Author(s): Timothy Genovese, MD, Joseph Ruiz, MD, Craig Carcuffe, DO, Hwajin Lee, MD, Mitra McLarney, MD
Originally published: July 17, 2013 Last updated: June 12, 2025
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Disease/Disorder

Definition

Cancer-related fatigue (CRF) is defined as a “distressing, persistent, subjective sense of physical, emotional or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning”.1 CRF is differentiated by other types of fatigue in that it is not alleviated through rest. CRF rarely occurs in isolation and can present with other symptoms depending on the patient’s diagnosis, treatment, or stage of disease.1

Etiology

The etiology of CRF is multifactorial, and involves the interplay of physiological, biochemical, and psychological systems.

Epidemiology including risk factors and primary prevention

Fatigue is one of the most common side effects in patients with cancer and nearly universal in those undergoing cytotoxic chemotherapy, radiation therapy, bone marrow transplantation, or treatment with biologic response modifiers. One meta-analysis of 129 studies published between 1993 and 2020 demonstrated an overall prevalence of CRF of 49% among nearly 72,000 individuals with a predominance among females.2 In over two-thirds of cancer survivors, this fatigue progresses into a chronic problem, persisting months or even years after treatment has concluded.3

CRF is most frequently reported in cancer survivors with sleep disturbance, pain, distress, depression, anxiety, pre-treatment history of fatigue, lymphedema, elevated body mass index (BMI), and low activity levels.4,5 Fatigue prevalence seems to be lower among those living with prostate or gynecological cancer (~26%), and higher in those with  advanced-stage (~60%) or metastatic cancer (75%), and those undergoing active treatment (62%).2,6

Patho-anatomy/physiology

The pathophysiology of CRF is not well understood but is believed to be multifactorial related to the tumor, cancer-related treatments and side effects from treatment. One proposed mechanism for CRF includes an increase in inflammatory markers due to cytokine dysregulation.7 Cancer survivors with fatigue have demonstrated higher serum levels of proinflammatory cytokines compared to non-fatigued survivors.7 The increased cytokine activity can occur from tissue damage from the tumor, chemotherapy and/or radiation. In a study of 46 terminally ill cancer patients (survival of 64.5 days), diagnosis of clinical fatigue strongly correlated with higher plasma interleukin (IL)-6 concentrations.8

Chronic exposure to high cytokine levels can impact the hypothalamic-pituitary-adrenal (HPA) axis, causing a blunted cortisol response and circadian rhythm, further adding to fatigue.4,7 In addition, abnormal (too high or too low) serotonin levels and activation of vagal afferents, in the setting of high levels of proinflammatory cytokines have also been implicated as contributors to CRF.7

Elevated tumor necrosis factor (TNF) has also been shown to result in changes in skeletal muscle protein stores and/or metabolite concentration. This can lead to muscle wasting requiring the patient to exert an unusually high amount of effort to generate adequate contractile force during exercise performance or during extended periods of sitting or standing.9

Comorbid conditions, such as anemia, cardiovascular disease, diabetes, and psychosocial factors, such as pain, nausea, depression, and poor sleep, also contribute greatly to CRF as well as the medications used for treatment of these conditions.4,10

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

CRF fluctuates over the course of cancer treatment. CRF in patients receiving chemotherapy is commonly cyclic and worst when blood counts are lowest; whereas, in patients receiving radiation therapy (RT), CRF peaks toward the end of therapy and decreases after radiation is completed. It is most common during active therapy but can persist for months or years after treatment.

Specific secondary or associated conditions and complications

Cancer prevalence increases with age and is likely to be associated with more comorbidities that should be evaluated. In this patient population, the most frequent comorbidities are hypertension, cardiovascular disease, diabetes mellitus, depression, and arthritis. Anemia, thyroid dysfunction, and obstructive sleep apnea are frequently considered during the evaluation. Initial assessments must begin with a good comprehensive medical history, review of systems, and medications taken.

