Santhosshi Narayanan, MD

From the University of Texas MD Anderson Cancer Center, Houston, TX (Drs. Narayanan, Lopez, Chaoul, Liu, Milbury, and Cohen, and Ms. Mallaiah); the University of Texas Health Science Center at Tyler (Dr. Meegada); and Texas Tech University Health Sciences Center, Lubbock, TX (Ms. Francisco).

Abstract

• Objective: To review the effects of yoga as an adjunct supportive care modality alongside conventional cancer treatment on quality of life (QOL), physical and mental health outcomes, and physiological and biological measures of cancer survivors.
• Methods: Nonsystematic review of the literature.
• Results: Yoga therapy, one of the most frequently used mind-body modalities, has been studied extensively in cancer survivors (from the time of diagnosis through long-term recovery). Yoga affects human physiology on multiple levels, including psychological outcomes, immune and endocrine function, and cardiovascular parameters, as well as multiple areas of QOL. It has been found to reduce psychological stress and fatigue and improve QOL in cancer patients and survivors. Yoga has also been used to manage symptoms such as arthralgia, fatigue, and insomnia. In addition, yoga offers benefits not only for cancer survivors but also for their caregivers.
• Conclusion: As part of an integrative, evidence-informed approach to cancer care, yoga may provide benefits that support the health of cancer survivors and caregivers.

Keywords: fatigue; cancer; proinflammatory cytokines; integrative; mind-body practices; meditation; DNA damage; stress; psychoneuro-immunoendocrine axis; lymphedema; insomnia.

A diagnosis of cancer and adverse effects related to its treatment may have negative effects on quality of life (QOL), contributing to emotional and physical distress in patients and caregivers. Many patients express an interest in pursuing nonpharmacological options, alone or as an adjunct to conventional therapy, to help manage symptoms. The use of complementary medicine approaches to health, including nonpharmacological approaches to symptom management, is highest among individuals with cancer.¹ According to a published expert consensus, integrative oncology is defined as a “patient-centered, evidence-informed field of cancer care that utilizes mind and body practices, natural products, and/or lifestyle modifications from different traditions alongside conventional cancer treatments. Integrative oncology aims to optimize health, QOL, and clinical outcomes across the cancer care continuum and to empower people to prevent cancer and become active participants before, during, and beyond cancer treatment.”² A key component of this definition, often misunderstood in the field of oncology, is that these modalities and treatments are used alongside conventional cancer treatments and not as an alternative. In an attempt to meet patients’ needs and appropriately use these approaches, integrative oncology programs are now part of most cancer centers in the United States.^3-6

Because of their overall safety, mind-body therapies are commonly used by patients and recommended by clinicians. Mind-body therapies include yoga, tai chi, qigong, meditation, and relaxation. Expressive arts such as journaling and music, art, and dance therapies also fall in the mind-body category.⁷ Yoga is a movement-based mind-body practice that focuses on synchronizing body, breath, and mind. Yoga has been increasingly used by patients for health benefits,⁸ and numerous studies have evaluated yoga as a complementary intervention for individuals with cancer.^9-14 Here, we review the physiological basis of yoga in oncology and the effects of yoga on biological processes, QOL, and symptoms during and after cancer treatment.

Physiological Basis

Many patients may use mind-body programs such as yoga to help manage the psychological and physiological consequences of unmanaged chronic stress and improve their overall QOL. The central nervous system, endocrine system, and immune system influence and interact with each other in a complex manner in response to chronic stress.^15,16 In a stressful situation, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) are activated. HPA axis stimulation leads to adrenocorticotrophic hormone production by the pituitary gland, which releases glucocorticoid hormones. SNS axis stimulation leads to epinephrine and norepinephrine production by the adrenal gland.^17,18 Recently, studies have explored modulation of signal transduction between the nervous and immune systems and how that may impact tumor growth and metastasis.¹⁹ Multiple studies, controlled for prognosis, disease stage, and other factors, have shown that patients experiencing more distress or higher levels of depressive symptoms do not live as long as their counterparts with low distress or depression levels.²⁰ Both the meditative and physical components of yoga can lead to enhanced relaxation, reduced SNS activation, and greater parasympathetic tone, countering the negative physiological effects of chronic stress. The effects of yoga on the HPA axis and SNS, proinflammatory cytokines, immune function, and DNA damage are discussed below.

Biological Processes

Nervous System

The effects of yoga and other forms of meditation on brain functions have been established through several studies. Yoga seems to influence basal ganglia function by improving circuits that are involved in complex cognitive functions, motor coordination, and somatosensory and emotional processes.^21,22 Additionally, changes in neurotransmitter levels have been observed after yoga practice. For instance, in a 12-week yoga intervention in healthy subjects, increased levels of thalamic gamma-aminobutyric acid (GABA) in the yoga group were reported to have a positive correlation with improved mood and decreased anxiety compared with a group who did metabolically matched walking exercise.²³ Levels of GABA, an inhibitory neurotransmitter, are decreased in conditions such as anxiety, depression, and epilepsy.²⁴ Yoga therapy has been shown to improve symptoms of mood disorders and epilepsy, which leads to the hypothesis that the mechanism driving the benefits of yoga may work through stimulation of vagal efferents and an increase in GABA-mediated cortical-inhibitory tone.^24,25

 

 

HPA Axis

Stress activates the HPA/SNS axis, which releases hormones such as cortisol and norepinephrine. These hormones may play a role in angiogenesis, inflammation, immune suppression, and other physiological functions, and may even reduce the effect of chemotherapeutic agents.^26,27 Regular yoga practice has been shown to reduce SNS and HPA axis activity, most likely by increasing parasympathetic dominance through vagal stimulation, as demonstrated through increases in heart rate variability.²⁸ One indicator of HPA axis dysregulation, diurnal salivary cortisol rhythm, was shown to predict survival in patients with advanced breast and renal cancer.^29-33 Yoga has been shown to lead to less cortisol dysregulation due to radiotherapy and to reductions in mean cortisol levels and early morning cortisol levels in breast cancer patients undergoing radiotherapy.³⁴ This lends support to the hypothesis that yoga helps restore HPA axis balance.

Proinflammatory Cytokines

Cancer patients tend to have increased levels of inflammatory markers such as interleukin (IL)-4, IL-10, tumor necrosis factor (TNF), interferon-γ, and C-reactive protein. This increase in inflammation is associated with worse outcomes in cancer.³⁵ This association becomes highly relevant because the effect of inflammation on host cells in the tumor microenvironment is connected to disease progression.²⁶ Inflammatory cytokines are also implicated in cancer-related symptoms such as fatigue, cognitive dysfunction, peripheral neuropathy, and sleep disturbances.³⁶

Yoga is known to reduce stress and may directly or indirectly decrease inflammatory cytokines. A randomized clinical trial of a 12-week hatha yoga intervention among breast cancer survivors demonstrated decreases in IL-6, IL-1β, TNF, corticotropin-releasing factor, and cognitive complaints in the yoga group compared with those in the standard care group after 3 months.^37,38 Furthermore, Carlson et al showed that, after mindfulness-based stress reduction involving a combination of gentle yoga, meditation techniques, and relaxation exercises, breast and prostate cancer patients had reduced levels of proinflammatory cytokines and cortisol.³⁹ These reductions translated into patients reporting decreased stress levels and enhanced QOL.

Immune Function

The effects of yoga practice on the immune system have been studied in both healthy individuals and individuals with cancer. The effects on T and B lymphocytes, natural killer (NK) cells, and other immune effector cells demonstrate that meditation and yoga have beneficial effects on immune activity.⁴⁰ Hormones such as catecholamines and glucocorticoids are thought to influence the availability and function of NK cells, and, as noted above, yoga has been shown to modulate stress hormones and lead to reduced immune suppression in patients with early-stage breast cancer undergoing chemotherapy.⁴¹ Additional evidence supports the ability of yoga to reduce immune suppression in the postsurgical setting, with no observed decrease in NK cell percentage after surgery for those in a yoga group compared with a control group.⁴² This finding is relevant to patients undergoing surgical management of their cancer and highlights the impact of yoga on the immune system.

DNA Damage

Radiation damages DNA in the peripheral blood lymphocytes of patients undergoing treatment.^43,44 This damage is significant in breast cancer patients undergoing radiotherapy.⁴⁵ Stress additionally causes DNA damage⁴⁶ and is correlated to impaired DNA repair capacity.^47,48 In a study conducted by Banerjee et al, breast cancer patients were randomly assigned to a yoga group or a supportive therapy group for 6 weeks during radiotherapy.⁴⁹ Prior to the intervention, patients in the study had significant genomic instability. After treatment, patients in the yoga group experienced not only a significant reduction in anxiety and depression levels, but also a reduction in DNA damage due to radiotherapy.

 

 

Yoga in Quality of Life and Symptom Management

There is evidence showing that yoga therapy improves multiple aspects of QOL, including physical functioning, emotional health outcomes, and the symptoms cancer patients may experience, such as sleep disturbances, fatigue, and pain. Danhauer et al systematically reviewed both nonrandomized trials and randomized controlled trials involving yoga during cancer treatment.⁵⁰ They found that yoga improved depression and anxiety as well as sleep and fatigue. Benefits of yoga in cancer based on randomized controlled trials are summarized in the Table. The role of yoga in improving QOL and managing symptoms patients experience during and after treatment is discussed in the following sections.

Quality of Life

Danhauer et al’s systematic review of trials involving yoga during cancer treatment found that yoga improved multiple aspects of QOL.⁵⁰ For example, yoga has been shown to improve QOL in breast cancer patients undergoing radiotherapy. In a study by Chandwani et al, yoga (60-minute sessions twice a week for 6 weeks) was associated with better general health perception and physical functioning scores as well as greater benefit finding, or finding meaning in their experience, after radiotherapy compared with a wait-list group.⁵¹ The yoga group had an increase in intrusive thoughts, believed to be due to a more thorough processing of the cancer experience, which helps to improve patients’ outlook on life.⁵² The benefits of yoga extend beyond psychological measures during radiation treatment. Yoga was found to increase physical functioning compared with stretching in breast cancer patients undergoing radiotherapy.⁵³

Cognitive Function

Cancer-related cognitive impairment commonly occurs during cancer treatments (eg, chemotherapy, radiotherapy, surgery, hormone therapy) and persists for months or years in survivors.⁵⁴ Impairment of memory, executive function, attention, and concentration are commonly reported. In a trial of a combined hatha and restorative yoga program called Yoga for Cancer Survivors (YOCAS), which was designed by researchers at the University of Rochester, patients in the yoga arm had less memory difficulty than did patients in the standard care arm.⁵⁵ However, the primary aim of the trial was to treat insomnia, so this secondary outcome needs to be interpreted with caution. Deficits in attention, memory, and executive function are often seen in cancer-related cognitive impairment, and the meditative aspect of yoga may have behavioral and neurophysical benefits that could improve cognitive functions.⁵⁶ More evidence is needed to understand the role of yoga in improving cognitive functioning.

Emotional Health

Psychosocial stress is high among breast cancer patients and survivors.^57,58 This causes circadian rhythm and cortisol regulation abnormalities, which are reported in women with breast cancer.^59-64 Yoga is known to help stress and psychosocial and physical functioning in patients with cancer.⁶⁵ Yoga was also shown to be equivalent to cognitive behavioral therapy in stress management in a population of patients without cancer.⁶⁶ Daily yoga sessions lasting 60 minutes were shown to reduce reactive anxiety and trait anxiety in early-stage breast cancer patients undergoing conventional radiotherapy and chemotherapy compared with patients receiving supportive therapy, highlighting the role of yoga in managing anxiety related to treatment.⁶⁷ In a study done by Culos-Reed et al, 20 cancer survivors who did 75 minutes of yoga per week for 7 weeks were compared with 18 cancer survivors who served as a control group.⁶⁸ The intervention group reported significant improvement in emotional well-being, depression, concentration, and mood disturbances. In a longitudinal study by Mackenzie et al, 66 cancer survivors completed a 7-week yoga program and were assessed at baseline, immediately after the final yoga session, and at 3 and 6 months after the final session.⁶⁹ Participants had significantly improved energy levels and affect. They also had moderate improvement in mindfulness and a moderate decrease in stress. Breast cancer patients who underwent restorative yoga sessions found improvements in mental health, depression, positive affect, and spirituality (peace/meaning).⁷⁰ This was more pronounced in women with higher negative affect and lower emotional well-being at baseline. In a study of patients with ovarian cancer receiving chemotherapy, patients were instructed to perform up to 15-minute sessions including awareness, body movement, and breathing.⁷¹ Even with just 1 session of yoga intervention, patients experienced decreased anxiety.

