubMed: 29936730]
34. 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 31 (25): 3076-82, 2013. [PubMed: 23897970]
35. Barton DL, Soori GS, Bauer BA, et al.: Pilot study of Panax quinquefolius (American ginseng) to improve cancer-related fatigue: a randomized, double-blind, dose-finding evaluation: NCCTG trial N03CA. Support Care Cancer 18 (2): 179-87, 2010. [PMC free article: PMC3911883] [PubMed: 19415341]
36. 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 105 (16): 1230-8, 2013. [PMC free article: PMC3888141] [PubMed: 23853057]
37. Budzinski JW, Foster BC, Vandenhoek S, et al.: An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine 7 (4): 273-82, 2000. [PubMed: 10969720]
38. King ML, Adler SR, Murphy LL: Extraction-dependent effects of American ginseng (Panax quinquefolium) on human breast cancer cell proliferation and estrogen receptor activation. Integr Cancer Ther 5 (3): 236-43, 2006. [PubMed: 16880429]
39. Cruciani RA, Zhang JJ, Manola J, et al.: L-carnitine supplementation for the management of fatigue in patients with cancer: an eastern cooperative oncology group phase III, randomized, double-blind, placebo-controlled trial. J Clin Oncol 30 (31): 3864-9, 2012. [PMC free article: PMC3478577] [PubMed: 22987089]
40. 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 11 (1): 31-42, 2013. [PMC free article: PMC3501550] [PubMed: 22682875]
41. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue. Version 2.2024. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2024. Available online with registration. Last accessed July 17, 2024.
42. Berger AM, Abernethy AP, Atkinson A, et al.: Cancer-related fatigue. J Natl Compr Canc Netw 8 (8): 904-31, 2010. [PubMed: 20870636]
43. Cramp F, Daniel J: Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev (2): CD006145, 2008. [PubMed: 18425939]
44. Jacobsen PB, Donovan KA, Vadaparampil ST, et al.: Systematic review and meta-analysis of psychological and activity-based interventions for cancer-related fatigue. Health Psychol 26 (6): 660-7, 2007. [PMC free article: PMC2398706] [PubMed: 18020836]
45. Arring NM, Barton DL, Brooks T, et al.: Integrative Therapies for Cancer-Related Fatigue. Cancer J 25 (5): 349-356, 2019 Sep/Oct. [PMC free article: PMC7388739] [PubMed: 31567463]
46. Berger AM, Mitchell SA, Jacobsen PB, et al.: Screening, evaluation, and management of cancer-related fatigue: Ready for implementation to practice? CA Cancer J Clin 65 (3): 190-211, 2015 May-Jun. [PubMed: 25760293]
47. 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: 12406050]
48. Carayol M, Delpierre C, Bernard P, et al.: Population-, intervention- and methodology-related characteristics of clinical trials impact exercise efficacy during adjuvant therapy for breast cancer: a meta-regression analysis. Psychooncology 24 (7): 737-47, 2015. [PubMed: 25483860]
49. 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. [PMC free article: PMC2996230] [PubMed: 18648952]
50. Rogers LQ, Courneya KS, Anton PM, et al.: Effects of a multicomponent physical activity behavior change intervention on fatigue, anxiety, and depressive symptomatology in breast cancer survivors: randomized trial. Psychooncology 26 (11): 1901-1906, 2017. [PMC free article: PMC5511085] [PubMed: 27530961]
51. Moy S, Kober KM, Viele C, et al.: Level of Exercise Influences the Severity of Fatigue, Energy Levels, and Sleep Disturbance in Oncology Outpatients Receiving Chemotherapy. Cancer Nurs 45 (1): 3-11, 2022 Jan-Feb 01. [PubMed: 32897907]
52. Yoshioka H: Rehabilitation for the terminal cancer patient. Am J Phys Med Rehabil 73 (3): 199-206, 1994. [PubMed: 7515247]
53. 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: 15484202]
54. Peters ME, Goedendorp MM, Verhagen SA, et al.: Exploring the contribution of psychosocial factors to fatigue in patients with advanced incurable cancer. Psychooncology 23 (7): 773-9, 2014. [PubMed: 24458595]
55. 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. [PMC free article: PMC1819494] [PubMed: 17307761]
56. van Waart H, Stuiver MM, van Harten WH, et al.: Effect of Low-Intensity Physical Activity and Moderate- to High-Intensity Physical Exercise During Adjuvant Chemotherapy on Physical Fitness, Fatigue, and Chemotherapy Completion Rates: Results of the PACES Randomized Clinical Trial. J Clin Oncol 33 (17): 1918-27, 2015. [PubMed: 25918291]
57. Cramp F, Byron-Daniel J: Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev 11: CD006145, 2012. [PMC free article: PMC8480137] [PubMed: 23152233]
58. 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 25 (11): 2237-43, 2014. [PubMed: 25096607]