Essentials of Assessment

History

When assessing patients for CRF, it is essential to recognize its two defining features: (1) fatigue disproportionate to exertion and (2) unrelieved by rest or sleep. Using open-ended questions can be valuable in identifying these characteristics along with a focused history of fatigue including onset, pattern, duration, change over time, associated or alleviating factors, and its interference with function. It is also important to include the patient’s self-assessment of the cause of fatigue because fatigue is a subjective condition.1A careful review of medical history and review of systems should also be conducted to detect reversible sources of CRF, such as hypothyroidism, obstructive sleep apnea, adrenal insufficiency, hypogonadism, poor nutrition, as well as psychosocial factors such as insomnia, anxiety, and depression. Assessment should also address coping mechanisms, with attention to catastrophizing and negative self-perceptions, which have been linked to persistent fatigue.11 Understanding patient’s current disease status including type and length of treatment, its tendency to cause fatigue, response to treatment, and recent hospitalization are also important components of medical history to consider when assessing fatigue.1 A review of medications is also important, with a focus on centrally acting medications that can cause fatigue, such as opioids, benzodiazepines, antihistamines and antiemetics.

There are multiple measures used to assess fatigue, including: Brief Fatigue Inventory, Cancer Fatigue Scale, Fatigue Symptom Inventory, Multidimensional Fatigue Inventory, Revised Piper Fatigue Scale, Revised Schwartz Cancer Fatigue Scale.12 However, there is no universal measure of CRF. The National Comprehensive Cancer Network (NCCN) has published guidelines for the evaluation and treatment of CRF. In this document there is a strong recommendation for screening all patients based on verbal report of their level of fatigue, graded on a scale of 0-10: mild at 1-3; moderate at 4-6; and severe at 7-10.1 While this screening method is quick and reliable, it is unidimensional. Therefore, it must be combined with careful history taking to identify contributing factors to generate a treatment plan.

Unfortunately, fatigue is often under-assessed, and contributing factors are overlooked, leading to inadequate treatment and persistent CRF.

A routine checklist including comorbidities, fatigue severity, and treatment outcomes can standardize care and improve results. Using standardized measures provides an objective framework for treatment design and evaluation. An example check list is provided below:

Comorbidities to consider

  • Cardiovascular: valvular disorders, murmurs
  • Pulmonary: chronic obstructive pulmonary disease (COPD), history of obstructive sleep apnea
  • Hematology: anemia
  • Gastrointestinal: poor nutrition, chronic diarrhea
  • Endocrine: hypothyroidism, hypogonadism, adrenal insufficiency
  • Infectious Disease: urinary tract infection, pneumonia
  • Psychiatric: insomnia, depression, anxiety, history of substance abuse
  • Neuro/MSK: fibromyalgia, chronic fatigue, previous neurologic disorders

Evaluation and follow up measure of fatigue

  • Verbal scale of 0-10 (with 10 being the most severe)
  • Fatigue Severity Scale
  • Multi-dimensional Fatigue Inventory (20-item and 9-item versions; most used)

Physical Examination

A thorough physical examination should be performed to identify reversible or treatable contributors to fatigue. Special attention should be paid to the cardiac and pulmonary systems, as chemotherapy and radiation can cause cardiomyopathies or interstitial fibrosis. Fluid status should be observed, as well as examination of the oral cavity for signs of mucositis that could affect nutrition. Manual muscle testing should be performed to assess strength and distribution of weakness, to help further guide exercise prescriptions.

Functional assessment

The NCCN guidelines recommend incorporating multidimensional fatigue measures assessing function and life satisfaction into routine cancer survivorship care.1 Traditionally, the Functional Assessment of Cancer Therapy-General 5 ((FACT-G5) provides a good evaluation of activities of daily living (ADLs). Other measures include MOS SF36, Fatigue Severity Scale, and Human Activity Profile. A standard instrumented ADL assessment can also be useful in assessing function. Dynamic mobility tests like the Activity Measure Post Acute Care (AMPAC), Get Up and Go, and 2-Minute Walk Test can assess cardiovascular endurance in fatigued patients.

Laboratory studies and imaging

Laboratory studies should be guided by history and physical exam to identify comorbidities and reversible causes of fatigue. Useful tests include hemoglobin, white blood cell count, thyroid function, complete metabolic panel, fasting blood glucose, urine analysis, and vitamin levels. A chest x-ray may be useful if congestive heart failure or pneumonia are suspected. Refer to sleep medicine if obstructive sleep apnea is a possible contributing factor.

Supplemental assessment tools

N/A

Environmental

An effective approach to fatigue is assessing the patient’s daily activities at home, work, and during leisure. Discussing priorities helps identify energy-draining tasks and opportunities for modification, such as hiring help, seeking support from friends/family, pacing activities, or breaking tasks into shorter segments. Adjusting schedules to align with peak energy times can be beneficial. Good sleep hygiene — regular bedtimes, short naps, and consistent wake times — also supports more restful sleep.1

Social role and social support system

CRF often disrupts usual home-work-life balance and specific activities. Family support for the patients, coordination of care, and consolidation of trips to various health providers is often beneficial. Support groups are often very helpful, and many websites are available for information. Online networks can be helpful for facilitating socialization and learning about cancer-specific programs while conserving energy expenditure. 