Fatigue

Studies on yoga show improvement in fatigue both during and after treatment. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit cognitive fatigue.⁷² Older cancer survivors also seem to benefit from yoga interventions.⁷³ In a trial of a DVD-based yoga program, the benefits of yoga were similar to those of strengthening exercises, and both interventions helped decrease fatigue and improve QOL during the first year after diagnosis in early-stage breast cancer patients with cancer-related fatigue.⁷⁴ Bower et al also showed that, for breast cancer survivors experiencing persistent chronic fatigue, a targeted yoga intervention led to significant improvements in fatigue and vigor over a 3-month follow-up compared with controls.⁷⁵ Fatigue is commonly seen in breast cancer patients who are receiving adjuvant chemotherapy. In a study by Taso et al, women with breast cancer receiving chemotherapy were assigned to 60-minute yoga sessions incorporating Anusara yoga, gentle stretching, and relaxation twice a week for 8 weeks.⁷⁶ By week 4, patients with low pretest fatigue in the yoga group experienced a reduction in fatigue. By week 8, all patients in the yoga group experienced a reduction in fatigue. Four weeks after the yoga intervention, patients in the group maintained the reduction in fatigue. This study shows the feasibility of an 8-week yoga program for women undergoing breast cancer therapy by improving fatigue. Yoga recently was added to National Comprehensive Cancer Network (NCCN) guidelines for management of cancer-related fatigue (level 1 evidence).⁷⁷ However, the evidence was based on studies in women with breast cancer and survivors; therefore, more studies are needed in men and women with other cancers.

 

 

Surgical Setting/Postoperative Distress

Distress surrounding surgery in patients with breast cancer can impact postoperative outcomes. Yoga interventions, including breathing exercises, regulated breathing, and yogic relaxation techniques, improved several postsurgical measures such as length of hospital stay, drain retention, and suture removal.⁷⁸ In this study, patients who practiced yoga also experienced a decrease in plasma TNF and better wound healing. Symptoms of anxiety and distress that occur preoperatively can lead to impaired immune function in addition to decreased QOL. In a study of yoga in early-stage breast cancer patients undergoing surgery, the benefit of yoga was seen not only with stress reduction but also with immune enhancement.⁴²

Yoga has been shown to help alleviate acute pain and distress in women undergoing major surgery for gynecological cancer. A regimen of 3 15-minute sessions of yoga, including awareness meditation, coordination of breath with movement, and relaxation breathing, was shown to reduce acute pain and distress in such patients in an inpatient setting.⁷⁹

Menopausal Symptoms

Breast cancer survivors have more severe menopausal symptoms compared with women without cancer.^80,81 Hot flashes cause sleep disturbances and worsen fatigue and QOL.⁸² Tamoxifen and aromatase inhibitors significantly worsen menopausal symptoms such as hot flashes.⁸¹ Carson et al conducted a study of yoga that included postures, breathing techniques, didactic presentations, and group discussions.⁸³ The yoga awareness regimen consisted of 8 weekly 120-minute group classes. Patients in the yoga arm had statistically significant improvements in the frequency, severity, and number of hot flashes. There were also improvements in arthralgia (joint pain), fatigue, sleep disturbance, vigor, and acceptance.

Arthralgia

Joint pain can be a major side effect that interferes with daily functions and activities in postmenopausal breast cancer survivors who receive aromatase inhibitor therapy.⁸⁴ Arthralgia is reported in up to 50% of patients treated with aromatase inhibitors.^84,85 It can affect functional status and lead to discontinuation of aromatase inhibitor therapy, jeopardizing clinical outcomes.⁸⁶ Yoga as a complementary therapy has been shown to improve conditions such as low back pain⁸⁷ and knee osteoarthritis⁸⁸ in patients who do not have cancer. In a single-arm pilot trial by Galantino et al, breast cancer patients with aromatase inhibitor–related joint pain were provided with twice-weekly yoga sessions for 8 weeks. There were statistically significant improvements in balance, flexibility, pain severity, and health-related QOL.⁸⁹ As noted above, improvement in arthralgia was also found in the study conducted by Carson et al.⁸³

Insomnia

Insomnia is common among cancer patients and survivors^90,91 and leads to increased fatigue and depression, decreased adherence to cancer treatments, and poor physical function and QOL.^90-92 Management of insomnia consists of pharmacologic therapies such as benzodiazepines^93,94 and nonpharmacologic options such as cognitive behavioral therapy.⁹⁵

The first study of yoga found to improve sleep quality was conducted at MD Anderson Cancer Center in lymphoma patients.⁹⁶ The effects of Tibetan yoga practices incorporating controlled breathing and visualization, mindfulness techniques, and low-impact postures were studied. Patients in the Tibetan yoga group had better subjective sleep quality, faster sleep latency, longer sleep duration, and less use of sleep medications. Mustian et al conducted a large yoga study in cancer survivors in which patients reporting chronic sleep disturbances were randomly assigned to the YOCAS program, which consisted of pranayama (breath control), 16 gentle hatha and restorative yoga postures, and meditation, or to usual care.⁹² The study reported improvements in global sleep quality, subjective sleep quality, actigraphy measures (wake after sleep onset, sleep efficiency), daytime dysfunction, and use of sleep medication after the yoga intervention compared with participants who received standard care.

 

Yoga to Address Other Symptoms

There is preliminary evidence supporting yoga as an integrative therapy for other symptoms unique to cancer survivors. For example, in head and neck cancer survivors, soft tissue damage involving the jaw, neck, shoulders, and chest results in swallowing issues, trismus, and aspiration, which are more pronounced in patients treated with conventional radiotherapy than in those treated with intensity-modulated radiotherapy.⁹⁷ Some late effects of radiotherapy for head and neck cancer—such as pain, anxiety, and impaired shoulder function—were shown to be improved through the practice of hatha yoga in 1 study.⁹⁸ Similarly, in a randomized controlled pilot study of patients with stage I to III breast cancer 6 months after treatment, participants in an 8-week yoga program experienced a reduction in arm induration and improvement in a QOL subscale of lymphedema symptoms. However, more evidence is needed to support the use of yoga as a therapeutic measure for breast cancer lymphedema.^99,100

Yoga for Caregivers

Along with cancer patients, caregivers face psychological and physical burdens as well as deterioration in their QOL. Caregivers tend to report clinical levels of anxiety, depression, sleep disturbance, and fatigue and have similar or in fact higher levels than those of the patients for whom they are caring.^101,102 Yoga has been found to help caregivers of patients with cancer. Recently, MD Anderson researchers conducted a trial in patients with high-grade glioma and their caregivers as dyads.^103,104 Each dyad attended 2 or 3 60-minute weekly Vivekananda yoga sessions involving breathing exercises, physical exercises, relaxation, and meditation. The researchers found that the yoga program was safe, feasible, acceptable, and subjectively useful for patients with high-grade glioma and their caregivers. Preliminary evidence of QOL improvement for both patients and caregivers was noted. An improvement in QOL was also demonstrated in another preliminary study of yoga in patients undergoing thoracic radiotherapy and their caregivers.¹⁰⁵

Another study by the group at MD Anderson evaluated a couple-based Tibetan yoga program that emphasized breathing exercises, gentle movements, guided visualizations, and emotional connectedness during radiotherapy for lung cancer.¹⁰⁶ This study included 10 patient‐caregiver dyads and found the program to be feasible, safe, and acceptable. The researchers also found preliminary evidence of improved QOL by the end of radiotherapy relative to baseline—specifically in the areas of spiritual well‐being for patients, fatigue for caregivers, and sleep disturbances and mental health issues such as anxiety and depressive symptoms for both patients and caregivers. This is noteworthy, as QOL typically deteriorates during the course of radiotherapy, and the yoga program was able to buffer these changes.

Conclusion

Yoga therapy has been used successfully as an adjunct modality to improve QOL and cancer-related symptoms. As a part of an integrative medicine approach, yoga is commonly recommended for patients undergoing cancer treatment. Danhauer et al reviewed randomized controlled trials during and after treatment and concluded that the evidence is clearly positive for QOL, fatigue, and perceived stress.¹⁰⁷ Results are less consistent but supportive for psychosocial outcomes such as benefit finding and spirituality. Evidence is mixed for sleep, anxiety, and depression. Post-treatment studies demonstrate improvements in fatigue, sleep, and multiple QOL domains. Yoga has been included in NCCN guidelines for fatigue management. Yoga, if approved by a physician, is also included among the behavioral therapies for anticipatory emesis and prevention and treatment of nausea in the recent update of the NCCN guidelines.¹⁰⁸ The Society for Integrative Oncology guidelines include yoga for anxiety/stress reduction as a part of integrative treatment in breast cancer patients during and after therapy, which was endorsed by the American Society of Clinical Oncology.¹⁰⁹

Because of the strong evidence for its benefits and a low side-effect profile, yoga is offered in group-class settings for patients during and after treatment and/or for caregivers in our institution. We often prescribe yoga as a therapeutic modality for selected groups of patients in our clinical practice. However, some patients may have restrictions after surgery that must be considered. In general, yoga has an excellent safety profile, the evidence base is strong, and we recommend that yoga therapy should be part of the standard of care as an integrative approach for patients with cancer undergoing active treatment as well as for cancer survivors and caregivers.

Acknowledgement: The authors thank Bryan Tutt for providing editorial assistance.

Corresponding author: Santhosshi Narayanan, MD, Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030; [email protected].

Financial disclosures: None.

From the University of Texas MD Anderson Cancer Center, Houston, TX (Drs. Narayanan, Lopez, Chaoul, Liu, Milbury, and Cohen, and Ms. Mallaiah); the University of Texas Health Science Center at Tyler (Dr. Meegada); and Texas Tech University Health Sciences Center, Lubbock, TX (Ms. Francisco).

Abstract

• Objective: To review the effects of yoga as an adjunct supportive care modality alongside conventional cancer treatment on quality of life (QOL), physical and mental health outcomes, and physiological and biological measures of cancer survivors.
• Methods: Nonsystematic review of the literature.
• Results: Yoga therapy, one of the most frequently used mind-body modalities, has been studied extensively in cancer survivors (from the time of diagnosis through long-term recovery). Yoga affects human physiology on multiple levels, including psychological outcomes, immune and endocrine function, and cardiovascular parameters, as well as multiple areas of QOL. It has been found to reduce psychological stress and fatigue and improve QOL in cancer patients and survivors. Yoga has also been used to manage symptoms such as arthralgia, fatigue, and insomnia. In addition, yoga offers benefits not only for cancer survivors but also for their caregivers.
• Conclusion: As part of an integrative, evidence-informed approach to cancer care, yoga may provide benefits that support the health of cancer survivors and caregivers.

Keywords: fatigue; cancer; proinflammatory cytokines; integrative; mind-body practices; meditation; DNA damage; stress; psychoneuro-immunoendocrine axis; lymphedema; insomnia.

A diagnosis of cancer and adverse effects related to its treatment may have negative effects on quality of life (QOL), contributing to emotional and physical distress in patients and caregivers. Many patients express an interest in pursuing nonpharmacological options, alone or as an adjunct to conventional therapy, to help manage symptoms. The use of complementary medicine approaches to health, including nonpharmacological approaches to symptom management, is highest among individuals with cancer.¹ According to a published expert consensus, integrative oncology is defined as a “patient-centered, evidence-informed field of cancer care that utilizes mind and body practices, natural products, and/or lifestyle modifications from different traditions alongside conventional cancer treatments. Integrative oncology aims to optimize health, QOL, and clinical outcomes across the cancer care continuum and to empower people to prevent cancer and become active participants before, during, and beyond cancer treatment.”² A key component of this definition, often misunderstood in the field of oncology, is that these modalities and treatments are used alongside conventional cancer treatments and not as an alternative. In an attempt to meet patients’ needs and appropriately use these approaches, integrative oncology programs are now part of most cancer centers in the United States.^3-6

Because of their overall safety, mind-body therapies are commonly used by patients and recommended by clinicians. Mind-body therapies include yoga, tai chi, qigong, meditation, and relaxation. Expressive arts such as journaling and music, art, and dance therapies also fall in the mind-body category.⁷ Yoga is a movement-based mind-body practice that focuses on synchronizing body, breath, and mind. Yoga has been increasingly used by patients for health benefits,⁸ and numerous studies have evaluated yoga as a complementary intervention for individuals with cancer.^9-14 Here, we review the physiological basis of yoga in oncology and the effects of yoga on biological processes, QOL, and symptoms during and after cancer treatment.

Physiological Basis

Many patients may use mind-body programs such as yoga to help manage the psychological and physiological consequences of unmanaged chronic stress and improve their overall QOL. The central nervous system, endocrine system, and immune system influence and interact with each other in a complex manner in response to chronic stress.^15,16 In a stressful situation, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) are activated. HPA axis stimulation leads to adrenocorticotrophic hormone production by the pituitary gland, which releases glucocorticoid hormones. SNS axis stimulation leads to epinephrine and norepinephrine production by the adrenal gland.^17,18 Recently, studies have explored modulation of signal transduction between the nervous and immune systems and how that may impact tumor growth and metastasis.¹⁹ Multiple studies, controlled for prognosis, disease stage, and other factors, have shown that patients experiencing more distress or higher levels of depressive symptoms do not live as long as their counterparts with low distress or depression levels.²⁰ Both the meditative and physical components of yoga can lead to enhanced relaxation, reduced SNS activation, and greater parasympathetic tone, countering the negative physiological effects of chronic stress. The effects of yoga on the HPA axis and SNS, proinflammatory cytokines, immune function, and DNA damage are discussed below.

