Cancer-related fatigue: Treatment

INTRODUCTION — Fatigue is a common problem in cancer patients, both among those undergoing active cancer treatment and in cancer survivors who have completed treatment. The most important factors contributing to cancer-related fatigue (CRF) are progressive tumor growth, treatment with cytotoxic chemotherapy, biologic response modifiers, molecularly targeted therapy (particularly the small molecular tyrosine kinase inhibitors and therapeutic monoclonal antibodies targeting the vascular endothelial growth factor [VEGF] and epidermal growth factor receptor [EGFR]) or radiation therapy (RT), anemia, pain, emotional distress, sleep disturbance, and poor nutrition. CRF is particularly prevalent with multimodality or dose-intense treatment protocols, and in patients with metastatic disease. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment".)

CRF profoundly affects quality of life of both patients and their caregivers, including physical, psychosocial, and economic/occupational aspects [1-7]. Fatigue is routinely identified by patients as one of the most distressing symptoms associated with cancer and its treatment, yet historically it has been consistently underreported and overlooked as a potentially remediable cause of treatment-related morbidity [8]. In contemporary oncologic treatment, however, screening for and treatment of CRF has become a major focus of supportive care. Guidelines from expert groups, including the American Society of Clinical Oncology and National Comprehensive Cancer Network, recommend screening for CRF at the initial visit, after completion of primary therapy, as clinically indicated (and at least annually) during the period of cancer survivorship, at the time that advanced disease is diagnosed, and at all chemotherapy visits [9-11]. Patients who have completed primary treatment and are undergoing posttreatment surveillance should continue to be monitored because fatigue may persist beyond the time of active treatment. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Screening' and "Overview of cancer survivorship care for primary care and oncology providers", section on 'Monitoring for late or long-term effects of cancer and its treatment'.)

Here we will review the management of CRF in patients receiving active cancer treatment and in cancer survivors who have completed treatment. The prevalence of fatigue in patients with cancer, screening and assessment for fatigue in this population, and an overview of fatigue in palliative care patients are discussed elsewhere. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment" and "Overview of fatigue in palliative care".)

GENERAL APPROACH — Some basic principles apply to patients with fatigue during active cancer therapy and cancer survivors who have persistent fatigue after the completion of therapy:

●All patients undergoing active cancer treatment, as well as cancer survivors and their caregivers, should be offered specific information about fatigue during and following treatment (eg, information about the difference between normal and cancer-related fatigue [CRF], persistence of fatigue beyond treatment, and causes and contributory factors).

●All patients with malignant disease should be screened for CRF during active cancer treatment, and as clinically indicated (and at least annually) during follow-up survivor care. The benefits of closely following patient-reported symptoms during treatment was shown in the PROTECT randomized trial, in which routine screening for fatigue and other symptoms using weekly electronic symptom monitoring for at least one year during treatment for metastatic cancer and subsequent intervention that is triggered by severe or worsening symptoms substantially improved patient-reported outcomes as compared with usual care [12]. In an analysis of individual symptom trajectories, significant mean differences in favor of the patient reported outcomes group were observed for fatigue at all time points up to 12 months, and at multiple time points for insomnia. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment".)

For patients with new or worsening CRF, further diagnostic evaluation may be warranted for those with moderate to severe fatigue. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Clinical assessment'.)

●Potentially treatable causes of fatigue should be sought for and treated (table 1). These include comorbidities (eg, anemia, electrolyte abnormalities, alcohol/substance abuse, endocrine dysfunction [eg, hypothyroidism, hypogonadism, adrenal insufficiency], cardiac, pulmonary, or renal dysfunction), medications, emotional distress, sleep disturbance, pain, nutritional issues (changes in weight/caloric intake), and deconditioning/loss of muscle mass. The clinical team must decide whether referral to an appropriately trained professional (eg, cardiologist, endocrinologist, mental health professional, internist) is needed [10]. (See 'Control of contributory factors' below.)

●Symptoms that may contribute to fatigue should be managed appropriately (eg, pain, dyspnea, nausea, sleep disturbance, depression, anxiety, and anorexia). (See 'Control of physical symptoms' below and 'Antidepressants' below.)

For patients with cancer-related pain who are receiving opioids, opioid analgesics should be titrated or the schedule/agent modified so as to alleviate pain without causing significant fatigue. If needed, a trial of psychostimulants may help to reverse opioid-related sedation. (See 'Patients receiving opioids' below.)

Pharmacologic and nonpharmacologic interventions for CRF are discussed in the sections below. Specific recommendations for managing CRF in patients receiving active treatment, cancer survivors, and in terminal patients receiving palliative care are summarized below. (See 'Interventions' below.)

Guidelines for screening, assessment, and management of adults with CRF during and after therapy are available from Canada (table 2) [13], the Oncology Nursing Society [14], the National Comprehensive Cancer Network (NCCN), and others.

INTERVENTIONS — Management of CRF involves specific treatment for potentially reversible causes (ie, treating anemia or metabolic or endocrine abnormalities, as well as managing pain, insomnia, depression, or anxiety) and symptomatic measures when no obvious etiology or reversible cause can be identified. Nonspecific symptom-based treatment measures include education, counseling, and pharmacologic (eg, psychostimulants and other wakefulness agents) as well as nonpharmacologic (eg, exercise, yoga, acupuncture) measures.

Control of contributory factors — If any of the factors known to be associated with fatigue is identified (eg, anemia, hypothyroidism, hypogonadism, sleep disorder, opioid-related sedation), these should be addressed as the initial approach to fatigue. Optimizing management of physical symptoms such as pain, nausea, and dyspnea can help to alleviate fatigue. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Main contributory factors'.)

Control of physical symptoms — Physical symptoms such as nausea, dyspnea, and pain may be associated with fatigue, particularly in patients with advanced cancer. Optimizing management of these physical symptoms may significantly alleviate fatigue. The benefits of systematic monitoring and treatment of physical symptoms in fatigued patients was shown in a randomized trial in which 152 fatigued patients (fatigue score ≥4 on a numerical rating scale of 0 to 10) with advanced cancer were randomly assigned to protocolized, patient-tailored treatment or usual care [15]. The intervention group consisted of four meetings over a 10-week period with a nurse specialist who coordinated a complex intervention aimed at identifying and treating symptoms of pain, nausea, vomiting, constipation, lack of appetite, shortness of breath, cough, and dry mouth. There were modest but significant improvements over time in favor of the nurse-led intervention for the primary outcome (general fatigue, as assessed by the Multidimensional Fatigue Inventory [MFI]) as well as for secondary outcomes such as level of reduced activity, symptom burden, interference of fatigue with daily life, anxiety, and intensity of fatigue as measured by the 0 to 10 numerical rating scale.

Anemic patients — Anemia is the most common reversible cause of CRF, particularly among patients receiving chemotherapy. Correction of anemia has been associated with an improvement in health-related quality of life (QOL) and fatigue [16].