Professional issues

Cancer survivors are a rapidly growing patient population, living longer and better. CRF presents a challenge to patients wishing to lead a longer, more functional life. As such, its management is best approached from the perspective of the needs of people with chronic illness. A surveillance model using a multidisciplinary approach is recommended, enabling care coordination among oncologists, primary care physicians, oncology nurses and the rehabilitation team.

Rehabilitation Management and Treatments

Fatigue in cancer patients, particularly those with advanced disease, is often multifactorial. Management of fatigue is cause-specific when conditions known to cause fatigue can be identified and treated.14 When specific causes, such as infection, fluid and electrolyte imbalances, or cardiac dysfunction, cannot be identified and corrected, non-pharmacologic and pharmacologic treatment of the fatigue should be considered.6 NCCN guidelines emphasize interventions based on the patient’s clinical status: active cancer treatment, post treatment, and end of life.1

Education, counseling, and non-pharmacologic interventions are central to the effective management of fatigue, which can be supplemented with pharmacologic interventions.  Education about fatigue should be offered to patients, especially before its onset, including reassuring the patient that fatigue is not an indication that the treatment is not working or that the disease is progressing. Daily self-monitoring through a log or diary should be encouraged, as they can provide information regarding peak energy periods. This can be used to plan activities accordingly and use energy conservation techniques.

Non-pharmacologic interventions may include a moderate exercise program to improve functional capacity and activity tolerance, restorative therapies to decrease cognitive alterations and improve mood state, and nutritional and sleep interventions for patients with disturbances in eating or sleeping. Of the non-pharmacologic treatment options, physically based therapies and psychosocial interventions have the strongest evidence base.

Pharmacologic therapy should be considered when non-pharmacologic interventions do not provide adequate improvement in fatigue and functioning. Pharmacologic therapy can include anti-depressants, psychostimulants, corticosteroids, and anabolic steroids. Methylphenidate appears to have the most evidence of effectiveness for the treatment of cancer-related fatigue.14 Two major systematic reviews concluded that methylphenidate showed a small but significant improvement in CRF over placebo in mixed tumor cancer patients with advanced disease. However, this finding was challenged by a more recent trial in 162 palliative cancer patients showed no benefit of 6 weeks of daily methylphenidate compared to placebo.15 All of these studies began with a lower dose of methylphenidate, such as 5mg daily, and titrated up to 20mg total dose per day, as according to patient symptoms and tolerance.16,17 As the evidence suggesting the use of methylphenidate is limited, a thorough examination and treatment of potential secondary causes of fatigue should be done prior initiation of this modality.1,5,11

Regarding corticosteroids, short-course dexamethasone has been found to be beneficial in treating fatigue, as well as pain, nausea, and impaired appetite, in advanced cancer patients.18,19 A recent phase II randomized, double-blinded control trial has shown that a combination of physical activity and dexamethasone was feasible in advanced cancer patients; and showed improvements in fatigue that continued up to three weeks after discontinuation of dexamethasone.19 Other corticosteroids such as methylprednisolone have also shown improvement of fatigue in advanced cancer patients as well. Treatment courses are usually a few days up to 4 weeks. Megestrol acetate is a progesterone analog that acts at progesterone, glucocorticoid, and corticosteroid receptors. It has a wide variety of indications and can treat fatigue due to cachexia due to its properties as an appetite stimulant. Long-term treatment with steroids is not recommended and therefore typically limited to advanced and end-of-life cancer patients with severe fatigue.19 

While cancer-related fatigue is often multifactorial, specific contributors to anemia can sometimes be identified and treated, including mood disorders, sleep disturbance, infection, fluid and electrolyte imbalances, or cardiac dysfunction.20 Anemia is one of the most common reversible causes of CRF in diverse tumor types. Anemia in the setting of cancer is usually secondary to malignancy or cancer treatment, but other reversible causes should be ruled out (infections, nutritional deficiencies, or other drug effects or interactions).  Patients with symptomatic anemia will experience improvement in fatigue after treatment of their anemia, which can include red blood cell transfusion, iron supplementation, and erythropoietin-stimulating agents.21 Erythropoietin agents are sparingly used, but not routinely recommended due to increased risk of thromboembolism.