Biological Processes

Nervous System

The effects of yoga and other forms of meditation on brain functions have been established through several studies. Yoga seems to influence basal ganglia function by improving circuits that are involved in complex cognitive functions, motor coordination, and somatosensory and emotional processes.^21,22 Additionally, changes in neurotransmitter levels have been observed after yoga practice. For instance, in a 12-week yoga intervention in healthy subjects, increased levels of thalamic gamma-aminobutyric acid (GABA) in the yoga group were reported to have a positive correlation with improved mood and decreased anxiety compared with a group who did metabolically matched walking exercise.²³ Levels of GABA, an inhibitory neurotransmitter, are decreased in conditions such as anxiety, depression, and epilepsy.²⁴ Yoga therapy has been shown to improve symptoms of mood disorders and epilepsy, which leads to the hypothesis that the mechanism driving the benefits of yoga may work through stimulation of vagal efferents and an increase in GABA-mediated cortical-inhibitory tone.^24,25

 

 

HPA Axis

Stress activates the HPA/SNS axis, which releases hormones such as cortisol and norepinephrine. These hormones may play a role in angiogenesis, inflammation, immune suppression, and other physiological functions, and may even reduce the effect of chemotherapeutic agents.^26,27 Regular yoga practice has been shown to reduce SNS and HPA axis activity, most likely by increasing parasympathetic dominance through vagal stimulation, as demonstrated through increases in heart rate variability.²⁸ One indicator of HPA axis dysregulation, diurnal salivary cortisol rhythm, was shown to predict survival in patients with advanced breast and renal cancer.^29-33 Yoga has been shown to lead to less cortisol dysregulation due to radiotherapy and to reductions in mean cortisol levels and early morning cortisol levels in breast cancer patients undergoing radiotherapy.³⁴ This lends support to the hypothesis that yoga helps restore HPA axis balance.

Proinflammatory Cytokines

Cancer patients tend to have increased levels of inflammatory markers such as interleukin (IL)-4, IL-10, tumor necrosis factor (TNF), interferon-γ, and C-reactive protein. This increase in inflammation is associated with worse outcomes in cancer.³⁵ This association becomes highly relevant because the effect of inflammation on host cells in the tumor microenvironment is connected to disease progression.²⁶ Inflammatory cytokines are also implicated in cancer-related symptoms such as fatigue, cognitive dysfunction, peripheral neuropathy, and sleep disturbances.³⁶

Yoga is known to reduce stress and may directly or indirectly decrease inflammatory cytokines. A randomized clinical trial of a 12-week hatha yoga intervention among breast cancer survivors demonstrated decreases in IL-6, IL-1β, TNF, corticotropin-releasing factor, and cognitive complaints in the yoga group compared with those in the standard care group after 3 months.^37,38 Furthermore, Carlson et al showed that, after mindfulness-based stress reduction involving a combination of gentle yoga, meditation techniques, and relaxation exercises, breast and prostate cancer patients had reduced levels of proinflammatory cytokines and cortisol.³⁹ These reductions translated into patients reporting decreased stress levels and enhanced QOL.

Immune Function

The effects of yoga practice on the immune system have been studied in both healthy individuals and individuals with cancer. The effects on T and B lymphocytes, natural killer (NK) cells, and other immune effector cells demonstrate that meditation and yoga have beneficial effects on immune activity.⁴⁰ Hormones such as catecholamines and glucocorticoids are thought to influence the availability and function of NK cells, and, as noted above, yoga has been shown to modulate stress hormones and lead to reduced immune suppression in patients with early-stage breast cancer undergoing chemotherapy.⁴¹ Additional evidence supports the ability of yoga to reduce immune suppression in the postsurgical setting, with no observed decrease in NK cell percentage after surgery for those in a yoga group compared with a control group.⁴² This finding is relevant to patients undergoing surgical management of their cancer and highlights the impact of yoga on the immune system.

DNA Damage

Radiation damages DNA in the peripheral blood lymphocytes of patients undergoing treatment.^43,44 This damage is significant in breast cancer patients undergoing radiotherapy.⁴⁵ Stress additionally causes DNA damage⁴⁶ and is correlated to impaired DNA repair capacity.^47,48 In a study conducted by Banerjee et al, breast cancer patients were randomly assigned to a yoga group or a supportive therapy group for 6 weeks during radiotherapy.⁴⁹ Prior to the intervention, patients in the study had significant genomic instability. After treatment, patients in the yoga group experienced not only a significant reduction in anxiety and depression levels, but also a reduction in DNA damage due to radiotherapy.

 

 

Yoga in Quality of Life and Symptom Management

There is evidence showing that yoga therapy improves multiple aspects of QOL, including physical functioning, emotional health outcomes, and the symptoms cancer patients may experience, such as sleep disturbances, fatigue, and pain. Danhauer et al systematically reviewed both nonrandomized trials and randomized controlled trials involving yoga during cancer treatment.⁵⁰ They found that yoga improved depression and anxiety as well as sleep and fatigue. Benefits of yoga in cancer based on randomized controlled trials are summarized in the Table. The role of yoga in improving QOL and managing symptoms patients experience during and after treatment is discussed in the following sections.

Quality of Life

Danhauer et al’s systematic review of trials involving yoga during cancer treatment found that yoga improved multiple aspects of QOL.⁵⁰ For example, yoga has been shown to improve QOL in breast cancer patients undergoing radiotherapy. In a study by Chandwani et al, yoga (60-minute sessions twice a week for 6 weeks) was associated with better general health perception and physical functioning scores as well as greater benefit finding, or finding meaning in their experience, after radiotherapy compared with a wait-list group.⁵¹ The yoga group had an increase in intrusive thoughts, believed to be due to a more thorough processing of the cancer experience, which helps to improve patients’ outlook on life.⁵² The benefits of yoga extend beyond psychological measures during radiation treatment. Yoga was found to increase physical functioning compared with stretching in breast cancer patients undergoing radiotherapy.⁵³

Cognitive Function

Cancer-related cognitive impairment commonly occurs during cancer treatments (eg, chemotherapy, radiotherapy, surgery, hormone therapy) and persists for months or years in survivors.⁵⁴ Impairment of memory, executive function, attention, and concentration are commonly reported. In a trial of a combined hatha and restorative yoga program called Yoga for Cancer Survivors (YOCAS), which was designed by researchers at the University of Rochester, patients in the yoga arm had less memory difficulty than did patients in the standard care arm.⁵⁵ However, the primary aim of the trial was to treat insomnia, so this secondary outcome needs to be interpreted with caution. Deficits in attention, memory, and executive function are often seen in cancer-related cognitive impairment, and the meditative aspect of yoga may have behavioral and neurophysical benefits that could improve cognitive functions.⁵⁶ More evidence is needed to understand the role of yoga in improving cognitive functioning.

Emotional Health

Psychosocial stress is high among breast cancer patients and survivors.^57,58 This causes circadian rhythm and cortisol regulation abnormalities, which are reported in women with breast cancer.^59-64 Yoga is known to help stress and psychosocial and physical functioning in patients with cancer.⁶⁵ Yoga was also shown to be equivalent to cognitive behavioral therapy in stress management in a population of patients without cancer.⁶⁶ Daily yoga sessions lasting 60 minutes were shown to reduce reactive anxiety and trait anxiety in early-stage breast cancer patients undergoing conventional radiotherapy and chemotherapy compared with patients receiving supportive therapy, highlighting the role of yoga in managing anxiety related to treatment.⁶⁷ In a study done by Culos-Reed et al, 20 cancer survivors who did 75 minutes of yoga per week for 7 weeks were compared with 18 cancer survivors who served as a control group.⁶⁸ The intervention group reported significant improvement in emotional well-being, depression, concentration, and mood disturbances. In a longitudinal study by Mackenzie et al, 66 cancer survivors completed a 7-week yoga program and were assessed at baseline, immediately after the final yoga session, and at 3 and 6 months after the final session.⁶⁹ Participants had significantly improved energy levels and affect. They also had moderate improvement in mindfulness and a moderate decrease in stress. Breast cancer patients who underwent restorative yoga sessions found improvements in mental health, depression, positive affect, and spirituality (peace/meaning).⁷⁰ This was more pronounced in women with higher negative affect and lower emotional well-being at baseline. In a study of patients with ovarian cancer receiving chemotherapy, patients were instructed to perform up to 15-minute sessions including awareness, body movement, and breathing.⁷¹ Even with just 1 session of yoga intervention, patients experienced decreased anxiety.

Fatigue

Studies on yoga show improvement in fatigue both during and after treatment. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit cognitive fatigue.⁷² Older cancer survivors also seem to benefit from yoga interventions.⁷³ In a trial of a DVD-based yoga program, the benefits of yoga were similar to those of strengthening exercises, and both interventions helped decrease fatigue and improve QOL during the first year after diagnosis in early-stage breast cancer patients with cancer-related fatigue.⁷⁴ Bower et al also showed that, for breast cancer survivors experiencing persistent chronic fatigue, a targeted yoga intervention led to significant improvements in fatigue and vigor over a 3-month follow-up compared with controls.⁷⁵ Fatigue is commonly seen in breast cancer patients who are receiving adjuvant chemotherapy. In a study by Taso et al, women with breast cancer receiving chemotherapy were assigned to 60-minute yoga sessions incorporating Anusara yoga, gentle stretching, and relaxation twice a week for 8 weeks.⁷⁶ By week 4, patients with low pretest fatigue in the yoga group experienced a reduction in fatigue. By week 8, all patients in the yoga group experienced a reduction in fatigue. Four weeks after the yoga intervention, patients in the group maintained the reduction in fatigue. This study shows the feasibility of an 8-week yoga program for women undergoing breast cancer therapy by improving fatigue. Yoga recently was added to National Comprehensive Cancer Network (NCCN) guidelines for management of cancer-related fatigue (level 1 evidence).⁷⁷ However, the evidence was based on studies in women with breast cancer and survivors; therefore, more studies are needed in men and women with other cancers.

 

 

Surgical Setting/Postoperative Distress

Distress surrounding surgery in patients with breast cancer can impact postoperative outcomes. Yoga interventions, including breathing exercises, regulated breathing, and yogic relaxation techniques, improved several postsurgical measures such as length of hospital stay, drain retention, and suture removal.⁷⁸ In this study, patients who practiced yoga also experienced a decrease in plasma TNF and better wound healing. Symptoms of anxiety and distress that occur preoperatively can lead to impaired immune function in addition to decreased QOL. In a study of yoga in early-stage breast cancer patients undergoing surgery, the benefit of yoga was seen not only with stress reduction but also with immune enhancement.⁴²

Yoga has been shown to help alleviate acute pain and distress in women undergoing major surgery for gynecological cancer. A regimen of 3 15-minute sessions of yoga, including awareness meditation, coordination of breath with movement, and relaxation breathing, was shown to reduce acute pain and distress in such patients in an inpatient setting.⁷⁹

Menopausal Symptoms

Breast cancer survivors have more severe menopausal symptoms compared with women without cancer.^80,81 Hot flashes cause sleep disturbances and worsen fatigue and QOL.⁸² Tamoxifen and aromatase inhibitors significantly worsen menopausal symptoms such as hot flashes.⁸¹ Carson et al conducted a study of yoga that included postures, breathing techniques, didactic presentations, and group discussions.⁸³ The yoga awareness regimen consisted of 8 weekly 120-minute group classes. Patients in the yoga arm had statistically significant improvements in the frequency, severity, and number of hot flashes. There were also improvements in arthralgia (joint pain), fatigue, sleep disturbance, vigor, and acceptance.