Optimal management of symptomatic anemia requires an accurate diagnosis to identify potentially remediable causes (eg, ongoing blood loss, hemolysis, iron, folic acid, or vitamin B12 deficiency). If a potentially treatable cause cannot be identified, treatment options include red blood cell (RBC) transfusion, or for patients with chemotherapy-related myelosuppression, an erythropoiesis-stimulating agent (ESA). (See "Causes of anemia in patients with cancer".)

Transfusions versus ESAs — Hemoglobin (Hb) levels can be raised with either erythropoiesis-stimulating agents (ESAs) or red blood cell (RBC) transfusions. The choice between these approaches must be individualized; the risks and benefits of either approach are outlined in the table (table 3), and discussed in more detail separately. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'ESAs versus transfusion'.)

Various topics related to RBC transfusion, including indications and transfusion thresholds, and complications are discussed in detail in other topics. (See "Indications and hemoglobin thresholds for RBC transfusion in adults" and "Hemolytic transfusion reactions" and "Immunologic transfusion reactions" and "Transfusion-associated circulatory overload (TACO)" and "Transfusion-transmitted bacterial infection" and "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload'.)

Cancer patients who are being considered for treatment with ESAs as an alternative to RBC transfusion should meet all of the following criteria [17] (see "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Minimal requirements'):

●Anemia should be due to chemotherapy treatment for a nonhematologic malignancy.

●Other treatable causes of anemia (eg, blood loss, hemolysis, nutritional deficiency [eg, iron, B12, folate]) should be excluded or treated if present. (See "Diagnostic approach to anemia in adults".)

●An initial hemoglobin level of 10 g/dL or less should be present, although patients with a hemoglobin level between 10 and 11 g/dL who are highly symptomatic can also be considered for ESA therapy on an individual basis.

●Contraindications to use of an ESA include predisposition to thromboembolism (eg, prior history of thromboses, surgery, prolonged periods of immobilization or limited activity, multiple myeloma treated with an immunomodulatory agent plus an anthracycline or high-dose corticosteroid) or uncontrolled hypertension.

However, treatment with RBC transfusions may still be appropriate for patients whose clinical condition indicates the need for immediate correction of the hemoglobin level and for those in whom reducing the frequency of transfusion is not an important consideration. This subject is discussed in detail elsewhere. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Clinical use of ESAs in cancer patients'.)

Sleep disturbance — For patients with insomnia or other sleep disturbance, specific measures to improve sleep hygiene should be suggested (table 4). Stress reduction and especially psychosocial and behavioral interventions, or integrative medicine approaches such as gentle yoga may help. Patients who do not respond to these measures may require short-term use of medications to help them sleep, but we generally discourage use of these agents, especially for long-term use, in patients with CRF. Complementary/integrative approaches are discussed in more detail below. (See 'Mind and body practices' below.)

Nonpharmacologic interventions

Exercise — Unless contraindicated (eg, by the presence of extensive lytic bone metastases, extreme thrombocytopenia, fever or active infection, or safety issues), we suggest an individualized program of moderate aerobic exercise for most patients with CRF, both during active treatment and for those who have completed treatment. We agree with guidelines from the American Society of Clinical Oncology (ASCO) for management of adult cancer survivors with fatigue that recommend 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with an additional two to three strength training (eg, weight-lifting) sessions weekly. (See 'Recommendations of expert groups' below.)

Walking programs are generally safe for most cancer survivors; patients can begin this type of program after consulting with their doctors, without any formal exercise testing (eg, a stress test) [18]. Patients at higher risk of injury (ie, those with neuropathy, cardiomyopathy, or other long-term effects of cancer therapy) should be referred to a physical therapist or exercise specialist. Breast cancer survivors with lymphedema should also consider meeting with an exercise specialist before initiating a program of upper-body strength training exercises [10]. (See "Clinical staging and conservative management of peripheral lymphedema", section on 'Diet and exercise'.)

To avoid fatigue, cancer patients, particularly those undergoing active treatment, are often advised to rest and downregulate their daily activities. However, because inactivity can induce muscular wasting, prolonged rest can lead to further loss of physical strength and endurance [19]. Although many fatigued patients have difficulty believing that exercise will improve their symptoms, physical exercise training programs can increase functional capacity, leading to reduced effort in performing usual activities and a decreased sense of fatigue [19-23].

Research on the effects of exercise on CRF includes studies of patients receiving active treatment and those who have completed treatment. Experimental designs vary, sample sizes often are small, and many series are limited to women with breast cancer or men with prostate cancer [24]. The available data on the benefits of exercise in individuals with colorectal cancer are mixed [25-28].

The type of exercise is also variable, with some studies evaluating walking [3,22,29,30], bicycling [31-33], resistance training [34-37], deep water aquatic exercise [38], or a combined approach [39-42], and still others where the patient was allowed to choose the type of exercise they preferred [20,43]. The recommended exercise programs vary in length from six weeks to six months.

Regardless of these limitations, all trials and meta-analyses have demonstrated significant benefits (less fatigue and emotional distress, decreased sleep disturbance, improved functional capacity, and better QOL) for moderate exercise in patients with cancer:

●A meta-analysis of nine randomized trials of home-based physical activity (ranging in duration from six weeks to six months, with the majority lasting 11 to 12 weeks) to alleviate fatigue in cancer survivors showed a significant effect in favor of the intervention immediately afterward (standardized mean difference [SMD] 0.22, 95% CI 0.06-0.37), and at three months (SMD 0.27, 95% CI 0.04-0.51) and six to nine months later (SMD 0.31, 95% CI 0.08-0.55) [44]. Interventions that included frequent counseling (every one to three weeks) were associated with larger improvements in fatigue than no or less frequent counseling.

●A later systematic review conducted by ASCO [45] noted that meta-analyses in several different types of cancer reported that exercise during cancer treatment led to improvements in cardiorespiratory fitness, strength, fatigue, and other patient reported outcomes [46-53], as well as a moderate reduction in sleep disturbance during cancer treatment [54]. They concluded that oncology providers should recommend aerobic and resistance exercise during active cancer treatment with curative intent to mitigate the side effects of treatment. However, the current evidence does not allow specific recommendations as to the specific duration or intensity of exercise during treatment required to favorably affect outcomes. The frequency of adverse events during exercise appears to be low.

Improved levels of meaningful and effective physical activity may be facilitated by the use of printed materials, supervised exercise programs, a step pedometer, or a combination of these approaches, rather than a simple recommendation to perform increased activity [55,56]. Specific exercise programs should be preceded by a careful evaluation of comorbidities and exercise contraindications (such as extensive lytic bone metastases, extreme thrombocytopenia). The prescribed exercise program should be individualized and take into consideration the patient's age, sex, type of cancer and treatment, and the patient's physical fitness level. The initial intensity and duration of exercise should be low and slowly increased, as the patient's medical condition allows. Pool activities are an especially good form of physiotherapy.

However, neutropenic patients must avoid environments where the risk of exposure to infectious agents is high (eg, public swimming pools).

