Kai Zhou,Jia-Yu Zhang,Xi-Wei Yang,Da Shen,Jun-Jin Li,Yan-Fang Cheng,Xiao-ling Qian,Pei-Xian Zhang,4＊

1The First Clinical Medical College of Yunnan University of Traditional Chinese Medicine, Kunming 650051, China.2Department of Oncology,Yan’an Hospital Affiliated to Kunming Medical University,Kunming 650051,China.3The People’s Hospital of Shilin, Shilin 652200,China.4Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province,Kunming 650051,China.

Abstract

Cancer-related fatigue is the most prevalent and persistently symptom in cancer survivors than any other symptom,which is caused by both the disease and its treatment.Patients with cancer show a severe symptom of fatigue,which cannot be relieved by general rest or sleep.Cancer-related fatigue negatively impacts a patient's physical and emotional function, social ability and even patients’prognosis.At present, the mechanism of cancer-related fatigue remain unclear despite much research, and a variety of mechanisms may contribute to its occurrence and development, including inflammatory reaction, metabolism dysregulation, immune activation, hormonal changes,central nervous system dysfunction,etc.Now a broad variety of drugs and non-drugs interventions are used against cancer-related fatigue.The intervention of conventional western medicine mainly contains hematopoietic stimulants, hormones, mental stimulants, and antidepressants, but their widely clinical application is limited by their effectiveness and possible side effects to a certain degree.There are also many forms of non-drug interventions for managing cancer-related fatigue, such as exercise intervention, psychological intervention, sleep intervention, nutrition intervention, bright white light therapy, etc.The aim of this review is to provide recommendations of non-drug interventions for patients with CRF during and after cancer treatment, in order to provide an evidence-based guideline for clinicians.

Keywords: Cancer-related fatigue, Mechanism, Non-drug therapy, Exercise intervention, Psychological intervention,Sleep intervention

Background

Cancer-related fatigue(CRF)is defined as a distressing,persistent, subjective sense of physical, emotional,and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning[1].CRF is a common complication of cancer patients,who often feel exhausted, lethargic, lose motivation and personal interest, and lack memory and concentration [2].CRF can be accompanied by the whole process of the occurrence and development of the disease, can appear before the diagnosis of cancer,maybe early symptoms, or occur in the course of treatment, even for a long time after the end of treatment [2], and the incidence rate is as high as 99%during treatment [3], seriously negatively impacts a patient's quality of life and the effectiveness of treatment.However, due to the intense subjectivity of this disease,CRF is often ignored in the clinic.

The etiology of CRF is mainly related to both the disease and its treatment.Cancer cells release proinflammatory factors such as interleukin-2 and tumor necrosis factor, which are able to affect the normal metabolism of cells, reduce the function of the body, and lead to fatigue [4].In addition, the routine treatment of cancer always promote the occurrence of CRF and aggravates its development, especially radiotherapy and chemotherapy, in which the chemotherapy is independently related to the severity of CRF in advanced cancer patients [5, 6].Excessive radiation dose and tumor load also aggravated the degree of fatigue [7].At present, the mechanism of cancer-related fatigue remain unclear despite much research, and a variety of mechanisms may contribute to its occurrence and development, including inflammatory reaction, metabolism dysregulation,immune activation, hormonal changes, central nervous system dysfunction,etc.[8,9].

A broad variety of drugs and non-drugs interventions are used against cancer-related fatigue.The intervention of conventional western medicine mainly contains hematopoietic stimulants, hormones,mental stimulants, and antidepressants [10].Hematopoietic stimulants such as erythropoietin can improve fatigue caused by anemia, but long-term use may lead to the high risk of thrombosis [11].Studies have shown that dexamethasone can improve the symptom of fatigue [12], but its long-term application can induce myopathy, an adverse effect of glucocorticoid use characterized by muscle weakness.[4].Previous studies have found that mental stimulants such as methylphenidate and modafinil can improve patients’ impaired concentration [13, 14].However, a systematic review and meta-analysis conducted by D Qu et al indicates that the treatment of CRF with modafinil provides no benefit [15].Antidepressants can reduce fatigue by improving the degree of depression in patients, however, judging from the results of the study, its efficacy is polarized, more clinical studies are needed to confirm its effectiveness[16, 17].There are also many forms of non-drug interventions for managing cancer-related fatigue,such as exercises intervention, psychological intervention,sleep intervention, nutrition intervention, bright white light therapy, acupuncture and massage, etc.The American Society of Oncology Nursing believes that exercise is the only intervention against CRF, which is supported by rigorous first-level evidence and is currently widely used[18].

