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Cancer-related fatigue: trigger factors and function of exercise

Introducción: Diversas publicaciones han teorizado sobre los desencadenantes de la fatiga relativa al cáncer, uno de los efectos secundarios de la enfermedad y sus tratamientos que más estresa a los supervivientes de esa enfermedad. Por otro lado, el ejercicio físico ha sido analizado como terapia para reducir el impacto de esta secuela, y diversas instituciones apoyan su inclusión dentro de los programas de cuidado para población oncológica. No obstante, la fatiga en cáncer y el papel que el entrenamiento tiene para su control, se ha expuesto sin realizar una valoración global que muestre su complejidad y por qué el ejercicio físico resulta de tanto valor para reducirla. Objetivos: El objetivo de este trabajo fue revisar la evidencia existente sobre los desencadenantes de fatiga en cáncer, para exponer en qué modo el ejercicio físico actúa sobre cada uno de ellos para controlar su sintomatología y conseguir un efecto terapéutico integral. Material y método: Se realizaron diversas búsquedas bibliográficas que permitieran conocer cuáles eran los desencadenantes de fatiga propuestos por la investigación, cómo se desarrollan y afectan al paciente oncológico y, por último, en qué grado el ejercicio físico sería una herramienta viable para controlar sus efectos. Resultados: Expuestos más de una veintena de desencadenantes y agravantes de la fatiga relativa al cáncer, encontramos que la mayoría de ellos podrían ser prevenidos o al menos controlados a través del ejercicio físico. Conclusiones: Resulta imposible aislar unos desencadenantes de otros, existiendo, además, algunos de ellos que son inevitables al ser parte del tratamiento médico de la enfermedad. Entender las relaciones que se producen entre desencadenantes y conocer los efectos positivos del ejercicio físico sobre cada uno de ellos, es claramente útil para controlar este efecto secundario. Palabras clave: Fatiga relativa al cáncer. Cansancio. Astenia. Ejercicio terapéutico. Summary


Introduction
Defined as a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness 1 , cancer-related fatigue (CRF) is one of the consequences of the disease and its treatment which most distresses survivors [1][2][3] . Its pathophysiology is multifactorial, and the trigger factors proposed include: psychological disturbances, endocrine and energy metabolism dysfunctions, pain, pro-inflammatory cytokine production, and rheumatic complications [2][3][4][5] .
The treatments to reduce CRF include both pharmacological and non-pharmacological interventions 1 . Of the latter, physical exercise (PE) has proven effective for reducing CRF [4][5][6] and is, compared with psychosocial therapies, the type of non-pharmacological intervention which leads to the greatest improvement during cancer treatment, which is precisely when CRF is at its most intense 7 . For some authors, PE affects fatigue because it improves one of its triggers, thereby reducing the overall intensity of the fatigue 8 . Many of the studies conducted have analysed the level of CRF in relation to variables such as the level of muscle strength 6 , inflammatory markers 9 , anaemia 10 , and cardiovascular capacity 11 .
The aim of this paper is to provide a narrative review of the evidence of reducing CRF through PE, analysing each trigger factor, its individual influence on the other factors, and the therapeutic effect of PE on each.

Materials and method
Three independent literature searches were carried out on the PubMed, Google Scholar, Springer Link, SciELO, and Dialnet databases. In the first search, the terms used were Cancer-Related Fatigue and similar (fatigue cancer, oncologic fatigue), selecting those publications containing information on its pathophysiology, symptoms, and/or trigger factors.
Secondly, a search was made to select publications describing each CRF trigger factor and its symptoms in cancer populations. Research conducted on healthy populations was also analysed in order to further study certain trigger factors which have not been studied too much in relation to cancer. Those sources which did not provide information on the development, physiological processes, and symptoms of the proposed trigger factors were excluded.
Finally, those publications analysing physical exercise as a tool to mitigate CRF or improve any of its trigger factors were reviewed, selecting those research and review papers giving results on the level of fatigue in cancer patients or survivors. Figure 1A shows the CRF triggers described in the literature and the direct relationships between them. On the Y axis, they are ordered from most to least influential on other trigger factors; and on the X axis, from least to most affected by other CRF factors. So, for example, chemotherapy is the first trigger factor on the Y axis, because it leads to alterations in more factors, but it is in eighth place on the X axis, because only three trigger factors can influence it. As can be seen, on average, each trigger factor is directly related to another seven, either because it affects them or is influenced by them. Those trigger factors whose degree of relationship is greater than this average are highlighted in Figure 1A.

Results
Beyond direct relationships, trigger factors may also have indirect effects on other triggers. For example, Figure 1B shows not only the relationship between chemotherapy and nutritional problems (direct) but also how psycho-emotional complications could potentially affect the treatment by worsening the nutritional condition of the patient (indirect).
Of the trigger factors with the greatest impact, some are inevitable, such as treatment, and others are difficult to tackle. So, knowing the effects of PE on each trigger factor provides a perspective on the therapeutic potential of exercise on CRF.