Barriers to exercise include physical and disease-related limitations, lack of time/interest/motivation/facilities, and lack of encouragement from family and friends [10]. Younger patients with limited or cured disease may be more motivated to engage in exercise programs than older patients or those with advanced disease or restrictive comorbidities.

Pre-exercise cardiovascular testing — Cancer patients are often older, and they may either have overt cardiovascular disease or be at risk for developing cardiovascular disease. Furthermore, direct and indirect effects of anticancer treatment may compound other risks. As a result of these issues, cancer patients may be at heightened risk for a cardiovascular event. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies" and "Cardiotoxicity of trastuzumab and other HER2-targeted agents" and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines".)

Pre-exercise clearance is not required for the majority of cancer patients who are planning to initiate an exercise program, screening should be considered for high-risk populations, including those with diabetes and multiple risk factors for coronary heart disease, including prior mediastinal irradiation or anthracycline use. (See "Screening for coronary heart disease", section on 'Recommendations from major societies'.).

Recommendations of expert groups — Guidelines from ASCO for management of adult cancer survivors with fatigue, recommend 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with an additional two to three strength training (eg, weight lifting) sessions weekly [10]. A later guideline also recommends exercise in patients undergoing active anticancer treatment [45]. Likewise, guidelines from the European Society of Medical Oncology (ESMO) also recommend physical exercise of moderate intensity and aerobic and functional resistance exercises for non-cachectic patients with cancer [57].

Mind and body practices — For most patients with CRF both during active treatment and after treatment is completed, we suggest some form of cognitive-behavioral intervention. Patients undergoing active anticancer treatment should be offered advice on general strategies that can help to manage fatigue and guidance on self-monitoring of fatigue levels. Specific suggestions to conserve energy during activities of daily living are outlined in the tables (table 5 and table 6). For patients undergoing active anticancer treatment and for survivors, cognitive behavioral therapy and mind-body practices such as yoga, acupuncture, Tai chi, or mindfulness-based approaches may also be of benefit, if patients are interested in these approaches, and practitioners are available.

These recommendations are consistent with guidelines for treatment of CRF from ESMO [57] and ASCO guidelines on management of fatigue in cancer survivors [10].

Mind and body practices (MBPs) refer to a group of complementary/integrative therapies that share a common perspective: emphasizing the potential value of training the "mind" (by shifting cognitions and/or creating a desirable emotional state) in a way that favorably influences bodily functions. Many of these treatments require a competent and specifically trained health professional. An overview of these approaches, which includes information on training, credentialing, and licensure is provided separately. (See "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm".)

Cognitive-behavioral interventions

Active cancer treatment — Multiple small randomized trials and a meta-analysis of 77 trials indicate that a variety of nonpharmacologic psychosocial and behavioral interventions are effective for improving CRF in patients receiving active cancer treatment [58-66], and its benefits have been shown to persist for at least two years after intervention [67]. However, not all data have been consistent. A meta-analysis of 12 randomized clinical trials (Cochrane review) enrolling patients undergoing cancer treatment with palliative intent for incurable cancer suggested no benefit from nonpharmacologic strategies [68]. Variations in methodologies of included studies, as well as patients enrolled, may account for differences in results of this meta-analysis and previous studies. For example, the Cochrane meta-analysis included only patients receiving treatment for incurable cancer. It is conceivable that such patients would not benefit from these interventions, whereas patients being treated with curative intent and long-term survivors may be more likely to derive some benefit.

Furthermore, whether all patients require formal psychosocial and behavioral intervention by a psychologist or psychiatrist in order to benefit from psychosocial interventions is unclear, and to the extent that fatigue has a physiologic basis, cognitive-behavioral interventions may not be effective in all patients. In a randomized study that included 115 patients receiving radiation therapy (RT) for advanced cancer, a structured multidisciplinary program that included cognitive, emotional, physical, social, and spiritual interventions did not prevent the development of fatigue [69], even though it was associated with an improvement in QOL [70].

Cancer survivors — Randomized trials, systematic reviews, and meta-analyses demonstrate that cognitive/behavioral interventions can also reduce fatigue in posttreatment survivors [67,71-74], and the benefits seem to be maintained with long-term follow-up [67].

Type of intervention — An example of a simple program of cognitive-behavioral intervention with specific adaptive strategies for management of symptoms such as fatigue is available (table 7) [75]. Patients should prioritize and pace activities in an attempt to conserve energy and delegate tasks to others, if feasible [76]. Nonessential activities should be postponed if moderate or severe fatigue is present. Daily self-monitoring in a treatment log or diary may help to identify peak energy periods and the effectiveness of specific interventions. Participation and incorporating family members in activities that are specifically designed to distract from the sense of fatigue (eg, card-playing, visiting) may be useful [77-79].

Structured support groups are helpful for some patients [80-83], although others may benefit from individual counseling for stress management, depression, and anxiety [61,84-86]; stress management/relaxation training [87-90]; or comprehensive programs that enhance coping skills through formal psychosocial and behavioral interventions [65,75,91-93].

The benefits of a combined approach to psychosocial and behavioral interventions were studied in a trial in which 273 survivors with moderate to severe CRF (≥4 on item 3 of the Brief Fatigue Inventory [BFI] (table 8)) who had completed primary cancer treatment within the past 24 months were randomly assigned to a 12-week individually tailored CRF program versus routine care [94]. The intervention, which was based upon NCCN guidelines for management of CRF, consisted of internet-based educational information covering six strategic areas of energy conservation, physical activity, nutrition, sleep hygiene, pain control, and distress management, as well as a general introduction to CRF that allowed individual patients to evaluate their CRF status. Patients were assessed at baseline and at 12 weeks with the BFI (table 8) and Fatigue Severity Scale (FSS; ranked on a seven-point scale) for the primary outcome, and the Hospital Anxiety and Depression Scale (HADS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) for secondary outcomes.

Patients who received the cognitive behavioral intervention had a significantly greater decrease in BFI global score (-0.66, 95% CI -1.04 to -0.27) and FSS total score (-0.49, 95% CI -0.78 to -0.21) from baseline, although the clinical meaningfulness of these small differences is unclear. The intervention group also experienced a significantly greater decrease in HADS score and significantly greater increase in global QOL, but the differences were also small and of unclear clinical meaningfulness.

Further study of educational interventions in a variety of cancer patients (those under current treatment with differing interventions, those without evidence of malignancy and on no treatment, etc) and in different geographical and cultural environments is necessary to determine the impact of any educational intervention on CRF in these different settings.

Although a variety of cognitive-behavioral and psychosocial interventions can be beneficial, discovering which patients benefit from what type of psychosocial intervention is an unresolved issue [95]. There are no randomized trials comparing different approaches, and as noted above, it is not clear that all patients require referral to a psychologist for formal psychosocial and behavioral intervention. The challenge to the practitioner is to match the characteristics of individual patients with the most helpful and cost-effective interventions. If possible, patients should be referred to psychosocial service providers specializing in cancer and trained to deliver empirically-based interventions [10].

Meditation and mindfulness-based approaches — For cancer survivors with persistent fatigue, we suggest mindfulness-based approaches such as mindfulness-based stress reduction (MBSR).