59. Juvet LK, Thune I, Elvsaas IKØ, et al.: The effect of exercise on fatigue and physical functioning in breast cancer patients during and after treatment and at 6 months follow-up: A meta-analysis. Breast 33: 166-177, 2017. [PubMed: 28415013]
60. Hilfiker R, Meichtry A, Eicher M, et al.: Exercise and other non-pharmaceutical interventions for cancer-related fatigue in patients during or after cancer treatment: a systematic review incorporating an indirect-comparisons meta-analysis. Br J Sports Med 52 (10): 651-658, 2018. [PMC free article: PMC5931245] [PubMed: 28501804]
61. Mazzoni AS, Strandberg E, Börjeson S, et al.: Reallocating sedentary time to physical activity: effects on fatigue and quality of life in patients with breast cancer in the Phys-Can project. Support Care Cancer 31 (2): 151, 2023. [PMC free article: PMC9899175] [PubMed: 36738358]
62. Oh B, Butow P, Mullan B, et al.: Impact of medical Qigong on quality of life, fatigue, mood and inflammation in cancer patients: a randomized controlled trial. Ann Oncol 21 (3): 608-14, 2010. [PMC free article: PMC2826100] [PubMed: 19880433]
63. Chen Z, Meng Z, Milbury K, et al.: Qigong improves quality of life in women undergoing radiotherapy for breast cancer: results of a randomized controlled trial. Cancer 119 (9): 1690-8, 2013. [PMC free article: PMC3852682] [PubMed: 23355182]
64. McQuade JL, Prinsloo S, Chang DZ, et al.: Qigong/tai chi for sleep and fatigue in prostate cancer patients undergoing radiotherapy: a randomized controlled trial. Psychooncology 26 (11): 1936-1943, 2017. [PMC free article: PMC5378667] [PubMed: 27548839]
65. Lin PJ, Kleckner IR, Loh KP, et al.: Influence of Yoga on Cancer-Related Fatigue and on Mediational Relationships Between Changes in Sleep and Cancer-Related Fatigue: A Nationwide, Multicenter Randomized Controlled Trial of Yoga in Cancer Survivors. Integr Cancer Ther 18: 1534735419855134, 2019 Jan-Dec. [PMC free article: PMC6552348] [PubMed: 31165647]
66. Bower JE, Garet D, Sternlieb B, et al.: Yoga for persistent fatigue in breast cancer survivors: a randomized controlled trial. Cancer 118 (15): 3766-75, 2012. [PMC free article: PMC3601551] [PubMed: 22180393]
67. Kiecolt-Glaser JK, Bennett JM, Andridge R, et al.: Yoga's impact on inflammation, mood, and fatigue in breast cancer survivors: a randomized controlled trial. J Clin Oncol 32 (10): 1040-9, 2014. [PMC free article: PMC3965259] [PubMed: 24470004]
68. Zhang LL, Wang SZ, Chen HL, et al.: Tai Chi Exercise for Cancer-Related Fatigue in Patients With Lung Cancer Undergoing Chemotherapy: A Randomized Controlled Trial. J Pain Symptom Manage 51 (3): 504-11, 2016. [PubMed: 26721747]
69. Song S, Yu J, Ruan Y, et al.: Ameliorative effects of Tai Chi on cancer-related fatigue: a meta-analysis of randomized controlled trials. Support Care Cancer 26 (7): 2091-2102, 2018. [PubMed: 29564620]
70. Montgomery GH, David D, Kangas M, et al.: Randomized controlled trial of a cognitive-behavioral therapy plus hypnosis intervention to control fatigue in patients undergoing radiotherapy for breast cancer. J Clin Oncol 32 (6): 557-63, 2014. [PMC free article: PMC3918539] [PubMed: 24419112]
71. 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: 17050873]
72. Van Gessel LD, Abrahams HJG, Prinsen H, et al.: Are the effects of cognitive behavior therapy for severe fatigue in cancer survivors sustained up to 14 years after therapy? J Cancer Surviv 12 (4): 519-527, 2018. [PubMed: 29651784]
73. Bennett S, Pigott A, Beller EM, et al.: Educational interventions for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev 11: CD008144, 2016. [PMC free article: PMC6464148] [PubMed: 27883365]
74. 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: 12096292]
75. 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: 16488348]
76. Borneman T, Koczywas M, Sun VC, et al.: Reducing patient barriers to pain and fatigue management. J Pain Symptom Manage 39 (3): 486-501, 2010. [PMC free article: PMC2844345] [PubMed: 20303026]

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of fatigue. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Fatigue are:

• Katharine Brock, MD, MS (Children's Healthcare of Atlanta)
• Marilyn J. Hammer, PhD, DC, RN, FAAN (Dana-Farber Cancer Institute)
• Jayesh Kamath, MD, PhD (University of Connecticut Health Center)
• Diane Von Ah, PhD, RN, FAAN (The Ohio State University)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Supportive and Palliative Care Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Supportive and Palliative Care Editorial Board. PDQ Fatigue. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/side-effects/fatigue/fatigue-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389484]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.