Here, in this review, the progress research on non-drug therapy in cancer-related fatigue, to provide evidence-based guideline for clinical workers.

Exercise intervention

The benefit of exercise is improving the body’s function,accelerating metabolism, and maintaining the muscle strength of patients, which can solve patients’fatigue.The possible mechanism may be associated with reducing the oxidative damage of skeletal muscle mitochondria, improving the related function of mitochondria, and increasing adenosine triphosphate content in plasma [19].Through the analysis of 170 studies, some scholars show that exercise can reduce the degree of fatigue of patients, and aerobic exercise(walking,running,cycling,etc.),neural exercise(yoga,Taijiquan, Qigong), resistance exercise (the use of heavy objects or instruments with resistance) and comprehensive exercise (a combination of multiple exercise modes) can effectively reduce fatigue [20].In terms of exercise time and intensity, at least two months of moderate-intensity exercise is high recommended.The study found that 12-week resistance exercise is a safe, feasible, and effective strategy to improve breast cancer patients’ fatigue during radiotherapy [21].Another study of 113 breast cancer patients confirmed that moderate personalized exercise (10 minutes of warm-up, 40 minutes of aerobic exercise, resistance exercise and stretching exercise, and 10 minutes of calm relaxation) could improve fatigue and cardiopulmonary function during and after treatment [22].Besides, yoga, Taijiquan, and Qigong are also exerting their clinical therapeutic effects.Studies have confirmed that supervised yoga classes can improve breast cancer patients’ fatigue during and after treatment [23].A meta-analysis of 22 studies, including 1,283 patients, showed that Taijiquan and Qigong also positively affected patient fatigue [24].Of course, there are risks during exercise,such as fractures, pain, falls, syncope, etc.It is worth noting that due to a certain degree of dyskinesia, CRF patients refuse to exercise at the beginning.This kind of obstacle comes from fatigue and physical discomfort related to the treatment side effects and the other is environmental factors and the timing of exercise initiation [25].Therefore, clinicians should make personalized exercise programs and give cancer patients psychological support to exert utmost the intervention effect of exercise on CRF.

Psychological intervention

From a clinical point of view, due to the insufficient understanding or knowledge of cancer, many patients often suffer from anxiety and depression after the disease, which are an inducing and aggravating factor for CRF.Because it would weaken patients’confidence for the following therapy, it is indispensable to start psychological intervention for them as early as possible.Cognitive behavioral therapy includes group therapy, relaxation training, fatigue-related psychological education, which can help patients to manage themselves, enhance confidence, alleviate anxiety, and better deal with ease [26].Some scholars randomly divided breast cancer patients into two groups with 66 cases for each group.The study group was given cognitive behavioral therapy,and the control group was given routine care.The results showed that internet-based cognitive behavioral therapy could effectively reduce fatigue and related symptoms [27].Mindfulness therapy is also an acceptable and possibly effective treatment, which advocates guiding patients to accept themselves through meditation and focus on breathing to relieve anxiety and fatigue.After nine weeks of mindfulness intervention in CRF patients,1/3 of patients no longer needed the appropriate treatment in some studies.After six months of intervention, as many as 39% of the patients no longer needed the appropriate treatment, indicating it enhances the participants’well-being, and improves the dysfunction after treatment [28].Although psychological intervention has achieved a beneficial effect, its long course of treatment might not be suitable for the patients at cancer end-stage.In psychological intervention, clinicians should pay more attention to listen attentively to patients, actively encourage patients to talk, enhance patient’s confidence,overcome fatigue,etc.

Sleep intervention

Sleep disorders directly or indirectly lead to the occurrence of CRF.With the prolongation of the course of cancer, correlation between CRF and sleep disorders increases significantly.Sleep disorders have become one of the crucial predictors of CRF [29].There are cognitive therapy, sleep restriction therapy,sleep education, relaxation therapy, stimulus control therapy, etc., in the way of intervention [30].Some scholars randomly divided patients with small cell lung cancer into two groups (n = 45).The control group with routine treatment, while the intervention group was treated with routine treatment plus comprehensive sleep intervention (including sleep health education,psychological intervention and stimulus control,relaxation training).After eight weeks of intervention,fatigue score of the two groups showed a significant decrease, and the intervention group experienced dramatically improved sleep quality, with the relief of fatigue better than that of the control group [31].However,some studies have shown that although sleep intervention for cancer patients has achieved good results, it does not mitigate the degree of fatigue [32].From the current point of view, it is an urgent need to strengthen the effectiveness of sleep interventions.