The term "meditation" is an umbrella term that covers a large number of traditions and practices with specific evidence on their effectiveness for improved symptom management and ability to improve the stress response. They all require an active participant in the meditation; specific training in the ability to "let go" of thoughts, feeling sensations, external distractions; and consistent daily or regular practice. Some examples include mindfulness meditation, transcendental meditation, and Zen meditation. MBSR is a well-defined and systematic patient-centered educational approach which uses relatively intensive training in mindfulness meditation as the core of a program to teach people how to take better care of themselves and live healthier and more adaptive lives. (See "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm", section on 'Meditation and mindfulness-based stress reduction'.)

There is evidence from multiple randomized trials (most of which enrolled fewer than 100 patients) that mindfulness-based approaches such as MBSR may relieve fatigue in cancer survivors [72,96-99]. In the largest trial, 229 women with early-stage breast cancer after surgery, chemotherapy, and radiotherapy were randomly assigned to an eight-week program of mindfulness-based stress reduction or usual care [97]. The intervention group had significant improvements at weeks 8 and 12 in the primary outcome scores on the Profile of Mood States (POMS) scale, which included fatigue.

Benefit for improving CRF is further supported by at least one meta-analysis, although a second analysis reports mixed benefits for improving sleep quality [100,101].

Yoga — Yoga is a collection of mind-body practice with origins in ancient South Asian philosophy and practice. It includes physical postures ("asanas"), breathing and relaxation techniques, as well as diet and meditation. (See "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm", section on 'Yoga'.)

There is some evidence from randomized trials and a meta-analysis that mind-body practices such as yoga may improve sleep quality and fatigue; most of the data (six of the nine randomized trials [102-112]) have enrolled cancer survivors with posttreatment fatigue, the majority with breast cancer:

●In the largest trial, 410 patients with breast cancer who reported moderate or severe sleep disruption within 2 to 24 months after completing treatment were randomly assigned to standard care monitoring with or without yoga [103]. The yoga intervention consisted of breathing exercises, 18 gentle Hatha and restorative yoga postures, and meditation, performed twice weekly. After four weeks, yoga participants demonstrated greater improvements compared with baseline in global sleep quality, the primary endpoint. In addition, the yoga group demonstrated a greater reduction in daytime dysfunction, fatigue, and a reduced use of sleep medications (in contrast to the control group, in which use of sleep aids increased) at postintervention compared with standard care participants. In a later analysis, the positive impact of the yoga intervention on CRF was mediated, in part, by the beneficial impacts on overall sleep quality [113].

●A meta-analysis of yoga for CRF in patients with breast cancer included 17 trials (2183 patients) [114]. The intervention consisted of a variety of yoga practices, and the supervised classes ranged from 40 to 90 minutes, and took place one to five times weekly for 4 to 24 weeks. The overall risk of bias for the included studies was moderate. For all 17 studies, there was a small but significant effect size for benefit of yoga on change in fatigue scores from baseline (SMD -0.31, 95% CI -0.52 to -0.10). When analyzed according to treatment status, yoga had a large effect in the four studies with only posttreatment patients (SMD -0.80, 95% CI -1.52 to -0.09). By contrast, the effect size was small in the 13 studies of patients undergoing anticancer treatment (SMD -0.25, 95% CI -0.47 to -0.03). The wide confidence intervals imply imprecision in the point estimates.

Acupuncture — Acupuncture appears to be helpful for CRF in cancer survivors; the data are less robust in those with CRF during active cancer therapy. However, given the overall safety of this approach, and the likelihood that benefits outweigh risks, interested patients may be offered a trial of acupuncture if symptoms of moderate to severe fatigue persist despite other forms of therapy, and experienced practitioners are available.

Benefit from acupuncture has been suggested in several (but not all [115]) randomized trials, mostly with fewer than 100 patients enrolled; some trials were conducted in cancer survivors and some in patients receiving active treatment [116-124]:

●In the largest of these trials, 302 patients with nonmetastatic breast cancer who had completed chemotherapy between one month and five years previously, and who were experiencing at least moderate fatigue (score ≥5 on a scale of 0 to 10) were randomly assigned to usual care with and without acupuncture [118]. The usual care group received a booklet with information about fatigue and its management, while the acupuncture group received both the booklet and a once weekly treatment by an acupuncturist (needling three pairs of acupoints) for six weeks. The primary outcome was general fatigue at six weeks, as measured by the MFI. Acupuncture was of significant benefit, with an estimated difference in the week 6 general fatigue score (acupuncture minus control) of -3.11 (95% CI -3.97 to -2.25), given equal baseline scores. Acupuncture also significantly improved other fatigue aspects as measured by the MFI, including physical and mental fatigue, anxiety and depression, and QOL.

A major problem with interpreting these results is the lack of a sham acupuncture control group; at least in the setting of noncancer disease such as chronic pain, both acupuncture and sham acupuncture have been shown to have much greater efficacy than no treatment, suggesting a strong placebo effect [125].

Benefit from acupuncture could not be confirmed in a preliminary report of a randomized trial comparing acupuncture versus sham acupuncture in 97 patients with chronic chemotherapy-related fatigue [115]. In both groups, scores on the BFI (table 8) fell by about one point, and there was no significant difference between groups. The study interpretation was limited by a high number of patients who were lost to follow-up.

●This issue was addressed in a meta-analysis of 10 randomized trials of acupuncture for CRF (1327 patients), in which acupuncture (variably administered for 20 to 30 min/session from one to three times weekly over a period of 2 to 10 weeks) was compared with sham acupuncture (five trials), typical care (eight trials), or American ginseng (one trial) [126]. Acupuncture had a marked effect on CRF, both in cancer survivors (four trials, SMD in BFI scores from baseline to posttreatment -1.38, 95% CI -1.80 to -0.71) and those undergoing active treatment (six trials, SMD -1.16, 95% CI -1.91 to -0.42). Acupuncture successfully mitigated CRF as compared with sham acupuncture, but the effect size was smaller (SMD -0.83, 95% CI -1.27 to -0.39) than when acupuncture was compared with usual care (SMD -1.74, 95% CI -2.74 to -0.74). Seven RCTs reported the occurrence of adverse events, but only one study reported five adverse events (spot bleeding, bruising, discomfort or nausea), none of which were classified as serious [117].

Hypnosis — The role of hypnosis for patients with CRF is unclear, and additional research is needed.

Hypnosis/hypnotherapy can be defined as an induced state of attentive, focused concentration with suspension of some peripheral awareness; it can be facilitated by a specially trained therapist or practiced on one's own self (self‐hypnosis). (See "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm", section on 'Hypnotherapy'.)

Several small trials of hypnosis as a component of treatment for CRF, as well as a systematic review of hypnosis in breast cancer care, suggest potential benefit for this approach, at least for patients with breast cancer [65,127-131], although the data are sparse and three of the trials combined hypnotherapy with psychosocial and behavioral interventions [65,127,131]. A systematic review of hypnosis in breast cancer care, which included the three trials of hypnotherapy plus psychosocial and behavioral interventions, all of which were conducted in women with breast cancer receiving radiotherapy, concluded that while the intervention improved distress and fatigue more research was needed to assess the benefits of hypnosis.