a) Exercise: More evidence is now available on the benefits of exercise in decreasing CRF. The largest meta-analysis to date including 4881 patients with cancer during or after treatment found that exercise reduced CRF by a mean effect size of 0.32 during treatment, and 0.38 following cancer treatment, both means indicating a mild size of the effect of exercise. Aerobic exercise was the common method.22 A systematic review looking at 3816 participants found that moderate intensity exercise resulted in significant reduction of fatigue and increased walking endurance.23 Recommendations for an individualized exercise program should take into consideration the stage of cancer, patient’s age, psychosocial status, and pain conditions. Exercise should be progressive, starting at a low intensity and gradually increasing as the individual’s aerobic capacity improves. While patients do not need exercise tolerance testing prior to initiating an exercise program, they warrant screening and education as appropriate for peripheral neuropathies, musculoskeletal disease, wasting syndromes, and increased risk of infection and fractures.

With regards to aerobic exercise, studies have shown that moderately intense aerobic exercise, as defined by 55-75% maximum heart rate, is effective in managing cancer related fatigue in early-stage diagnosis. Modes of exercise include walking, or stationary cycling for those with ataxia or balance difficulties. Duration is typically 10-90 minutes, with a frequency of three to seven days a week. Recommendations for resistance exercise prescription include modes such as resistance bands, dumbbells, or fixed weight systems. Moderate to vigorous intensity (60-90% of one-repetition maximum) is suggested with two to four sets of exercises ranging from 8 to 15 repetitions performed. Frequency of resistance training should be three times a week.24 Overall, the American College of Sports Medicine (ACSM) recommends a total of 150 minutes of weekly moderate intensity exercise and 2 days of strength training for this patient population.25

ACSM guidelines do not recommend specific changes to the exercise regimen on the basis of having a cancer diagnosis. However, certain patients may warrant precautions or modifications, and possibly supervision of exercise by a physical therapist or trainer. For example, for patients with breast cancer, the first several exercise sessions should be supervised, with controlled progression starting with low resistance and close monitoring of lymphedema and arm and shoulder symptoms. Bony involvement of cancer can increase risk of fracture. 

b) Psychosocial interventions: Patients should be counselled about coping with anxiety and depression, as they are commonly associated with fatigue. Interventions that have been shown to help can be grouped into three categories: cognitive behavioral therapy, psychoeducational therapies, and supportive expressive therapies.26 Cognitive-behavioral therapy for insomnia (CBT-I) is a short, structured therapy program for insomnia that addresses sleep behaviors and has high level of evidence demonstrating effectiveness.27

c) Adaptive equipment: Equipment in the home or for mobility may be helpful for energy conservation, fall prevention, and active lifestyle promotion. Patients with weakness, balance problems, or difficulty standing for long periods may benefit from a shower chair, installing grab bars in the home, or using an assistive device such as a cane or walker. The use of a walking aid needs to be considered against the added weight of the device and managing its usage and storage in space.

d) Complementary approaches: Numerous complementary therapies are commonly used to treat CRF, including acupuncture, aromatherapy, activity modification and intentional energy conservation, healing touch/therapeutic touch, hypnosis, herbal and dietary supplements, massage, mindfulness-based stress reduction, polarity therapy, relaxation, sleep promotion, support groups and Tibetan yoga. These various therapies have varying amounts of evidence supporting their use, but current data are insufficient to routinely recommend any of these modalities as an effective treatment for cancer fatigue.28

Acupuncture is one of the most highly studied and utilized complementary therapies for CRF. Multiple small randomized controlled trials have demonstrated significant improvement in CRF with acupuncture compared to inactive controls.29 In 2014, Mao et al. studied 67 subjects with breast cancer and found significant improvement with acupuncture compared to both waitlist control and sham acupuncture.30 In 2019, Mao et al. treated 160 subjects with various cancers with either acupuncture or CBT-I and demonstrated similar effectiveness for both treatments, which reduced the average Insomnia Score Index by 8 points out of 28.3 Acupuncture may also be helpful for treating other cancer-related symptoms including nausea, reduced appetite, pain, insomnia, anxiety, and depression. It is generally well-tolerated but may warrant physician clearance for patients with active cancer due to increased risk of bleeding and infection.                          