Arthralgia

Joint pain can be a major side effect that interferes with daily functions and activities in postmenopausal breast cancer survivors who receive aromatase inhibitor therapy.⁸⁴ Arthralgia is reported in up to 50% of patients treated with aromatase inhibitors.^84,85 It can affect functional status and lead to discontinuation of aromatase inhibitor therapy, jeopardizing clinical outcomes.⁸⁶ Yoga as a complementary therapy has been shown to improve conditions such as low back pain⁸⁷ and knee osteoarthritis⁸⁸ in patients who do not have cancer. In a single-arm pilot trial by Galantino et al, breast cancer patients with aromatase inhibitor–related joint pain were provided with twice-weekly yoga sessions for 8 weeks. There were statistically significant improvements in balance, flexibility, pain severity, and health-related QOL.⁸⁹ As noted above, improvement in arthralgia was also found in the study conducted by Carson et al.⁸³

Insomnia

Insomnia is common among cancer patients and survivors^90,91 and leads to increased fatigue and depression, decreased adherence to cancer treatments, and poor physical function and QOL.^90-92 Management of insomnia consists of pharmacologic therapies such as benzodiazepines^93,94 and nonpharmacologic options such as cognitive behavioral therapy.⁹⁵

The first study of yoga found to improve sleep quality was conducted at MD Anderson Cancer Center in lymphoma patients.⁹⁶ The effects of Tibetan yoga practices incorporating controlled breathing and visualization, mindfulness techniques, and low-impact postures were studied. Patients in the Tibetan yoga group had better subjective sleep quality, faster sleep latency, longer sleep duration, and less use of sleep medications. Mustian et al conducted a large yoga study in cancer survivors in which patients reporting chronic sleep disturbances were randomly assigned to the YOCAS program, which consisted of pranayama (breath control), 16 gentle hatha and restorative yoga postures, and meditation, or to usual care.⁹² The study reported improvements in global sleep quality, subjective sleep quality, actigraphy measures (wake after sleep onset, sleep efficiency), daytime dysfunction, and use of sleep medication after the yoga intervention compared with participants who received standard care.

 

Yoga to Address Other Symptoms

There is preliminary evidence supporting yoga as an integrative therapy for other symptoms unique to cancer survivors. For example, in head and neck cancer survivors, soft tissue damage involving the jaw, neck, shoulders, and chest results in swallowing issues, trismus, and aspiration, which are more pronounced in patients treated with conventional radiotherapy than in those treated with intensity-modulated radiotherapy.⁹⁷ Some late effects of radiotherapy for head and neck cancer—such as pain, anxiety, and impaired shoulder function—were shown to be improved through the practice of hatha yoga in 1 study.⁹⁸ Similarly, in a randomized controlled pilot study of patients with stage I to III breast cancer 6 months after treatment, participants in an 8-week yoga program experienced a reduction in arm induration and improvement in a QOL subscale of lymphedema symptoms. However, more evidence is needed to support the use of yoga as a therapeutic measure for breast cancer lymphedema.^99,100

Yoga for Caregivers

Along with cancer patients, caregivers face psychological and physical burdens as well as deterioration in their QOL. Caregivers tend to report clinical levels of anxiety, depression, sleep disturbance, and fatigue and have similar or in fact higher levels than those of the patients for whom they are caring.^101,102 Yoga has been found to help caregivers of patients with cancer. Recently, MD Anderson researchers conducted a trial in patients with high-grade glioma and their caregivers as dyads.^103,104 Each dyad attended 2 or 3 60-minute weekly Vivekananda yoga sessions involving breathing exercises, physical exercises, relaxation, and meditation. The researchers found that the yoga program was safe, feasible, acceptable, and subjectively useful for patients with high-grade glioma and their caregivers. Preliminary evidence of QOL improvement for both patients and caregivers was noted. An improvement in QOL was also demonstrated in another preliminary study of yoga in patients undergoing thoracic radiotherapy and their caregivers.¹⁰⁵

Another study by the group at MD Anderson evaluated a couple-based Tibetan yoga program that emphasized breathing exercises, gentle movements, guided visualizations, and emotional connectedness during radiotherapy for lung cancer.¹⁰⁶ This study included 10 patient‐caregiver dyads and found the program to be feasible, safe, and acceptable. The researchers also found preliminary evidence of improved QOL by the end of radiotherapy relative to baseline—specifically in the areas of spiritual well‐being for patients, fatigue for caregivers, and sleep disturbances and mental health issues such as anxiety and depressive symptoms for both patients and caregivers. This is noteworthy, as QOL typically deteriorates during the course of radiotherapy, and the yoga program was able to buffer these changes.

Conclusion

Yoga therapy has been used successfully as an adjunct modality to improve QOL and cancer-related symptoms. As a part of an integrative medicine approach, yoga is commonly recommended for patients undergoing cancer treatment. Danhauer et al reviewed randomized controlled trials during and after treatment and concluded that the evidence is clearly positive for QOL, fatigue, and perceived stress.¹⁰⁷ Results are less consistent but supportive for psychosocial outcomes such as benefit finding and spirituality. Evidence is mixed for sleep, anxiety, and depression. Post-treatment studies demonstrate improvements in fatigue, sleep, and multiple QOL domains. Yoga has been included in NCCN guidelines for fatigue management. Yoga, if approved by a physician, is also included among the behavioral therapies for anticipatory emesis and prevention and treatment of nausea in the recent update of the NCCN guidelines.¹⁰⁸ The Society for Integrative Oncology guidelines include yoga for anxiety/stress reduction as a part of integrative treatment in breast cancer patients during and after therapy, which was endorsed by the American Society of Clinical Oncology.¹⁰⁹

Because of the strong evidence for its benefits and a low side-effect profile, yoga is offered in group-class settings for patients during and after treatment and/or for caregivers in our institution. We often prescribe yoga as a therapeutic modality for selected groups of patients in our clinical practice. However, some patients may have restrictions after surgery that must be considered. In general, yoga has an excellent safety profile, the evidence base is strong, and we recommend that yoga therapy should be part of the standard of care as an integrative approach for patients with cancer undergoing active treatment as well as for cancer survivors and caregivers.

Acknowledgement: The authors thank Bryan Tutt for providing editorial assistance.

Corresponding author: Santhosshi Narayanan, MD, Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030; [email protected].

Financial disclosures: None.

From the University of Texas MD Anderson Cancer Center, Houston, TX (Drs. Narayanan, Lopez, Chaoul, Liu, Milbury, and Cohen, and Ms. Mallaiah); the University of Texas Health Science Center at Tyler (Dr. Meegada); and Texas Tech University Health Sciences Center, Lubbock, TX (Ms. Francisco).

Abstract

• Objective: To review the effects of yoga as an adjunct supportive care modality alongside conventional cancer treatment on quality of life (QOL), physical and mental health outcomes, and physiological and biological measures of cancer survivors.
• Methods: Nonsystematic review of the literature.
• Results: Yoga therapy, one of the most frequently used mind-body modalities, has been studied extensively in cancer survivors (from the time of diagnosis through long-term recovery). Yoga affects human physiology on multiple levels, including psychological outcomes, immune and endocrine function, and cardiovascular parameters, as well as multiple areas of QOL. It has been found to reduce psychological stress and fatigue and improve QOL in cancer patients and survivors. Yoga has also been used to manage symptoms such as arthralgia, fatigue, and insomnia. In addition, yoga offers benefits not only for cancer survivors but also for their caregivers.
• Conclusion: As part of an integrative, evidence-informed approach to cancer care, yoga may provide benefits that support the health of cancer survivors and caregivers.

Keywords: fatigue; cancer; proinflammatory cytokines; integrative; mind-body practices; meditation; DNA damage; stress; psychoneuro-immunoendocrine axis; lymphedema; insomnia.

A diagnosis of cancer and adverse effects related to its treatment may have negative effects on quality of life (QOL), contributing to emotional and physical distress in patients and caregivers. Many patients express an interest in pursuing nonpharmacological options, alone or as an adjunct to conventional therapy, to help manage symptoms. The use of complementary medicine approaches to health, including nonpharmacological approaches to symptom management, is highest among individuals with cancer.¹ According to a published expert consensus, integrative oncology is defined as a “patient-centered, evidence-informed field of cancer care that utilizes mind and body practices, natural products, and/or lifestyle modifications from different traditions alongside conventional cancer treatments. Integrative oncology aims to optimize health, QOL, and clinical outcomes across the cancer care continuum and to empower people to prevent cancer and become active participants before, during, and beyond cancer treatment.”² A key component of this definition, often misunderstood in the field of oncology, is that these modalities and treatments are used alongside conventional cancer treatments and not as an alternative. In an attempt to meet patients’ needs and appropriately use these approaches, integrative oncology programs are now part of most cancer centers in the United States.^3-6

Because of their overall safety, mind-body therapies are commonly used by patients and recommended by clinicians. Mind-body therapies include yoga, tai chi, qigong, meditation, and relaxation. Expressive arts such as journaling and music, art, and dance therapies also fall in the mind-body category.⁷ Yoga is a movement-based mind-body practice that focuses on synchronizing body, breath, and mind. Yoga has been increasingly used by patients for health benefits,⁸ and numerous studies have evaluated yoga as a complementary intervention for individuals with cancer.^9-14 Here, we review the physiological basis of yoga in oncology and the effects of yoga on biological processes, QOL, and symptoms during and after cancer treatment.

Physiological Basis

Many patients may use mind-body programs such as yoga to help manage the psychological and physiological consequences of unmanaged chronic stress and improve their overall QOL. The central nervous system, endocrine system, and immune system influence and interact with each other in a complex manner in response to chronic stress.^15,16 In a stressful situation, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) are activated. HPA axis stimulation leads to adrenocorticotrophic hormone production by the pituitary gland, which releases glucocorticoid hormones. SNS axis stimulation leads to epinephrine and norepinephrine production by the adrenal gland.^17,18 Recently, studies have explored modulation of signal transduction between the nervous and immune systems and how that may impact tumor growth and metastasis.¹⁹ Multiple studies, controlled for prognosis, disease stage, and other factors, have shown that patients experiencing more distress or higher levels of depressive symptoms do not live as long as their counterparts with low distress or depression levels.²⁰ Both the meditative and physical components of yoga can lead to enhanced relaxation, reduced SNS activation, and greater parasympathetic tone, countering the negative physiological effects of chronic stress. The effects of yoga on the HPA axis and SNS, proinflammatory cytokines, immune function, and DNA damage are discussed below.

Biological Processes

Nervous System

The effects of yoga and other forms of meditation on brain functions have been established through several studies. Yoga seems to influence basal ganglia function by improving circuits that are involved in complex cognitive functions, motor coordination, and somatosensory and emotional processes.^21,22 Additionally, changes in neurotransmitter levels have been observed after yoga practice. For instance, in a 12-week yoga intervention in healthy subjects, increased levels of thalamic gamma-aminobutyric acid (GABA) in the yoga group were reported to have a positive correlation with improved mood and decreased anxiety compared with a group who did metabolically matched walking exercise.²³ Levels of GABA, an inhibitory neurotransmitter, are decreased in conditions such as anxiety, depression, and epilepsy.²⁴ Yoga therapy has been shown to improve symptoms of mood disorders and epilepsy, which leads to the hypothesis that the mechanism driving the benefits of yoga may work through stimulation of vagal efferents and an increase in GABA-mediated cortical-inhibitory tone.^24,25

 

 

HPA Axis

Stress activates the HPA/SNS axis, which releases hormones such as cortisol and norepinephrine. These hormones may play a role in angiogenesis, inflammation, immune suppression, and other physiological functions, and may even reduce the effect of chemotherapeutic agents.^26,27 Regular yoga practice has been shown to reduce SNS and HPA axis activity, most likely by increasing parasympathetic dominance through vagal stimulation, as demonstrated through increases in heart rate variability.²⁸ One indicator of HPA axis dysregulation, diurnal salivary cortisol rhythm, was shown to predict survival in patients with advanced breast and renal cancer.^29-33 Yoga has been shown to lead to less cortisol dysregulation due to radiotherapy and to reductions in mean cortisol levels and early morning cortisol levels in breast cancer patients undergoing radiotherapy.³⁴ This lends support to the hypothesis that yoga helps restore HPA axis balance.

Proinflammatory Cytokines

Cancer patients tend to have increased levels of inflammatory markers such as interleukin (IL)-4, IL-10, tumor necrosis factor (TNF), interferon-γ, and C-reactive protein. This increase in inflammation is associated with worse outcomes in cancer.³⁵ This association becomes highly relevant because the effect of inflammation on host cells in the tumor microenvironment is connected to disease progression.²⁶ Inflammatory cytokines are also implicated in cancer-related symptoms such as fatigue, cognitive dysfunction, peripheral neuropathy, and sleep disturbances.³⁶

Yoga is known to reduce stress and may directly or indirectly decrease inflammatory cytokines. A randomized clinical trial of a 12-week hatha yoga intervention among breast cancer survivors demonstrated decreases in IL-6, IL-1β, TNF, corticotropin-releasing factor, and cognitive complaints in the yoga group compared with those in the standard care group after 3 months.^37,38 Furthermore, Carlson et al showed that, after mindfulness-based stress reduction involving a combination of gentle yoga, meditation techniques, and relaxation exercises, breast and prostate cancer patients had reduced levels of proinflammatory cytokines and cortisol.³⁹ These reductions translated into patients reporting decreased stress levels and enhanced QOL.