Tai chi/qigong — Tai chi is a subset of qigong, which is a form of ancient and traditional Chinese medicine that integrates movement (physical postures), meditation (focused attention), and controlled breathing. (See "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm", section on 'Tai chi/qigong'.)

Several randomized trials and two meta-analyses suggest potential benefit for Tai chi/qigong in patients with CRF and/or sleep disturbance [132-138]. The larger meta-analysis included 22 studies, including 15 randomized trials (1283 participants) evaluating the benefits of Tai chi/qigong for fatigue, sleep difficulty, depression, pain, and QOL in patients with breast (seven trials), prostate (two trials), or lung cancer (one trial), lymphoma (one trial) or a mix of different cancer types (four trials) [132].The duration of the intervention varied from 3 to 12 weeks. Methodologic bias was described as low in 12 of the randomized trials and high in 3. The following results were noted:

●CRF was assessed in 10 randomized trials; the pooled overall effect size suggested a significant improvement with a medium effect size (effect size [ES] -0.53, 95% CI -0.97 to -0.28, p <0.001).

●Cancer-related sleep difficulty was assessed in six randomized trials; the pooled analysis suggested a significant small to medium ES (ES -0.49, 95% CI -0.89 to -0.09, p = 0.018).

●QOL was assessed in 12 randomized trials; data from 11 were pooled for analysis. The overall ES favored the intervention with a small ES (ES 0.33, 95% CI 0.10-0.56, p = 0.004).

Data are also available from another trial of 90 breast cancer survivors that postdated the meta-analysis; overall, Tai chi was found to be noninferior to psychosocial and behavioral interventions for insomnia [137].

Other — Biofield therapies (touch therapy, reiki), and other mind-body practices (eg, massage therapy, music therapy, relaxation) may offer some benefit [139-143]; however, additional research, especially in the posttreatment population, is needed before any of these complementary therapies can be routinely recommended [10]. (See "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm", section on 'Reiki' and "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm", section on 'Relaxation therapy and stress management' and "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm", section on 'Music therapy'.)

Clinical practice guidelines — A year 2017 clinical practice guideline on the use of integrative therapies in patients during and after breast cancer treatment from the Society for Integrative Oncology (SIO) rated the strength of available evidence for each integrative modality based upon a modified version of the recommendations of the US Preventive Services Task Force [144]. They emphasized the lack of A- or B-graded (ie, high-quality) integrative therapies for cancer- and cancer treatment-associated fatigue. Hypnosis for improving fatigue during treatment, and acupuncture and yoga for improving posttreatment fatigue all received a "C" grade (weak evidence of benefit) due primarily to a lack of multiple large trials. The authors concluded that these modalities could be offered or recommended to selected patients based on the understanding that they may bring a small benefit, and that in most cases, the benefits outweighed the risks. There was insufficient evidence on the benefit of other mind-body interventions, including MBSR, to form a clinical recommendation.

These guidelines were subsequently endorsed by ASCO in 2018 [145].

Pharmacologic management — Double-blinded trials are essential to prove benefit from any type of pharmacologic intervention in view of the subjective nature of fatigue and the demonstrated therapeutic effect from placebo in at least two double-blind trials [146,147]. Almost all of the randomized trials addressing pharmacologic management of CRF have been conducted in patients receiving active cancer treatment.

Psychostimulants and other wakefulness agents — For patients with severe fatigue (BFI, question #3 >7) during cancer therapy in whom nonpharmacologic methods are not helpful, and anemia and other medical conditions and symptoms causing fatigue are controlled, we suggest a therapeutic trial of a psychostimulant or other wakefulness agent (methylphenidate, dexmethylphenidate, or modafinil), although the studies supporting efficacy have reached variable conclusions. Another group of patients that may benefit from the use of psychostimulants are those with opioid-related sedation. Benefit is less certain in patients with mild-to-moderate fatigue during treatment and in those who have completed cancer treatment and have persistent fatigue, but a therapeutic trial is also reasonable if no potentially reversible contributory factors are identified and nonpharmacologic methods are not helpful. (See 'Nonpharmacologic interventions' above.)

These recommendations are consistent with those of ASCO [10] and ESMO, although guidelines from ESMO suggest not using modafinil for treatment of CRF given the mixed results of clinical trials [57].

Starting doses of modafinil are usually 100 to 200 mg in the morning and again at noon. The maximum daily dose is 400 mg. For methylphenidate, we suggest starting with 5 mg in the morning and 5 mg at noon, titrating as necessary; the maximal dose with the potential for benefit in CRF is 40 mg daily.

A benefit for psychostimulants in patients with CRF was suggested in a year 2010 Cochrane review [148] of five trials, in which four used methylphenidate and one used dextroamphetamine [146,149-152]. There was a small but statistically significant improvement in fatigue score relative to placebo (standardized mean difference [SMD] in fatigue score -0.28, 95% CI -0.48 to -0.09). However, the results of these and other trials published since the meta-analysis have been mixed, with most failing to demonstrate a statistically significant benefit over placebo.

Methylphenidate and dexmethylphenidate — Methylphenidate is a central nervous system stimulant that is structurally related to amphetamines, with a short half-life and a rapid onset of action. Both the pharmacologic properties and clinical efficacy as a central nervous system stimulant reside in the d-isomer, which is available clinically as a distinct drug (dexmethylphenidate, Focalin) and effective at approximately one-half the dose of methylphenidate.

Of at least eight published randomized controlled trials [146,149,151-156], only two [149,155] have concluded that methylphenidate has a significantly better impact than placebo on CRF. The following represents the range of findings:

●In an early trial, 112 patients with a fatigue score of at least 4 on a scale of 0 to 10 were randomly assigned to 5 mg of methylphenidate or placebo, with patients able to repeat dosing as needed every two hours to a maximum of four tablets per day [146]. Patient-reported fatigue intensity improved over baseline by day 8 in both the methylphenidate- and placebo-treated patients. Thereafter, patients were given the option of receiving open-label methylphenidate. In the open-label phase, the lower fatigue intensity was maintained through day 36.

Within the constraints of a very early endpoint, this study could not identify clinical benefits that were attributable to treatment with methylphenidate and suggested that the observed benefits might be in part because of daily contact with the study nurse as well as a possible placebo effect. This is consistent with observations from other randomized trials that patients with CRF can benefit from active psychosocial intervention. (See 'Cognitive-behavioral interventions' above.)