Numerous dietary supplements and herbs have been investigated as treatments for CRF, and the level of evidence supporting specific treatments is highly diverse.  Because fatigue in cancer patients seems to be associated with reduced lean muscle mass and increased inflammatory markers, nutritional interventions for fatigue are generally intended to be anabolic and/or anti-inflammatory.  Commonly used supplements include eicosapentaenoic acid (EPA), levocarnitine, and multivitamins, among many others. Nutritional supplements generally have little or low-quality evidence supporting their effectiveness for treating fatigue, and their use in cancer patients is associated with increased risk of drug-drug or drug-disease interaction, as well as financial burden.4

There is a high level of evidence for a few specific herbs, including American ginseng and Ginger.  All herbs and dietary supplements should be reviewed with a physician for patients with active cancer or cancer treatments due to significant risk of adverse effects, American ginseng has demonstrated effectiveness for treatment of CRF in heterogeneous cancer samples, most of whom were on active treatment. The most effective and commonly studied dose was 2,000mg daily.32 Ginseng is a cytochrome P450 3A4 inhibitor, so it has numerous drug interactions, including potentiating the toxicity of many common chemotherapies (including docetaxel and cisplatin) and increasing risk of bleeding with warfarin. 

Patient & family education

Many websites offer information for patients and families that are frequently updated. Listed below are some of them. Support groups and community resources also offer information which is also available through the American Cancer Society (www.cancer.org) and The Wellness Community (www.thewellnesscommunity.org).

Self-management

Incorporating self-management strategies, such as physical activity and exercise, energy conservation strategies and understanding the mind-body relationship, has been shown to benefit the management of CRF. Recently, a 44-item practice framework (13 Key Practices, 31 Practice Components) was developed to guide health care providers in how to support self-management behaviors in cancer survivors with CRF.33 Strategies discussed include establishing context and defining the problem to providing evidence-based lifestyle adaptation and support for coping.

Cutting Edge/Emerging and Unique Concepts and Practice

A recent scoping review highlighted the strong correlation between abnormal gene expression and CRF involving inflammatory mediators, tumor necrosis factors, catechol-O-methyltransferase and circadian rhythms. Larger prospective studies with higher power are required to solidify casual relationships, however, examining links between genetic loci using genome-wide association studies, transcriptomics, and epigenetic analysis would help advance our prevention and treatment strategies.34

Immune modulators

There have been recent studies in the role of the activation of the Toll-like receptor 2/4 radical cycle in fatigue, both in cancer patients and a variety of patients with chronic medical conditions. A better understanding of this pathway would be helpful in drug development.35 Studies of beta glucan have been shown to be helpful in augmenting endurance of physical activity levels in animal models via suggested immune mechanisms.36 One human trial of D-glucan showed decreased fatigue, but did not report statistical significance.19

Gaps in the Evidence-Based Knowledge

From a meta-analysis of studies published from 1996 to 2000 compared to ones from 2016 to 2020, there has been an overall reduction in prevalence of CRF from 64% to 43%.2 While this improvement likely reflects a more robust body of research in risk factors and interventions, there can always be better quality studies with higher power focusing on complementary therapies.

Educational Materials for Patients and Families

National Cancer Comprehensive Network: https://www.nccn.org/patients/resources/default.aspx

Eastern Cooperative Oncological Group (ECOG) in collaboration with American College of Radiology Imaging Network (ACRIN):
http://ecog-acrin.org/patients/resources

Center for Disease Control: https://www.cdc.gov/cancer-survivors/

Cancer Hope Network: www.cancerhopenetwork.org/

American Cancer Society (Cancer Survivor Network): https://csn.cancer.org/

The Wellness Community Cancer Support Community www.cancersupportcommunity.org

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Original Version of the Topic

Naomi Lynn H. Gerber, MD. Exercise effects and fatigue in cancer patients. 7/17/2013

Previous Revision(s) of the Topic

Sravani Venkata Anjana Mudumbi, MD, Teresa Tang, MD. Exercise effects and fatigue in cancer patients. 9/19/2016

Toure Barksdale, MD. Exercise Effects and Fatigue in Cancer Patients. 5/11/2022

Author Disclosure

Timothy Genovese, MD
Nothing to Disclose

Joseph Ruiz, MD
Nothing to Disclose

Craig Carcuffe, DO
Nothing to Disclose

Hwajin Lee, MD
Nothing to Disclose

Mitra McLarney, MD
Nothing to Disclose