Immune Function

The effects of yoga practice on the immune system have been studied in both healthy individuals and individuals with cancer. The effects on T and B lymphocytes, natural killer (NK) cells, and other immune effector cells demonstrate that meditation and yoga have beneficial effects on immune activity.⁴⁰ Hormones such as catecholamines and glucocorticoids are thought to influence the availability and function of NK cells, and, as noted above, yoga has been shown to modulate stress hormones and lead to reduced immune suppression in patients with early-stage breast cancer undergoing chemotherapy.⁴¹ Additional evidence supports the ability of yoga to reduce immune suppression in the postsurgical setting, with no observed decrease in NK cell percentage after surgery for those in a yoga group compared with a control group.⁴² This finding is relevant to patients undergoing surgical management of their cancer and highlights the impact of yoga on the immune system.

DNA Damage

Radiation damages DNA in the peripheral blood lymphocytes of patients undergoing treatment.^43,44 This damage is significant in breast cancer patients undergoing radiotherapy.⁴⁵ Stress additionally causes DNA damage⁴⁶ and is correlated to impaired DNA repair capacity.^47,48 In a study conducted by Banerjee et al, breast cancer patients were randomly assigned to a yoga group or a supportive therapy group for 6 weeks during radiotherapy.⁴⁹ Prior to the intervention, patients in the study had significant genomic instability. After treatment, patients in the yoga group experienced not only a significant reduction in anxiety and depression levels, but also a reduction in DNA damage due to radiotherapy.

 

 

Yoga in Quality of Life and Symptom Management

There is evidence showing that yoga therapy improves multiple aspects of QOL, including physical functioning, emotional health outcomes, and the symptoms cancer patients may experience, such as sleep disturbances, fatigue, and pain. Danhauer et al systematically reviewed both nonrandomized trials and randomized controlled trials involving yoga during cancer treatment.⁵⁰ They found that yoga improved depression and anxiety as well as sleep and fatigue. Benefits of yoga in cancer based on randomized controlled trials are summarized in the Table. The role of yoga in improving QOL and managing symptoms patients experience during and after treatment is discussed in the following sections.

Quality of Life

Danhauer et al’s systematic review of trials involving yoga during cancer treatment found that yoga improved multiple aspects of QOL.⁵⁰ For example, yoga has been shown to improve QOL in breast cancer patients undergoing radiotherapy. In a study by Chandwani et al, yoga (60-minute sessions twice a week for 6 weeks) was associated with better general health perception and physical functioning scores as well as greater benefit finding, or finding meaning in their experience, after radiotherapy compared with a wait-list group.⁵¹ The yoga group had an increase in intrusive thoughts, believed to be due to a more thorough processing of the cancer experience, which helps to improve patients’ outlook on life.⁵² The benefits of yoga extend beyond psychological measures during radiation treatment. Yoga was found to increase physical functioning compared with stretching in breast cancer patients undergoing radiotherapy.⁵³

Cognitive Function

Cancer-related cognitive impairment commonly occurs during cancer treatments (eg, chemotherapy, radiotherapy, surgery, hormone therapy) and persists for months or years in survivors.⁵⁴ Impairment of memory, executive function, attention, and concentration are commonly reported. In a trial of a combined hatha and restorative yoga program called Yoga for Cancer Survivors (YOCAS), which was designed by researchers at the University of Rochester, patients in the yoga arm had less memory difficulty than did patients in the standard care arm.⁵⁵ However, the primary aim of the trial was to treat insomnia, so this secondary outcome needs to be interpreted with caution. Deficits in attention, memory, and executive function are often seen in cancer-related cognitive impairment, and the meditative aspect of yoga may have behavioral and neurophysical benefits that could improve cognitive functions.⁵⁶ More evidence is needed to understand the role of yoga in improving cognitive functioning.

Emotional Health

Psychosocial stress is high among breast cancer patients and survivors.^57,58 This causes circadian rhythm and cortisol regulation abnormalities, which are reported in women with breast cancer.^59-64 Yoga is known to help stress and psychosocial and physical functioning in patients with cancer.⁶⁵ Yoga was also shown to be equivalent to cognitive behavioral therapy in stress management in a population of patients without cancer.⁶⁶ Daily yoga sessions lasting 60 minutes were shown to reduce reactive anxiety and trait anxiety in early-stage breast cancer patients undergoing conventional radiotherapy and chemotherapy compared with patients receiving supportive therapy, highlighting the role of yoga in managing anxiety related to treatment.⁶⁷ In a study done by Culos-Reed et al, 20 cancer survivors who did 75 minutes of yoga per week for 7 weeks were compared with 18 cancer survivors who served as a control group.⁶⁸ The intervention group reported significant improvement in emotional well-being, depression, concentration, and mood disturbances. In a longitudinal study by Mackenzie et al, 66 cancer survivors completed a 7-week yoga program and were assessed at baseline, immediately after the final yoga session, and at 3 and 6 months after the final session.⁶⁹ Participants had significantly improved energy levels and affect. They also had moderate improvement in mindfulness and a moderate decrease in stress. Breast cancer patients who underwent restorative yoga sessions found improvements in mental health, depression, positive affect, and spirituality (peace/meaning).⁷⁰ This was more pronounced in women with higher negative affect and lower emotional well-being at baseline. In a study of patients with ovarian cancer receiving chemotherapy, patients were instructed to perform up to 15-minute sessions including awareness, body movement, and breathing.⁷¹ Even with just 1 session of yoga intervention, patients experienced decreased anxiety.

Fatigue

Studies on yoga show improvement in fatigue both during and after treatment. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit cognitive fatigue.⁷² Older cancer survivors also seem to benefit from yoga interventions.⁷³ In a trial of a DVD-based yoga program, the benefits of yoga were similar to those of strengthening exercises, and both interventions helped decrease fatigue and improve QOL during the first year after diagnosis in early-stage breast cancer patients with cancer-related fatigue.⁷⁴ Bower et al also showed that, for breast cancer survivors experiencing persistent chronic fatigue, a targeted yoga intervention led to significant improvements in fatigue and vigor over a 3-month follow-up compared with controls.⁷⁵ Fatigue is commonly seen in breast cancer patients who are receiving adjuvant chemotherapy. In a study by Taso et al, women with breast cancer receiving chemotherapy were assigned to 60-minute yoga sessions incorporating Anusara yoga, gentle stretching, and relaxation twice a week for 8 weeks.⁷⁶ By week 4, patients with low pretest fatigue in the yoga group experienced a reduction in fatigue. By week 8, all patients in the yoga group experienced a reduction in fatigue. Four weeks after the yoga intervention, patients in the group maintained the reduction in fatigue. This study shows the feasibility of an 8-week yoga program for women undergoing breast cancer therapy by improving fatigue. Yoga recently was added to National Comprehensive Cancer Network (NCCN) guidelines for management of cancer-related fatigue (level 1 evidence).⁷⁷ However, the evidence was based on studies in women with breast cancer and survivors; therefore, more studies are needed in men and women with other cancers.

 

 

Surgical Setting/Postoperative Distress

Distress surrounding surgery in patients with breast cancer can impact postoperative outcomes. Yoga interventions, including breathing exercises, regulated breathing, and yogic relaxation techniques, improved several postsurgical measures such as length of hospital stay, drain retention, and suture removal.⁷⁸ In this study, patients who practiced yoga also experienced a decrease in plasma TNF and better wound healing. Symptoms of anxiety and distress that occur preoperatively can lead to impaired immune function in addition to decreased QOL. In a study of yoga in early-stage breast cancer patients undergoing surgery, the benefit of yoga was seen not only with stress reduction but also with immune enhancement.⁴²

Yoga has been shown to help alleviate acute pain and distress in women undergoing major surgery for gynecological cancer. A regimen of 3 15-minute sessions of yoga, including awareness meditation, coordination of breath with movement, and relaxation breathing, was shown to reduce acute pain and distress in such patients in an inpatient setting.⁷⁹

Menopausal Symptoms

Breast cancer survivors have more severe menopausal symptoms compared with women without cancer.^80,81 Hot flashes cause sleep disturbances and worsen fatigue and QOL.⁸² Tamoxifen and aromatase inhibitors significantly worsen menopausal symptoms such as hot flashes.⁸¹ Carson et al conducted a study of yoga that included postures, breathing techniques, didactic presentations, and group discussions.⁸³ The yoga awareness regimen consisted of 8 weekly 120-minute group classes. Patients in the yoga arm had statistically significant improvements in the frequency, severity, and number of hot flashes. There were also improvements in arthralgia (joint pain), fatigue, sleep disturbance, vigor, and acceptance.

Arthralgia

Joint pain can be a major side effect that interferes with daily functions and activities in postmenopausal breast cancer survivors who receive aromatase inhibitor therapy.⁸⁴ Arthralgia is reported in up to 50% of patients treated with aromatase inhibitors.^84,85 It can affect functional status and lead to discontinuation of aromatase inhibitor therapy, jeopardizing clinical outcomes.⁸⁶ Yoga as a complementary therapy has been shown to improve conditions such as low back pain⁸⁷ and knee osteoarthritis⁸⁸ in patients who do not have cancer. In a single-arm pilot trial by Galantino et al, breast cancer patients with aromatase inhibitor–related joint pain were provided with twice-weekly yoga sessions for 8 weeks. There were statistically significant improvements in balance, flexibility, pain severity, and health-related QOL.⁸⁹ As noted above, improvement in arthralgia was also found in the study conducted by Carson et al.⁸³

Insomnia

Insomnia is common among cancer patients and survivors^90,91 and leads to increased fatigue and depression, decreased adherence to cancer treatments, and poor physical function and QOL.^90-92 Management of insomnia consists of pharmacologic therapies such as benzodiazepines^93,94 and nonpharmacologic options such as cognitive behavioral therapy.⁹⁵

The first study of yoga found to improve sleep quality was conducted at MD Anderson Cancer Center in lymphoma patients.⁹⁶ The effects of Tibetan yoga practices incorporating controlled breathing and visualization, mindfulness techniques, and low-impact postures were studied. Patients in the Tibetan yoga group had better subjective sleep quality, faster sleep latency, longer sleep duration, and less use of sleep medications. Mustian et al conducted a large yoga study in cancer survivors in which patients reporting chronic sleep disturbances were randomly assigned to the YOCAS program, which consisted of pranayama (breath control), 16 gentle hatha and restorative yoga postures, and meditation, or to usual care.⁹² The study reported improvements in global sleep quality, subjective sleep quality, actigraphy measures (wake after sleep onset, sleep efficiency), daytime dysfunction, and use of sleep medication after the yoga intervention compared with participants who received standard care.

 

Yoga to Address Other Symptoms

There is preliminary evidence supporting yoga as an integrative therapy for other symptoms unique to cancer survivors. For example, in head and neck cancer survivors, soft tissue damage involving the jaw, neck, shoulders, and chest results in swallowing issues, trismus, and aspiration, which are more pronounced in patients treated with conventional radiotherapy than in those treated with intensity-modulated radiotherapy.⁹⁷ Some late effects of radiotherapy for head and neck cancer—such as pain, anxiety, and impaired shoulder function—were shown to be improved through the practice of hatha yoga in 1 study.⁹⁸ Similarly, in a randomized controlled pilot study of patients with stage I to III breast cancer 6 months after treatment, participants in an 8-week yoga program experienced a reduction in arm induration and improvement in a QOL subscale of lymphedema symptoms. However, more evidence is needed to support the use of yoga as a therapeutic measure for breast cancer lymphedema.^99,100

Yoga for Caregivers

Along with cancer patients, caregivers face psychological and physical burdens as well as deterioration in their QOL. Caregivers tend to report clinical levels of anxiety, depression, sleep disturbance, and fatigue and have similar or in fact higher levels than those of the patients for whom they are caring.^101,102 Yoga has been found to help caregivers of patients with cancer. Recently, MD Anderson researchers conducted a trial in patients with high-grade glioma and their caregivers as dyads.^103,104 Each dyad attended 2 or 3 60-minute weekly Vivekananda yoga sessions involving breathing exercises, physical exercises, relaxation, and meditation. The researchers found that the yoga program was safe, feasible, acceptable, and subjectively useful for patients with high-grade glioma and their caregivers. Preliminary evidence of QOL improvement for both patients and caregivers was noted. An improvement in QOL was also demonstrated in another preliminary study of yoga in patients undergoing thoracic radiotherapy and their caregivers.¹⁰⁵

Another study by the group at MD Anderson evaluated a couple-based Tibetan yoga program that emphasized breathing exercises, gentle movements, guided visualizations, and emotional connectedness during radiotherapy for lung cancer.¹⁰⁶ This study included 10 patient‐caregiver dyads and found the program to be feasible, safe, and acceptable. The researchers also found preliminary evidence of improved QOL by the end of radiotherapy relative to baseline—specifically in the areas of spiritual well‐being for patients, fatigue for caregivers, and sleep disturbances and mental health issues such as anxiety and depressive symptoms for both patients and caregivers. This is noteworthy, as QOL typically deteriorates during the course of radiotherapy, and the yoga program was able to buffer these changes.