●A lack of benefit for methylphenidate (and from a nursing telephone intervention) was also shown in a later randomized phase II trial involving 142 patients with advanced cancer and a fatigue score of at least 4 on a scale of 0 to 10 [154]. Patients were randomly assigned to one of four groups: methylphenidate (5 mg orally every two hours up to 20 mg daily up to 14 days) plus a nursing telephone intervention (four to six phone calls by a nurse trained in palliative care over a 14-day period focusing on symptom assessment, medication review, psychosocial support, and education), placebo plus the intervention, methylphenidate with a control telephone intervention (nontherapeutic calls conducted by a nonprofessional providing neither support nor education), or placebo plus a control telephone intervention. At the end of 14 days, median scores on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale improved from baseline in all groups, and there were no significant differences among the groups, leading the authors to conclude that methylphenidate and nursing telephone intervention, either alone or combined, were not superior to placebo in improving CRF. Several cancer-related symptoms were significantly improved in the nursing telephone intervention group compared with those receiving the control telephone intervention (including fatigue, nausea, depression, anxiety, drowsiness, appetite, and feeling of well-being).

●On the other hand, benefit for dexmethylphenidate was suggested in a randomized phase II trial in which 152 patients who received ≥4 cycles of chemotherapy and had persistent fatigue and cognitive impairment at least two months after treatment were randomly assigned to dexmethylphenidate (5 mg twice daily or as needed up to 20 mg daily) or placebo [149]. After eight weeks, the use of dexmethylphenidate was associated with a significant improvement in fatigue but not cognitive function.

●Benefit for methylphenidate was also suggested in a very small trial of 30 hospice patients (one each with chronic obstructive pulmonary disease and cirrhosis, the rest cancer) who had fatigue scores of at least 4 on a scale of 0 to 10, and who were assigned to methylphenidate (initial dose 5 mg at 8 AM and 1 PM and titrated every three days according to response and adverse effects) or placebo [155]. Patients taking methylphenidate were found to have significantly lower fatigue scores at day 14 compared with baseline, while there was no improvement in those assigned to placebo.

Some of this discrepancy in outcomes could be related to dose. The single positive dexmethylphenidate study used a high mean daily dose (27.7 mg) of dexmethylphenidate (which is about twice as active, mg for mg, as methylphenidate) [149], while the second positive study titrated the dose of methylphenidate over the course of two weeks with a mean effective dose of 10 mg on day 3 and 20 mg on day 14 [155]. One negative study used a relatively small dose of methylphenidate (average daily consumption 6.4 mg per day) [154]. However, another trial, delivering 27 mg per day of dexmethylphenidate, failed to show any benefit for treatment over placebo [153].

Another potential explanation for these discrepant results is the heterogeneity inherent in the populations studied in these trials. Subset analysis of at least one trial concluded that there might be benefit for methylphenidate in patients presenting with more severe fatigue or more advanced disease [153]. Similar findings have been reported with modafinil. (See 'Modafinil' below.)

Finally, benefit from drugs such as these may depend on the underlying mechanism by which CRF has been generated [157]. A greater understanding of the pathophysiology of CRF may lead to the identification of subtypes that are more responsive to specific treatments. As an example, patients with opioid-related fatigue may benefit from methylphenidate [158]. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Psychostimulants'.)

Dextroamphetamine — Benefit could not be shown for dexamphetamine (10 mg twice daily) in the only placebo-controlled trial involving 50 fatigued patients with advanced cancer who were receiving palliative care [150]. However, the short duration of treatment (eight days), poor performance status of the group as a whole (the majority were Eastern Cooperative Oncology Group [ECOG] performance status 3 (table 9)), and the wide array of other neurologically active medications being administered could all have contributed to the negative result.

Modafinil — Modafinil, a nonamphetamine "wake-promoting agent," is used for the treatment of narcolepsy. Limited experience in cancer patients suggests that modafinil is well tolerated, but the data on efficacy for CRF from randomized trials are mixed [159-162]:

●In a randomized trial, 867 patients reporting any level of fatigue during chemotherapy (a value of >1 on a BFI scale 0 to 10, item 3 (table 8)) were randomly assigned to modafinil (200 mg daily) or placebo [161]. In an analysis of 631 patients with evaluable data, modafinil significantly reduced fatigue only for the subgroup of patients with high baseline fatigue (BFI item 3 score ≥7 (table 8)), while there were no significant differences in patients with mild to moderate fatigue at baseline. Modafinil did not improve depression, reinforcing the view that depression and CRF are not linked.

●Benefit in patients with severe fatigue could not be confirmed in a later trial in which 208 adults with locally advanced or metastatic lung cancer and severe fatigue (score ≥5 out of 10) were randomly assigned to modafinil or a matched placebo (100 mg daily for 14 days, then 200 mg daily for 14 days) [162]. In an intention-to-treat analysis of the 160 patients who completed questionnaires at both baseline and day 28, both modafinil and placebo led to a clinically significant five-point improvement in the FACIT-F subscale, and there was no difference between the two groups.

●The benefits of modafinil were not addressed in the above-mentioned meta-analysis [148]. (See 'Psychostimulants and other wakefulness agents' above.)

Testosterone for hypogonadal men — We suggest a therapeutic trial of testosterone supplementation in men with fatigue who are found to have hypogonadism.

Hypogonadism affects two-thirds of men with advanced cancer. Previous studies have shown that low testosterone levels in men with cancer are associated with fatigue, anorexia, depression, insomnia, and diminished physical function [163,164]. (See "Clinical features and diagnosis of male hypogonadism" and "Causes of secondary hypogonadism in males".)

Testosterone replacement improves QOL and diminishes fatigue in patients with noncancer conditions. (See "Testosterone treatment of male hypogonadism", section on 'Clinical benefits of testosterone therapy in hypogonadal men'.)

The benefit of testosterone replacement for treatment of fatigue in hypogonadal men with advanced cancer has been addressed in the following studies:

●In a small double-blind placebo-controlled trial in which 16 patients treated with placebo and 13 patients treated with testosterone (weight-based intramuscular testosterone administered every 14 days to achieve a bioavailable testosterone level 70 to 270 ng/dL) were evaluable for the primary outcome at day 29 [165]. No statistically significant difference was found for FACIT-F total scores between arms, but sexual desire inventory scores and performance status were better with supplementation. In addition, fatigue subscale scores were significantly better in the testosterone group by day 72.

●Benefit was also shown in a randomized phase II study comparing testosterone versus no testosterone in 60 men with advanced renal cell cancer receiving targeted therapy with sunitinib or pazopanib who had low total testosterone levels (<12.1 nmol/L) and no evidence of hypothyroidism [166]. Fatigue scores dropped from a mean of 37 to 20.3 from baseline to day 28 in the supplemented group, whereas they increased from 35.3 to 42.5 in the control group. The difference in fatigue score at day 28 between groups was statistically significant (22.5 points, 95% CI 18.4-22.6), and improvements in quality of life were also observed.

Patients receiving opioids — For patients with fatigue and cancer-related pain who are receiving opioids, opioid analgesics should be titrated or the schedule/agent modified so as to alleviate pain without significantly altering mentation. If needed, a trial of psychostimulants may help to reverse opioid-related sedation. (See 'Control of contributory factors' above and "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Somnolence and mental clouding'.)

