Clinical Assessment and Management of Cancer-Related Fatigue
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.