Nutrition intervention

Nutritional status is also closely related to CRF, and the occurrence of fatigue is partly due to protein loss[33].For cancer patients, low protein intake due to anorexia and other reasons, cannot satisfy their increased protein demand, which may lead to CRF.Through the study of 285 patients who received chemotherapy,it was found that low protein intake was the main indicator of CRF [34].Protein supplementation can reduce the disorder of protein muscle metabolism, and muscle atrophy caused by muscle proteolysis, and help maintain and build muscle, reduce CRF [34].The intake of fatty acids is also beneficial to alleviate the fatigue of patients.In the nutritional intervention of experiment 30 breast cancer patients by Zick et al., it was demonstrated that a 3-month fatigue reduction diet(rich in omega-3 fatty acids, fruits, vegetables, whole grains) could greatly reduce patients’fatigue [35].The possible mechanism by which these fatigue-reducing diets work is to mitigate chronic inflammation and regulate immune activation, primarily by slowing down the release of inflammatory markers such as C-reactive protein,IL-6,IL-1RA[8, 35, 36].In clinical practice, doctors should strengthen the diet management of patients and ask for nutrition experts’advance to lighten patients’fatigue.

Bright white light therapy

Although only few studies focus on bright white light therapy, it has been found that bright white light therapy has the characteristics of safety,low cost, high compliance, easy operation, and easy management,which may fill the gap in CRF treatment [37].The mechanism of bright white light therapy may include the following: normalizing the sleep-awakening cycle,regulating circadian rhythm, and affecting inflammatory factors’ activity [38].In a multicenter,randomized controlled trial, 128 patients with lymphoma were randomly divided into intervention group (exposed to bright white light) and a control group (exposed to dark white light).The results confirmed the positive effect of bright white light therapy[38].Previous studies on breast cancer patients had also found that exposure to bright white light can prevent the deterioration of fatigue during chemotherapy [39].Although this therapy shows its advantages, clinical research should be conducted in more countries, worthy of clinical treatment and summary of experience and further promotion.

Other intervention

Acupuncture and massage are typical treatment of traditional Chinese medicine, including acupuncture,moxibustion, acupoint massage, ear acupuncture, etc.It has been used in CRF treatment and plays a positive role in reducing cancer patients’ fatigue levels.According to traditional Chinese medicine theory,various therapeutic methods can dredge meridians,regulate Qi and Blood, and reconcile Yin and Yang by stimulating local lesions of meridians and acupoints to promote blood circulation, relax muscles and alleviate fatigue.Some scholars randomly divided 28 lung cancer patients with CRF into an active acupuncture group or placebo acupuncture group.They received acupoint acupuncture (LI-4, Ren-6, St-36, KI-3, and Sp-6) twice a week for 45 minutes each time for 4 weeks.Two weeks later, patients’fatigue symptoms in the active acupuncture group showed apparent improvement [40].Some scholars have adopted a randomized trial for stage 0-III breast cancer survivors who have undergone surgery plus radiotherapy and/or chemotherapy/chemoprevention and have CRF and pointed out that weekly Swedish massage therapy can tremendously improve the symptoms of fatigue in patients [41].Acupuncture and massage have a high degree of acceptance and few side effects for patients,which is worthwhile to arrange active study.However,at present, the sample size is small, and there is a lack of high-quality clinical randomized controlled trials.It is necessary to use large sample data to further verify its long-term efficacy and adverse reactions.

Summary and prospect

Fatigue is a common symptom of cancer patients, who often complain of “fatigue, dizziness, heavy limbs,insomnia, distress, and so on”.This feeling can occur at any stage of the tumor and cannot be relieved by the general rest.CRF seriously affects patients’quality of life, the effectiveness of treatment, and even promote disease progression and negatively influence the prognosis of the disease, bringing considerable trouble to the patients themselves and their families.The etiology of CRF is mainly caused by the tumor itself and the side effects of routine treatment.Furthermore,its mechanism is very complex, and the understanding has not been completely unified at present.The clinical treatment of CRF is mainly non-drug treatment, and exercise is the mainstream intervention method.Psychological intervention, sleep intervention,nutrition intervention, bright white light therapy, etc.,have also shown beneficial therapeutic effects.Acupuncture and massage also have certain effects.Although the current treatment of CRF is diversified,due to its small sample size, some studies have found that the curative effect is not accurate and sometimes contradictory.Due to the lack of a reasonable and standardized assessment scale for CRF to date,patients cannot be better screened, evaluated and treated.At present, medical staff should pay more attention to the patients with CRF, objectively and accurately assess the patient’s CRF, and clarify the cause, so as to formulate efficient, low-cost, safe and individualized intervention measures for them and to alleviate patient fatigue and give patients a strong psychological support.