Conclusion

Yoga therapy has been used successfully as an adjunct modality to improve QOL and cancer-related symptoms. As a part of an integrative medicine approach, yoga is commonly recommended for patients undergoing cancer treatment. Danhauer et al reviewed randomized controlled trials during and after treatment and concluded that the evidence is clearly positive for QOL, fatigue, and perceived stress.¹⁰⁷ Results are less consistent but supportive for psychosocial outcomes such as benefit finding and spirituality. Evidence is mixed for sleep, anxiety, and depression. Post-treatment studies demonstrate improvements in fatigue, sleep, and multiple QOL domains. Yoga has been included in NCCN guidelines for fatigue management. Yoga, if approved by a physician, is also included among the behavioral therapies for anticipatory emesis and prevention and treatment of nausea in the recent update of the NCCN guidelines.¹⁰⁸ The Society for Integrative Oncology guidelines include yoga for anxiety/stress reduction as a part of integrative treatment in breast cancer patients during and after therapy, which was endorsed by the American Society of Clinical Oncology.¹⁰⁹

Because of the strong evidence for its benefits and a low side-effect profile, yoga is offered in group-class settings for patients during and after treatment and/or for caregivers in our institution. We often prescribe yoga as a therapeutic modality for selected groups of patients in our clinical practice. However, some patients may have restrictions after surgery that must be considered. In general, yoga has an excellent safety profile, the evidence base is strong, and we recommend that yoga therapy should be part of the standard of care as an integrative approach for patients with cancer undergoing active treatment as well as for cancer survivors and caregivers.

Acknowledgement: The authors thank Bryan Tutt for providing editorial assistance.

Corresponding author: Santhosshi Narayanan, MD, Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030; [email protected].

Financial disclosures: None.

INTRODUCTION

Fatigue is a common distressing effect of cancer.¹ It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors alike. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”² CRF differs from fatigue reported by individuals without cancer in that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, with estimates ranging between 25% and 99%.^2,3 The methods used for screening patients for fatigue and the characteristics of the patient groups may account for this variability. In this article, we review evaluation of CRF and approaches to its management.

PATHOPHYSIOLOGY

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of multiple mechanisms contributing to fatigue in an individual patient.

CENTRAL NERVOUS SYSTEM DISTURBANCES

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores.⁴ Increased levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF.⁵ However, there is not enough evidence at this time to support central nervous system disturbance as the main factor contributing to fatigue in cancer patients.

CIRCADIAN RHYTHM DYSREGULATION

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways.² Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors.⁶ These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

INHIBITION OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis.⁶ Inhibition of the HPA axis may occur with higher levels of serotonin as well.⁷ The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue.⁸ Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue.²

SKELETAL MUSCLE EFFECT

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction.⁹ ATP infusion improved muscle strength in 1 trial, but this was not confirmed in another trial.^10,11 Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls.¹² This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles.^13,14

PRO-INFLAMMATORY CYTOKINES

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom of fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Levels of interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma.¹⁵ IL-6 was also associated with increased fatigue in breast cancer survivors.¹⁶ Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy.¹⁷ Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients.^18,19 Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients.²⁰ Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF.²¹

 

OTHER HYPOTHESES

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support,²² genetic alterations in the immune pathway,²³ epigenetic changes,²⁴ accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation,²⁵ elevated vascular endothelial growth factor levels,²⁶ and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction¹³ all have been postulated to cause CRF.

EVALUATION AND TREATMENT

Fours steps are involved in the evaluation and treatment of CRF (Figure).

Patients are screened for fatigue as the first step, and those who have fatigue undergo a primary evaluation to assess for potential precipitating causes. The third step is implementation of pharmacologic and nonpharmacologic interventions aimed at alleviating or mitigating fatigue. The fourth step involves reevaluating patients periodically to recognize and manage changes in fatigue levels. A multidisciplinary approach involving nursing, physical therapy, social work, and nutrition is critical in managing fatigue in these patients. Education and counselling of patients and involvement of the family are essential for effective management as well.

SCREENING

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to under-recognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue.² Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials.²⁷ A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF.² This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors.²⁸ The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue.^29,30 The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day.³¹ The 9-item BFI is often used in clinical trials.²⁹ It measures the severity of fatigue over the previous 24 hours and has been validated in patients who do not speak English.³²

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which assesses 5 dimensions of fatigue—general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue—and compares the patient’s results with those of individuals without cancer.^33,34 The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments.³⁵

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales.³⁶ Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic reevaluation, and moderate and severe fatigue need further evaluation and management.³⁷

PRIMARY EVALUATION

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living.³⁷ Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse, which may cause poor sleep and fatigue.

 

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below. 

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels.³⁸ Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or auto-immune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes.³⁹ Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond.⁴⁰ Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL.⁴¹

Sleep disturbance. Poor sleep is common in fatigued cancer survivors.⁴² Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuro­endocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue.⁴³ Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep.⁴⁴ Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep.⁴⁵ Melatonin agonists are approved for insomnia in the United States, but not in Europe.⁴⁶

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men.⁴⁷

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster.⁴⁸ A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating one of these symptoms without addressing other symptoms is not effective.⁴⁹ Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy— such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue.⁵⁰

MANAGEMENT

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time.^51,52 When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients.⁵³

 

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy.⁵⁴ CBT interventions that optimize sleep quality may improve fatigue.⁵⁵ More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF.⁵⁶

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations.⁵⁷ Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship.⁵⁸ Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve their cardiorespiratory fitness, muscle strength, and body composition.⁵⁷ Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended for younger patients as well as for the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors.⁵⁹ In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone.⁶⁰ This effect was also shown in a randomized controlled trial of 160 patients with stage 0 to III breast cancer undergoing radiation therapy.⁶¹ The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits only in the physical fatigue components, but not in the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week.⁶² An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes.⁶³ Patients with comorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy.³⁷ Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life.^64,65 We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training.⁶⁶ Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life.⁶⁷

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors.⁶⁸ In breast cancer patients undergoing chemotherapy, yoga was shown to benefit both physical and cognitive fatigue.⁶⁹ DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF.⁷⁰ More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months.⁷¹ Additional research is needed in this area.

Acupuncture. A randomized controlled trial in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue.⁷² However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue.⁷³ Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done; of the studies that have been done, the results are mixed, and additional research is needed.⁷⁴ Currently, there are not sufficient data to recommend any of these modalities.

 

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF,^75–77 but randomized controlled trials have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of nonpharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment.³⁷

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. Randomized controlled trials of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF.⁷⁸ Likewise, in an analysis of 5 randomized controlled trials, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo.⁷⁹ However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease.⁸⁰ Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically.⁸¹ In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner.⁸² However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment.⁸³ Also, other randomized controlled trials in patients undergoing adjuvant chemotherapy for breast cancer⁸⁴ and patients receiving radiation therapy for brain tumors⁸⁵ failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm.⁸⁶ Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation.⁸⁷ A placebo effect was also noted in patients with multiple myeloma⁸⁸ and patients with primary brain tumors.⁸⁹ In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue.⁹⁰ In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7).⁹¹ This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional randomized controlled trials are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF.³⁷

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines.⁹² In a randomized controlled trial evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo.⁹³ A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo.⁹⁴ Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis.³⁷

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups.⁹⁵

Antidepressants have failed to demonstrate benefit in CRF without depression.⁸ However, if a patient has both fatigue and depression, antidepressants may help.⁹⁶ A selective serotonin receptor inhibitor is recommended as a first-line antidepressant.⁹⁷ Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

 

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF.⁷⁴ The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF.⁹⁸

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo.⁹⁹ Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects.¹⁰⁰ Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

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

Reevaluation

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

CONCLUSION

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

Acknowledgment: The authors thank Bryan Tutt for providing editorial assistance during the writing of this article.

INTRODUCTION

Fatigue is a common distressing effect of cancer.¹ It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors alike. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”² CRF differs from fatigue reported by individuals without cancer in that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, with estimates ranging between 25% and 99%.^2,3 The methods used for screening patients for fatigue and the characteristics of the patient groups may account for this variability. In this article, we review evaluation of CRF and approaches to its management.

PATHOPHYSIOLOGY

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of multiple mechanisms contributing to fatigue in an individual patient.

CENTRAL NERVOUS SYSTEM DISTURBANCES

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores.⁴ Increased levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF.⁵ However, there is not enough evidence at this time to support central nervous system disturbance as the main factor contributing to fatigue in cancer patients.

CIRCADIAN RHYTHM DYSREGULATION

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways.² Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors.⁶ These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

INHIBITION OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis.⁶ Inhibition of the HPA axis may occur with higher levels of serotonin as well.⁷ The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue.⁸ Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue.²

SKELETAL MUSCLE EFFECT

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction.⁹ ATP infusion improved muscle strength in 1 trial, but this was not confirmed in another trial.^10,11 Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls.¹² This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles.^13,14

PRO-INFLAMMATORY CYTOKINES

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom of fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Levels of interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma.¹⁵ IL-6 was also associated with increased fatigue in breast cancer survivors.¹⁶ Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy.¹⁷ Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients.^18,19 Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients.²⁰ Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF.²¹

 

OTHER HYPOTHESES

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support,²² genetic alterations in the immune pathway,²³ epigenetic changes,²⁴ accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation,²⁵ elevated vascular endothelial growth factor levels,²⁶ and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction¹³ all have been postulated to cause CRF.

EVALUATION AND TREATMENT

Fours steps are involved in the evaluation and treatment of CRF (Figure).

Patients are screened for fatigue as the first step, and those who have fatigue undergo a primary evaluation to assess for potential precipitating causes. The third step is implementation of pharmacologic and nonpharmacologic interventions aimed at alleviating or mitigating fatigue. The fourth step involves reevaluating patients periodically to recognize and manage changes in fatigue levels. A multidisciplinary approach involving nursing, physical therapy, social work, and nutrition is critical in managing fatigue in these patients. Education and counselling of patients and involvement of the family are essential for effective management as well.

SCREENING

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to under-recognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue.² Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials.²⁷ A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF.² This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors.²⁸ The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue.^29,30 The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day.³¹ The 9-item BFI is often used in clinical trials.²⁹ It measures the severity of fatigue over the previous 24 hours and has been validated in patients who do not speak English.³²

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which assesses 5 dimensions of fatigue—general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue—and compares the patient’s results with those of individuals without cancer.^33,34 The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments.³⁵

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales.³⁶ Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic reevaluation, and moderate and severe fatigue need further evaluation and management.³⁷

PRIMARY EVALUATION

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living.³⁷ Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse, which may cause poor sleep and fatigue.

 

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below. 

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels.³⁸ Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or auto-immune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes.³⁹ Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond.⁴⁰ Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL.⁴¹

Sleep disturbance. Poor sleep is common in fatigued cancer survivors.⁴² Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuro­endocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue.⁴³ Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep.⁴⁴ Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep.⁴⁵ Melatonin agonists are approved for insomnia in the United States, but not in Europe.⁴⁶

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men.⁴⁷

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster.⁴⁸ A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating one of these symptoms without addressing other symptoms is not effective.⁴⁹ Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy— such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue.⁵⁰

MANAGEMENT

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time.^51,52 When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients.⁵³

 

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy.⁵⁴ CBT interventions that optimize sleep quality may improve fatigue.⁵⁵ More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF.⁵⁶

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations.⁵⁷ Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship.⁵⁸ Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve their cardiorespiratory fitness, muscle strength, and body composition.⁵⁷ Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended for younger patients as well as for the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors.⁵⁹ In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone.⁶⁰ This effect was also shown in a randomized controlled trial of 160 patients with stage 0 to III breast cancer undergoing radiation therapy.⁶¹ The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits only in the physical fatigue components, but not in the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week.⁶² An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes.⁶³ Patients with comorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy.³⁷ Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life.^64,65 We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training.⁶⁶ Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life.⁶⁷

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors.⁶⁸ In breast cancer patients undergoing chemotherapy, yoga was shown to benefit both physical and cognitive fatigue.⁶⁹ DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF.⁷⁰ More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months.⁷¹ Additional research is needed in this area.

Acupuncture. A randomized controlled trial in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue.⁷² However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue.⁷³ Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done; of the studies that have been done, the results are mixed, and additional research is needed.⁷⁴ Currently, there are not sufficient data to recommend any of these modalities.