Antidepressants — We suggest a therapeutic trial of an antidepressant in patients with fatigue accompanied by depression. (See "Management of psychiatric disorders in patients with cancer", section on 'Pharmacotherapy'.)

At least three placebo-controlled, randomized trials (and a Cochrane review [148]) in patients undergoing cancer treatment have failed to demonstrate any improvement in fatigue in patients randomly assigned to receive an antidepressant (paroxetine, sertraline) [167-169].

However, antidepressants may be helpful when a patient has both fatigue and depression [169]. For patients who also have insomnia, nortriptyline or amitriptyline are good choices. Case reports suggest efficacy for bupropion in patients with chronic fatigue syndrome, also known as myalgic encephalomyelitis/chronic fatigue syndrome, but no data are available in patients with CRF.

Glucocorticoids — For patients who are in the terminal phase of their illness who have a high symptom burden that includes fatigue, we suggest a trial of glucocorticoid therapy.

Glucocorticoids such as dexamethasone may be beneficial for patients with CRF [170,171], but data are limited. In a meta-analysis including three randomized controlled trials in 165 patients with advanced cancer and fatigue, the small improvement in fatigue observed with dexamethasone versus placebo after one week did not reach statistical significance; one trial showed that both modafinil and dexamethasone improved fatigue after two weeks relative to baseline, but there were no differences compared with each other [172]. (See 'Modafinil' above.)

As an example of one of the trials included in the meta-analysis, 84 patients with advanced cancer and three or more symptoms related to CRF (fatigue, pain, nausea, loss of appetite, depression, anxiety, or sleep disturbance) of severity ≥4 of 10 on the Edmonton Symptom Assessment Scale (table 10) were randomly assigned to dexamethasone (4 mg orally twice daily) or placebo [171]. At the end of 14 days, dexamethasone was associated with a significantly better mean improvement of FACIT-F fatigue subscale scores compared with placebo at both day 8 and day 15, and a significantly better mean improvement in FACIT-F total QOL scores at day 15. Within the short time frame of this study, there were no significant differences in the frequency or severity of adverse effects seen with dexamethasone as compared with placebo.

In a separate, prospective, observational study of 179 patients with metastatic or locally advanced cancer, independent factors predicting improvement in CRF with steroids were higher levels of fatigue (greater than 5 on a 0 to 10 scale), better overall general condition (Palliative Performance Scale score greater than 40), absence of drowsiness, and lack of either ascites or pleural effusion [173].

However, glucocorticoid side effects limit their long-term use. As such, steroids may be most helpful for patients with CRF who are in the terminal phase of advanced cancer. Dose management is important, as this class of drugs may induce insomnia and/or behavioral changes. These subjects are discussed in more detail separately. (See "Overview of fatigue in palliative care", section on 'Glucocorticoids' and "Major adverse effects of systemic glucocorticoids".)

Complementary/integrative approaches

Ginseng and guarana

●Ginseng – For patients who have moderate-to-severe fatigue who are undergoing active anticancer therapy, a therapeutic trial of American or Korean red ginseng is reasonable, as long as the patient is not receiving drugs that may interact unfavorably with ginseng, such as anticoagulants.

A benefit for American ginseng was initially suggested in a pilot study conducted by the North Central Cancer Treatment Group (NCCTG) [174]. A subsequent double-blind trial randomly assigned 364 patients with cancer undergoing or having completed curative-intent therapy and who had a fatigue score of 4 or more (on a scale of 0 to 10) for at least one month to placebo or ginseng (2000 mg daily of a pure ground product) [175]. Patients assigned to ginseng had significantly better scores on the general subscale of the Multidimensional Fatigue Symptom Inventory short-form (MFSI-SF) at eight weeks (change score from baseline 20 versus 10.3 in the placebo group, p = 0.003); the difference was not significant at four weeks (change score from baseline 14.4 versus 8.2). Use of ginseng was also associated with significant improvements in the physical subscale and the total score of the MFSI-SF at eight (but not four) weeks, and in the fatigue inertia subscale of the POMS, but not the vigor activity subscale. Greater benefit was reported in patients receiving active cancer treatment as compared with those who had completed treatment. There were no discernible toxicities associated with treatment.

Benefit for Korean red ginseng (KRG, a processed product of Asian ginseng [panax ginseng]) was also shown in a double-blind trial in which 438 patients receiving oxaliplatin-containing chemotherapy for colorectal cancer either in the adjuvant or metastatic disease setting were randomly assigned to KRG (1000 mg orally twice daily) or an identical appearing placebo for 16 consecutive weeks concurrent with chemotherapy [176]. The primary endpoint was the mean change in the area under the curve (AUC) of the Brief Fatigue Inventory (BFI) from baseline over 16 weeks, with higher AUC levels indicative of a greater improvement in fatigue. At 16 weeks, KRG improved CRF compared with placebo, but the differences were significant only in "mood" and "walking ability." The KRG group had less deterioration in the FACIT-Fatigue Total score and a reduction in the perceived stress scale from baseline to week 16, but the differences were not significant. Neutropenia was more frequent with KRG (19 versus 10 percent), but the incidence of all adverse events was similar. The only potential side effect attributed to KRG was hypertensive crisis (defined as grade 3 hypertension (table 11)), which developed in three patients receiving KRG compared with only one in the placebo group.

One concern about recommending widespread use of ginseng as a treatment for CRF is the potential for drug interactions (especially with warfarin, monoamine oxidase inhibitors, calcium channel blockers, cholesterol-lowering agents, antiplatelet agents, thrombolytic agents, diuretics, hormonal agents, and some chemotherapy drugs) [177,178]. In vitro studies suggest that ginseng inhibits CYP3A4, and clinical studies suggest a potentially relevant interaction between ginseng and some antineoplastic agents that inhibit CYP3A4, such as imatinib [179], but not other CYP3A4 inducers such as irinotecan and docetaxel [180,181].

An overview of herbal medicines and potential interactions of herbal medicines with chemotherapy agents is available elsewhere in UpToDate. (See "Overview of herbal medicine and dietary supplements" and "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm".)

In addition, patient-oriented information about American and Asian ginseng is available through MedlinePlus National Library of Medicine (NLM). More comprehensive clinician-oriented information on specific interactions of ginseng with other medications is available using the drug interactions program included with UpToDate. This program can be accessed from the UpToDate online search page or through the individual drug information topics in the section on Drug interactions.

●Guarana – For most patients with CRF, we suggest not pursuing treatment with guarana.

Guarana is a stimulant derived from an extract of seeds from a plant in the Amazon (Paullinia cupana). In an early small double-blind, placebo-controlled crossover study of 75 breast cancer patients receiving chemotherapy, oral guarana at a dose of 100 mg daily significantly improved fatigue scores at the end of 21 days of treatment [182]. On the other hand, a second small trial failed to confirm benefit in patients with postradiotherapy fatigue [183].

Benefit for guarana for treatment of CRF could also not be shown in a systematic review and meta-analysis of seven placebo-controlled trials of guarana that addressed the impact on fatigue in cancer patients (including the double-blind trial reported above); all studies had been conducted in Brazil [184]. The quantity of guarana extract varied between 15 and 100 mg daily, and intervention periods varied between 21 and 90 days. In the meta-analysis, which was restricted to three randomized trials conducted in women with breast cancer, guarana did not reduce CRF compared with placebo (mean difference in brief fatigue inventory -0.2, 95% CI -1.54 to +1.50); however, the quality of the evidence was very low. The most common adverse effects of treatment were tachycardia, insomnia, nausea, and anxiety, in both groups.

Additional high-quality studies are needed to address the benefits of guarana for chronic CRF in breast cancer and in other types of cancer, and to evaluate long-term side effects and drug-drug interactions.

Vitamins — The evidence to date suggests that multivitamin supplementation is ineffective at reducing CRF [139,185]. However, the available trials vary greatly in quality; most are methodologically weak and at high risk of bias. Consequently, the evidence is inconclusive.

Clinical practice guidelines — Our recommendations for use of ginseng and guarana in patients with CRF are consistent with the year 2017 clinical practice guideline on the use of integrative therapies in patients during and after breast cancer treatment from the SIO [144], which was subsequently endorsed by ASCO [145]. The recommendation to consider a trial of ginseng for improving fatigue during treatment received a "C" grade (weak evidence of benefit) due primarily to a lack of multiple large trials. The use of guarana was not recommended for improving fatigue during treatment. There was insufficient evidence on vitamins to form a recommendation for or against.

EXPERT GROUP RECOMMENDATIONS FOR CANCER SURVIVORS — Specific guidelines for screening, assessment, and management of fatigue in adult survivors of cancer are available from the American Society of Clinical Oncology, and outlined in the table (table 12) [10].

Guidelines are also available from the National Comprehensive Cancer Network that emphasize [186]:

●Maintenance of adequate levels of physical activity with use of local resources to help patients to increase exercise, and referral to a physical therapist or exercise specialist for survivors at higher risk of injury (eg, those living with neuropathy, cardiomyopathy, or lymphedema).

●Behavioral interventions such as cognitive behavioral therapy, psychoeducational therapy, and nutritional consultation.

●A trial of psychostimulants after ruling out other causes of fatigue and failure of other interventions.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: When your cancer treatment makes you tired (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Screening and assessment

•Cancer-related fatigue (CRF) is a common, distressing, and potentially treatable condition. The most important contributory factors are cancer and cancer treatment, anemia, pain (and its treatment), emotional distress, sleep disturbance, poor nutrition, and other comorbidities. (See 'Introduction' above.)

•All cancer patients should be screened for fatigue at the initial visit, at the end of treatment, as clinically indicated (at least annually) during the period of cancer survivorship, at the time that advanced disease is diagnosed, and at all chemotherapy visits. Specific recommendations for screening and assessment are provided separately. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment".)

●General measures and control of contributory factors

•Patients with mild fatigue (VAS score 1 to 3 on a scale of 1 to 10) that does not interfere with activities of daily living (ADLs) can be reassured and counseled as to coping strategies that conserve energy (table 5 and table 6).

•For individuals with moderate to severe fatigue, potentially treatable causes of or contributory factors to fatigue should be sought for and treated (table 1). (See 'General approach' above and 'Control of contributory factors' above.)

-For patients with insomnia or sleep disorders, specific measures to improve sleep hygiene should be suggested (table 4). For most patients, we discourage the use of medications to aid sleep. (See 'Sleep disturbance' above.)

-For patients with suspected opioid-induced sedation the dose should be titrated or the schedule/agent modified so as to alleviate pain without causing significant sedation. If needed, a trial of psychostimulants may help. (See 'Patients receiving opioids' above.)

-For patients with a significant mood disorder, we suggest a therapeutic trial of an antidepressant (Grade 2B). (See 'Antidepressants' above.)

-For men with CRF with hypogonadism we suggest a therapeutic trial of testosterone supplementation (Grade 2B). (See 'Testosterone for hypogonadal men' above.)

●Patients receiving active cancer therapy

•Patients with anemia – The underlying causes of anemia should be identified and treated if possible. If a potentially reversible cause cannot be identified, hemoglobin (Hb) levels can be raised with either erythropoiesis-stimulating agents (ESAs) or red blood cell (RBC) transfusions (table 3). Specific recommendations are provided separately. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Managing anemia in cancer patients'.)

•Patients without anemia

-For most patients, we encourage an individualized program of moderate aerobic exercise unless contraindicated (eg, by the presence of extensive lytic bone metastases, extensive cachexia, extreme thrombocytopenia, fever or active infection, or safety issues). (See 'Exercise' above.)

-Additionally, some form of psychosocial and behavioral intervention is likely to be of benefit. Structured support groups may help some patients, while others may benefit from individual counseling for stress management, depression, and anxiety; relaxation training; or a comprehensive program that enhances coping skills. (See 'Cognitive-behavioral interventions' above.)

-Mind-body practices such as yoga, acupuncture, Tai chi, or mindfulness-based approaches may also be of helpful, if patients are interested in these approaches and practitioners are available. (See 'Mind and body practices' above.)

-For patients with severe fatigue (Brief Fatigue Inventory [BFI] question #3 >7) in whom nonpharmacologic methods do not resolve fatigue we suggest a psychostimulant (eg, methylphenidate, dexmethylphenidate, or modafinil) rather than other agents (Grade 2C). However, for those in the terminal phase of their illness, a trial of glucocorticoids is an appropriate alternative. (See 'Psychostimulants and other wakefulness agents' above and 'Glucocorticoids' above.)

-A trial of ginseng is a reasonable complementary option, as long as the patient is not receiving drugs that may interact unfavorably with ginseng, such as anticoagulants. For most patients, we do not offer guarana. (See 'Ginseng and guarana' above.)

●Cancer survivors – Our recommended approach to treatment of cancer survivors is consistent with guidelines from the American Society of Clinical Oncology (table 12) and the National Comprehensive Cancer Network (see 'Expert group recommendations for cancer survivors' above):

•For most patients, we suggest an individualized program of moderate aerobic exercise (Grade 2B). Walking programs are generally safe for most cancer survivors; patients can begin this type of program after consulting with their doctors, without any formal exercise testing (eg, a stress test). Patients at higher risk of injury (ie, those with neuropathy, cardiomyopathy, or other long-term effects of cancer therapy) should be referred to a physical therapist or exercise specialist prior to embarking on an exercise program. (See 'Exercise' above.)

•If fatigue persists despite exercise, cognitive behavioral therapy and mind-body practices such as yoga, acupuncture, Tai chi, or mindfulness-based approaches may be of benefit, if patients are interested in these approaches and practitioners are available. (See 'Mind and body practices' above.)

•For survivors with severe fatigue after completing cancer treatment (BFI question #3 >7) that remains unresolved with nonpharmacologic treatments, and no other potentially treatable cause is identified, some clinicians would offer a therapeutic trial of a psychostimulant or other wakefulness agent. (See 'Psychostimulants and other wakefulness agents' above.)