 

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF,^75–77 but randomized controlled trials have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of nonpharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment.³⁷

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. Randomized controlled trials of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF.⁷⁸ Likewise, in an analysis of 5 randomized controlled trials, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo.⁷⁹ However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease.⁸⁰ Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically.⁸¹ In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner.⁸² However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment.⁸³ Also, other randomized controlled trials in patients undergoing adjuvant chemotherapy for breast cancer⁸⁴ and patients receiving radiation therapy for brain tumors⁸⁵ failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm.⁸⁶ Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation.⁸⁷ A placebo effect was also noted in patients with multiple myeloma⁸⁸ and patients with primary brain tumors.⁸⁹ In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue.⁹⁰ In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7).⁹¹ This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional randomized controlled trials are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF.³⁷

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines.⁹² In a randomized controlled trial evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo.⁹³ A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo.⁹⁴ Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis.³⁷

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups.⁹⁵

Antidepressants have failed to demonstrate benefit in CRF without depression.⁸ However, if a patient has both fatigue and depression, antidepressants may help.⁹⁶ A selective serotonin receptor inhibitor is recommended as a first-line antidepressant.⁹⁷ Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

 

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF.⁷⁴ The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF.⁹⁸

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo.⁹⁹ Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects.¹⁰⁰ Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

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

Reevaluation

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

CONCLUSION

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

Acknowledgment: The authors thank Bryan Tutt for providing editorial assistance during the writing of this article.

INTRODUCTION

Fatigue is a common distressing effect of cancer.¹ It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors alike. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”² CRF differs from fatigue reported by individuals without cancer in that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, with estimates ranging between 25% and 99%.^2,3 The methods used for screening patients for fatigue and the characteristics of the patient groups may account for this variability. In this article, we review evaluation of CRF and approaches to its management.

PATHOPHYSIOLOGY

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of multiple mechanisms contributing to fatigue in an individual patient.

CENTRAL NERVOUS SYSTEM DISTURBANCES

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores.⁴ Increased levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF.⁵ However, there is not enough evidence at this time to support central nervous system disturbance as the main factor contributing to fatigue in cancer patients.

CIRCADIAN RHYTHM DYSREGULATION

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways.² Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors.⁶ These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

INHIBITION OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis.⁶ Inhibition of the HPA axis may occur with higher levels of serotonin as well.⁷ The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue.⁸ Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue.²

SKELETAL MUSCLE EFFECT

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction.⁹ ATP infusion improved muscle strength in 1 trial, but this was not confirmed in another trial.^10,11 Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls.¹² This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles.^13,14

PRO-INFLAMMATORY CYTOKINES

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom of fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Levels of interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma.¹⁵ IL-6 was also associated with increased fatigue in breast cancer survivors.¹⁶ Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy.¹⁷ Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients.^18,19 Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients.²⁰ Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF.²¹

 

OTHER HYPOTHESES

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support,²² genetic alterations in the immune pathway,²³ epigenetic changes,²⁴ accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation,²⁵ elevated vascular endothelial growth factor levels,²⁶ and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction¹³ all have been postulated to cause CRF.

EVALUATION AND TREATMENT

Fours steps are involved in the evaluation and treatment of CRF (Figure).

Patients are screened for fatigue as the first step, and those who have fatigue undergo a primary evaluation to assess for potential precipitating causes. The third step is implementation of pharmacologic and nonpharmacologic interventions aimed at alleviating or mitigating fatigue. The fourth step involves reevaluating patients periodically to recognize and manage changes in fatigue levels. A multidisciplinary approach involving nursing, physical therapy, social work, and nutrition is critical in managing fatigue in these patients. Education and counselling of patients and involvement of the family are essential for effective management as well.

SCREENING

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to under-recognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue.² Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials.²⁷ A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF.² This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors.²⁸ The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue.^29,30 The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day.³¹ The 9-item BFI is often used in clinical trials.²⁹ It measures the severity of fatigue over the previous 24 hours and has been validated in patients who do not speak English.³²

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which assesses 5 dimensions of fatigue—general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue—and compares the patient’s results with those of individuals without cancer.^33,34 The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments.³⁵

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales.³⁶ Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic reevaluation, and moderate and severe fatigue need further evaluation and management.³⁷

PRIMARY EVALUATION

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living.³⁷ Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse, which may cause poor sleep and fatigue.

 

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below. 

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels.³⁸ Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or auto-immune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes.³⁹ Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond.⁴⁰ Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL.⁴¹

Sleep disturbance. Poor sleep is common in fatigued cancer survivors.⁴² Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuro­endocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue.⁴³ Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep.⁴⁴ Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep.⁴⁵ Melatonin agonists are approved for insomnia in the United States, but not in Europe.⁴⁶

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men.⁴⁷

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster.⁴⁸ A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating one of these symptoms without addressing other symptoms is not effective.⁴⁹ Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy— such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue.⁵⁰

MANAGEMENT

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time.^51,52 When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients.⁵³

 

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy.⁵⁴ CBT interventions that optimize sleep quality may improve fatigue.⁵⁵ More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF.⁵⁶

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations.⁵⁷ Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship.⁵⁸ Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve their cardiorespiratory fitness, muscle strength, and body composition.⁵⁷ Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended for younger patients as well as for the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors.⁵⁹ In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone.⁶⁰ This effect was also shown in a randomized controlled trial of 160 patients with stage 0 to III breast cancer undergoing radiation therapy.⁶¹ The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits only in the physical fatigue components, but not in the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week.⁶² An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes.⁶³ Patients with comorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy.³⁷ Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life.^64,65 We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training.⁶⁶ Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life.⁶⁷

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors.⁶⁸ In breast cancer patients undergoing chemotherapy, yoga was shown to benefit both physical and cognitive fatigue.⁶⁹ DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF.⁷⁰ More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months.⁷¹ Additional research is needed in this area.

Acupuncture. A randomized controlled trial in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue.⁷² However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue.⁷³ Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done; of the studies that have been done, the results are mixed, and additional research is needed.⁷⁴ Currently, there are not sufficient data to recommend any of these modalities.

 

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF,^75–77 but randomized controlled trials have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of nonpharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment.³⁷

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. Randomized controlled trials of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF.⁷⁸ Likewise, in an analysis of 5 randomized controlled trials, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo.⁷⁹ However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease.⁸⁰ Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically.⁸¹ In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner.⁸² However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment.⁸³ Also, other randomized controlled trials in patients undergoing adjuvant chemotherapy for breast cancer⁸⁴ and patients receiving radiation therapy for brain tumors⁸⁵ failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm.⁸⁶ Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation.⁸⁷ A placebo effect was also noted in patients with multiple myeloma⁸⁸ and patients with primary brain tumors.⁸⁹ In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue.⁹⁰ In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7).⁹¹ This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional randomized controlled trials are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF.³⁷

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines.⁹² In a randomized controlled trial evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo.⁹³ A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo.⁹⁴ Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis.³⁷

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups.⁹⁵

Antidepressants have failed to demonstrate benefit in CRF without depression.⁸ However, if a patient has both fatigue and depression, antidepressants may help.⁹⁶ A selective serotonin receptor inhibitor is recommended as a first-line antidepressant.⁹⁷ Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

 

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF.⁷⁴ The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF.⁹⁸

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo.⁹⁹ Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects.¹⁰⁰ Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

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

Reevaluation

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

CONCLUSION

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

Acknowledgment: The authors thank Bryan Tutt for providing editorial assistance during the writing of this article.

From the University of Texas MD Anderson Cancer Center, Houston, TX.

 

Abstract

• Objective: To review the evidence on interventions for managing cancer-related fatigue (CRF) and provide evidence-based guidance on approaches to its management.
• Methods: Nonsystematic review of the literature.
• Results: Several theories have been proposed to explain the biology of CRF, but there is no single clear mechanism that can be targeted for therapy. The approach to patients begins with screening for fatigue and assessing its intensity, followed by a thorough history and examination to determine whether any reversible medical conditions are contributing to fatigue. Management of underlying medical comorbidities may help some patients. For patients whose fatigue persists, pharmacologic and nonpharmacologic treatment options are available. Pharmacologic options include psychostimulants, such as methylphenidate and modafinil, and corticosteroids. Nonpharmacologic approaches include exercise, cognitive behavior therapy, yoga, acupuncture, and tai chi.
• Conclusion: We recommend an individualized approach, often with a combination of the available options. Patients need to be evaluated periodically to assess their fatigue, and since cancer-related fatigue affects survivors, long-term follow-up is needed.

Key words: fatigue; cancer; pro-inflammatory cytokines; nonpharmacologic; psychostimulants.

 

Fatigue is a common distressing effect of cancer [1].It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning [2].” Differences between CRF and fatigue reported by individuals without cancer are that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, ranging between 25% and 99% [2,3]. This variability may be secondary to methods used for screening fatigue and characteristics of the patient groups. In this article, we discuss recognition of CRF and approaches to its management.

Pathophysiology

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of more than 1 mechanism contributing to fatigue in an individual patient.

Central Nervous System Disturbances

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores [4]. Higher levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF [5]. However, there is not enough evidence at this time to support central nervous system disturbance as the main contributing factor to fatigue in cancer patients.

Circadian Rhythm Dysregulation

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways [2]. Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors [6]. These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

Inhibition of Hypothalamic–Pituitary–Adrenal Axis

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis [6]. The inhibition of the HPA axis may occur with higher levels of serotonin as well [7]. The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue [8]. Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue [2].

Skeletal Muscle Effect

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction [9]. ATP infusion improved muscle strength in one trial, but this was not confirmed in another trial [10,11]. Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls [12]. This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles [13,14].

Pro-inflammatory Cytokines

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma [15]. IL-6 was also associated with increased fatigue in breast cancer survivors [16]. Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy [17]. Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients [18,19]. Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients [20]. Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF [21].

Other Hypotheses

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support [22], genetic alterations in immune pathway [23], epigenetic changes [24], accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation [25], elevated vascular endothelial growth factor levels [26], and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction [13] all have been postulated to cause CRF.

Approach to Evaluation and Treatment

The evaluation and treatment of CRF involve 4 steps (Figure). First, patients are screened for fatigue, and in the second step those who have fatigue undergo primary evaluation to assess for potential precipitating causes. The third step is implementation of pharmacologic and non-pharmacologic interventions aimed at alleviating or mitigating fatigue. The fourth step involves re-evaluating patients at periodic intervals to recognize and manage changes in fatigue levels. A multidisciplinary approach involving nursing, physical therapy, social work, and nutrition is critical in managing fatigue in these patients. Education and counselling of patients and involvement of the family are essential for effective management.

Screening

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to underrecognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue [2]. Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials [27]. A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF [2]. This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors [28]. The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue [29,30]. The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day [31]. The 9-item BFI is often used in clinical trials [29]. It measures the severity of fatigue over the previous 24 hours and has been validated in non-English speaking patients [32].

 

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which measures general, physical, mental, and emotional fatigue domains as well as activity and compares them with those of individuals without cancer [33,34]. The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments [35].

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales [36]. Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic re-evaluation, and moderate and severe fatigue need further evaluation and management [37].

Primary Evaluation

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living [37]. Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse which may cause poor sleep and fatigue.

 

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below.

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels [38]. Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or autoimmune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes [39]. Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond [40]. Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL [41].

Sleep disturbance. Poor sleep is common in fatigued cancer survivors [42]. Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuroendocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue [43]. Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep [44]. Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep [45]. Melatonin agonists are approved for insomnia in the United states, but not in Europe [46].

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men [47].

 

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster [48]. A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating of one of these symptoms without addressing other symptoms is not effective [49]. Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy—such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue [50].

Management

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time [51,52]. When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients [53].

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy [54]. CBT interventions that optimize sleep quality may improve fatigue [55]. More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials (RCTs) showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF [56].

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations [57]. Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship [58]. Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve cardiorespiratory fitness, muscle strength, and body composition [57]. Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended not only for younger patients, but also in the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors [59]. In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone [60]. This effect was also shown in an RCT of 160 patients with stage 0 to III breast cancer undergoing radiation therapy [61]. The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits in the physical fatigue but not the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week [62]. An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes [63]. Patients withcomorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy [37]. Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life [64,65]. We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training [66]. Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life [67].

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors [68]. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit not only physical fatigue, but also cognitive fatigue [69]. DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF [70]. More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months [71]. Additional research is needed in this area.

Acupuncture. An RCT in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue [72]. However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue [73]. Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done, with mixed results, and additional research is needed [74]. Currently, there are not sufficient data to recommend any of these modalities.

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF [75–77], but RCTs have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of non-pharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment [37].

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. RCTs of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF [78]. Likewise, in an analysis of 5 RCTs, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo [79]. However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease [80]. Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically [81]. In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner [82]. However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment [83]. Also, other RCTs in patients undergoing adjuvant chemotherapy for breast cancer [84] and patients receiving radiation therapy for brain tumors [85] failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm [86]. Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation [87]. A placebo effect was also noted in patients with multiple myeloma [88] and patients with primary brain tumors [89]. In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue [90]. In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7) [91]. This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional RCTs are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF [37].

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines [92]. In a RCT evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo [93]. A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo [94]. Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis [37].

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups [95].

Antidepressants have failed to demonstrate benefit in CRF without depression [8]. However, if a patient has both fatigue and depression, antidepressants may help [96]. A selective serotonin receptor inhibitor is recommended as a first-line antidepressant [97]. Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

 

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF [74]. The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF [98].

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo [99]. Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects [100]. Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

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

Re-evaluation

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

Conclusion

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

 

Acknowledgment: Bryan Tutt provided editorial assistance.

Corresponding author: Carmelita P. Escalante, MD, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030, [email protected].

Financial disclosures: None.

From the University of Texas MD Anderson Cancer Center, Houston, TX.

 

Abstract

• Objective: To review the evidence on interventions for managing cancer-related fatigue (CRF) and provide evidence-based guidance on approaches to its management.
• Methods: Nonsystematic review of the literature.
• Results: Several theories have been proposed to explain the biology of CRF, but there is no single clear mechanism that can be targeted for therapy. The approach to patients begins with screening for fatigue and assessing its intensity, followed by a thorough history and examination to determine whether any reversible medical conditions are contributing to fatigue. Management of underlying medical comorbidities may help some patients. For patients whose fatigue persists, pharmacologic and nonpharmacologic treatment options are available. Pharmacologic options include psychostimulants, such as methylphenidate and modafinil, and corticosteroids. Nonpharmacologic approaches include exercise, cognitive behavior therapy, yoga, acupuncture, and tai chi.
• Conclusion: We recommend an individualized approach, often with a combination of the available options. Patients need to be evaluated periodically to assess their fatigue, and since cancer-related fatigue affects survivors, long-term follow-up is needed.

Key words: fatigue; cancer; pro-inflammatory cytokines; nonpharmacologic; psychostimulants.

 

Fatigue is a common distressing effect of cancer [1].It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning [2].” Differences between CRF and fatigue reported by individuals without cancer are that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, ranging between 25% and 99% [2,3]. This variability may be secondary to methods used for screening fatigue and characteristics of the patient groups. In this article, we discuss recognition of CRF and approaches to its management.

Pathophysiology

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of more than 1 mechanism contributing to fatigue in an individual patient.

Central Nervous System Disturbances

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores [4]. Higher levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF [5]. However, there is not enough evidence at this time to support central nervous system disturbance as the main contributing factor to fatigue in cancer patients.

Circadian Rhythm Dysregulation

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways [2]. Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors [6]. These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

Inhibition of Hypothalamic–Pituitary–Adrenal Axis

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis [6]. The inhibition of the HPA axis may occur with higher levels of serotonin as well [7]. The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue [8]. Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue [2].

Skeletal Muscle Effect

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction [9]. ATP infusion improved muscle strength in one trial, but this was not confirmed in another trial [10,11]. Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls [12]. This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles [13,14].

Pro-inflammatory Cytokines

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma [15]. IL-6 was also associated with increased fatigue in breast cancer survivors [16]. Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy [17]. Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients [18,19]. Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients [20]. Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF [21].

Other Hypotheses

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support [22], genetic alterations in immune pathway [23], epigenetic changes [24], accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation [25], elevated vascular endothelial growth factor levels [26], and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction [13] all have been postulated to cause CRF.

Approach to Evaluation and Treatment

The evaluation and treatment of CRF involve 4 steps (Figure). First, patients are screened for fatigue, and in the second step those who have fatigue undergo primary evaluation to assess for potential precipitating causes. The third step is implementation of pharmacologic and non-pharmacologic interventions aimed at alleviating or mitigating fatigue. The fourth step involves re-evaluating patients at periodic intervals to recognize and manage changes in fatigue levels. A multidisciplinary approach involving nursing, physical therapy, social work, and nutrition is critical in managing fatigue in these patients. Education and counselling of patients and involvement of the family are essential for effective management.

Screening

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to underrecognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue [2]. Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials [27]. A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF [2]. This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors [28]. The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue [29,30]. The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day [31]. The 9-item BFI is often used in clinical trials [29]. It measures the severity of fatigue over the previous 24 hours and has been validated in non-English speaking patients [32].

 

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which measures general, physical, mental, and emotional fatigue domains as well as activity and compares them with those of individuals without cancer [33,34]. The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments [35].

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales [36]. Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic re-evaluation, and moderate and severe fatigue need further evaluation and management [37].

Primary Evaluation

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living [37]. Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse which may cause poor sleep and fatigue.

 

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below.

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels [38]. Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or autoimmune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes [39]. Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond [40]. Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL [41].

Sleep disturbance. Poor sleep is common in fatigued cancer survivors [42]. Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuroendocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue [43]. Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep [44]. Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep [45]. Melatonin agonists are approved for insomnia in the United states, but not in Europe [46].

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men [47].

 

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster [48]. A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating of one of these symptoms without addressing other symptoms is not effective [49]. Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy—such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue [50].

Management

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time [51,52]. When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients [53].

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy [54]. CBT interventions that optimize sleep quality may improve fatigue [55]. More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials (RCTs) showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF [56].

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations [57]. Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship [58]. Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve cardiorespiratory fitness, muscle strength, and body composition [57]. Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended not only for younger patients, but also in the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors [59]. In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone [60]. This effect was also shown in an RCT of 160 patients with stage 0 to III breast cancer undergoing radiation therapy [61]. The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits in the physical fatigue but not the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week [62]. An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes [63]. Patients withcomorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy [37]. Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life [64,65]. We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training [66]. Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life [67].

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors [68]. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit not only physical fatigue, but also cognitive fatigue [69]. DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF [70]. More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months [71]. Additional research is needed in this area.

Acupuncture. An RCT in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue [72]. However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue [73]. Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done, with mixed results, and additional research is needed [74]. Currently, there are not sufficient data to recommend any of these modalities.

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF [75–77], but RCTs have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of non-pharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment [37].

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. RCTs of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF [78]. Likewise, in an analysis of 5 RCTs, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo [79]. However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease [80]. Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically [81]. In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner [82]. However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment [83]. Also, other RCTs in patients undergoing adjuvant chemotherapy for breast cancer [84] and patients receiving radiation therapy for brain tumors [85] failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm [86]. Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation [87]. A placebo effect was also noted in patients with multiple myeloma [88] and patients with primary brain tumors [89]. In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue [90]. In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7) [91]. This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional RCTs are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF [37].

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines [92]. In a RCT evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo [93]. A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo [94]. Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis [37].

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups [95].

Antidepressants have failed to demonstrate benefit in CRF without depression [8]. However, if a patient has both fatigue and depression, antidepressants may help [96]. A selective serotonin receptor inhibitor is recommended as a first-line antidepressant [97]. Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

 

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF [74]. The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF [98].

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo [99]. Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects [100]. Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

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

Re-evaluation

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

Conclusion

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

 

Acknowledgment: Bryan Tutt provided editorial assistance.

Corresponding author: Carmelita P. Escalante, MD, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030, [email protected].

Financial disclosures: None.

From the University of Texas MD Anderson Cancer Center, Houston, TX.

 

Abstract

• Objective: To review the evidence on interventions for managing cancer-related fatigue (CRF) and provide evidence-based guidance on approaches to its management.
• Methods: Nonsystematic review of the literature.
• Results: Several theories have been proposed to explain the biology of CRF, but there is no single clear mechanism that can be targeted for therapy. The approach to patients begins with screening for fatigue and assessing its intensity, followed by a thorough history and examination to determine whether any reversible medical conditions are contributing to fatigue. Management of underlying medical comorbidities may help some patients. For patients whose fatigue persists, pharmacologic and nonpharmacologic treatment options are available. Pharmacologic options include psychostimulants, such as methylphenidate and modafinil, and corticosteroids. Nonpharmacologic approaches include exercise, cognitive behavior therapy, yoga, acupuncture, and tai chi.
• Conclusion: We recommend an individualized approach, often with a combination of the available options. Patients need to be evaluated periodically to assess their fatigue, and since cancer-related fatigue affects survivors, long-term follow-up is needed.

Key words: fatigue; cancer; pro-inflammatory cytokines; nonpharmacologic; psychostimulants.

 

Fatigue is a common distressing effect of cancer [1].It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning [2].” Differences between CRF and fatigue reported by individuals without cancer are that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, ranging between 25% and 99% [2,3]. This variability may be secondary to methods used for screening fatigue and characteristics of the patient groups. In this article, we discuss recognition of CRF and approaches to its management.

Pathophysiology

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of more than 1 mechanism contributing to fatigue in an individual patient.

Central Nervous System Disturbances

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores [4]. Higher levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF [5]. However, there is not enough evidence at this time to support central nervous system disturbance as the main contributing factor to fatigue in cancer patients.

Circadian Rhythm Dysregulation

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways [2]. Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors [6]. These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

Inhibition of Hypothalamic–Pituitary–Adrenal Axis

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis [6]. The inhibition of the HPA axis may occur with higher levels of serotonin as well [7]. The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue [8]. Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue [2].

Skeletal Muscle Effect

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction [9]. ATP infusion improved muscle strength in one trial, but this was not confirmed in another trial [10,11]. Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls [12]. This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles [13,14].

Pro-inflammatory Cytokines

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma [15]. IL-6 was also associated with increased fatigue in breast cancer survivors [16]. Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy [17]. Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients [18,19]. Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients [20]. Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF [21].

Other Hypotheses

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support [22], genetic alterations in immune pathway [23], epigenetic changes [24], accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation [25], elevated vascular endothelial growth factor levels [26], and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction [13] all have been postulated to cause CRF.

Approach to Evaluation and Treatment

The evaluation and treatment of CRF involve 4 steps (Figure). First, patients are screened for fatigue, and in the second step those who have fatigue undergo primary evaluation to assess for potential precipitating causes. The third step is implementation of pharmacologic and non-pharmacologic interventions aimed at alleviating or mitigating fatigue. The fourth step involves re-evaluating patients at periodic intervals to recognize and manage changes in fatigue levels. A multidisciplinary approach involving nursing, physical therapy, social work, and nutrition is critical in managing fatigue in these patients. Education and counselling of patients and involvement of the family are essential for effective management.

Screening

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to underrecognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue [2]. Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials [27]. A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF [2]. This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors [28]. The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue [29,30]. The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day [31]. The 9-item BFI is often used in clinical trials [29]. It measures the severity of fatigue over the previous 24 hours and has been validated in non-English speaking patients [32].

 

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which measures general, physical, mental, and emotional fatigue domains as well as activity and compares them with those of individuals without cancer [33,34]. The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments [35].

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales [36]. Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic re-evaluation, and moderate and severe fatigue need further evaluation and management [37].

Primary Evaluation

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living [37]. Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse which may cause poor sleep and fatigue.

 

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below.

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels [38]. Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or autoimmune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes [39]. Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond [40]. Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL [41].

Sleep disturbance. Poor sleep is common in fatigued cancer survivors [42]. Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuroendocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue [43]. Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep [44]. Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep [45]. Melatonin agonists are approved for insomnia in the United states, but not in Europe [46].

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men [47].

 

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster [48]. A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating of one of these symptoms without addressing other symptoms is not effective [49]. Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy—such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue [50].

Management

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time [51,52]. When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients [53].

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy [54]. CBT interventions that optimize sleep quality may improve fatigue [55]. More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials (RCTs) showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF [56].

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations [57]. Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship [58]. Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve cardiorespiratory fitness, muscle strength, and body composition [57]. Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended not only for younger patients, but also in the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors [59]. In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone [60]. This effect was also shown in an RCT of 160 patients with stage 0 to III breast cancer undergoing radiation therapy [61]. The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits in the physical fatigue but not the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week [62]. An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes [63]. Patients withcomorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy [37]. Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life [64,65]. We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training [66]. Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life [67].

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors [68]. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit not only physical fatigue, but also cognitive fatigue [69]. DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF [70]. More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months [71]. Additional research is needed in this area.

Acupuncture. An RCT in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue [72]. However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue [73]. Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done, with mixed results, and additional research is needed [74]. Currently, there are not sufficient data to recommend any of these modalities.

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF [75–77], but RCTs have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of non-pharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment [37].

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. RCTs of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF [78]. Likewise, in an analysis of 5 RCTs, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo [79]. However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease [80]. Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically [81]. In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner [82]. However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment [83]. Also, other RCTs in patients undergoing adjuvant chemotherapy for breast cancer [84] and patients receiving radiation therapy for brain tumors [85] failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm [86]. Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation [87]. A placebo effect was also noted in patients with multiple myeloma [88] and patients with primary brain tumors [89]. In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue [90]. In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7) [91]. This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional RCTs are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF [37].

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines [92]. In a RCT evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo [93]. A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo [94]. Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis [37].

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups [95].

Antidepressants have failed to demonstrate benefit in CRF without depression [8]. However, if a patient has both fatigue and depression, antidepressants may help [96]. A selective serotonin receptor inhibitor is recommended as a first-line antidepressant [97]. Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

 

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF [74]. The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF [98].

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo [99]. Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects [100]. Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

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

Re-evaluation

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

Conclusion

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

 

Acknowledgment: Bryan Tutt provided editorial assistance.

Corresponding author: Carmelita P. Escalante, MD, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030, [email protected].

Financial disclosures: None.