Decreased activity and physical deconditioning
Because they are also key factors in the development of chronic fatigue, it has been suggested that decreased activity and the consequent drop in fitness are precursors to CRF 8 . It has been observed that decreased activity in breast cancer survivors (BCS) contributes to the development of osteoporosis 12 , poorer cardiovascular health 13 , and the loss of muscle mass and strength 12,14 , thus aggravating CRF 3 .
The research conducted on the effects of physical exercise on these trigger factors argues that exercise is associated with a higher level of non-sporting activity both during and after treatment 15 , and can also induce further improvements in up to ten CRF triggers. Nevertheless, there are still barriers to cancer survivors (CS) acquiring exercise-related habits 16,17 . On the one hand, patients are faced with external limitations, such as a lack of information and advice on what exercise they can do, and at what intensity they can do it 16 . On the other, patients are also limited by intrinsic factors, such as muscle and joint pain, fatigue itself, the side effects specific to the type of cancer 16 , and not having enough time 17 .

Organ dysfunctions
The main organ dysfunctions related to cancer are cardiac, pulmonary, renal and hepatic dysfunctions. These are related to other CRF triggers in varying degrees.
− Heart conditions: The cardiovascular system can be affected by physical deconditioning 18 , weight gain 19 , dysfunctions in other organs 20 , and treatment 18,19 . This type of condition is a major risk in CS and is, in fact, the leading cause of death in CS aged 65 and over 21 . − Lung conditions: Radiotherapy to the chest influences the development of pulmonary complications, with an increased risk of developing pulmonary fibrosis, pneumonitis, and alterations of the respiratory function 22 . In the case of chemotherapy, the mani-  Stress, anxiety, and/or depression.

Malnutrition
Increased toxicity 1B festations of toxicity are often delayed and come with coughing, fever, and fatigue 23 . − Kidney and liver conditions: The kidneys, which are key to eliminating the drugs used in chemotherapy, are exposed to the risk of renal failure, nephrotic syndrome, and tubulopathies 23 . Similarly, radiotherapy can produce acute hyporeninaemic hypertension and nephropathy 22 . Chemotherapy is not considered problematic for the liver unless the patient has a previous condition 23 . However, radiotherapy can alter the values of transaminases and liver disease markers such as gamma-glutamyl transpeptidase 22 .
Although PE is part of rehabilitation therapies for different cardiopulmonary conditions, in cancer its use has not yet been standardised 11 . However, the general consensus is that PE is safe and tolerable for CS 11,19 , and PE programmes with BCS have been observed to produce improvements in cardiovascular efficiency 9,11 and blood circulation, and reductions in cholesterol levels, blood pressure 24 , attendant symptoms (including CRF), and risk of mortality from all causes 11 .
Similarly, PE has proven effective in increasing maximal oxygen consumption (VO 2max ) both during and after chemotherapy in patients with Hodgkin lymphoma 25 , breast cancer 26 , and solid tumours, even when being treated for anaemia 27 . Nevertheless, it is yet to be demonstrated whether PE acts on other cardiovascular health markers 11,19 , such as cardiac output, the differences in oxygen content between venous and arterial blood, or defects in oxygen pathways 11 .

Musculoskeletal problems
− Cancer cachexia: Although some authors state that a reduction in fatty tissue does not necessarily accompany cancer cachexia, there is a loss of muscle tissue, associated with a lower tolerance to the treatment, a reduction in the effectiveness of the treatment, and loss of quality of life (QOL) 28 . The cachectic state is particularly serious because it is very difficult to reverse through conventional nutritional support 28,29 . Cachexia is usually accompanied by anaemia, fatigue, and malnutrition 30 , affecting protein metabolism 30,31 and, therefore, the possibility of ATP regeneration 31 . It is also associated with the development of osteoporosis 32 and can induce cardiac atrophy and dysfunction 33 . − Bone loss: Bone health is especially important for BCS and prostate cancer survivors (PCS) 34 because they often need androgen deprivation therapy. This indirectly affects the process of bone formation and resorption, and can increase the risk of fracture in PCS by up to five times compared to healthy men 34 . In BCS, the consequences of treatment on bone mineral density (BMD) may appear as of chemotherapy 34 . Osteoporosis means a loss of independence for older subjects and, of course, both increases the risk of fracture and impairs QoL 32 . It has been confirmed that regular exercise reduces the risk of bone problems in PCS 34 . It is also known that increased lower limb strength prevents loss of muscle mass, reduces fat percentage increases during treatment 29 , and decreases the level of CRF in BCS 35 . Resistance training (RT) can, therefore, be an effective tool for PCS with androgen deprivation, due to its effects on muscle function, lean mass, and BMD 15 . The effectiveness of programmes that include impact and resistance training for the bone health of BCS has also been demonstrated 36 .

Pain
Pain in cancer patients can be basal 37 , appear suddenly, or be caused by neuropathic problems [37][38][39][40] due to nerve compression caused by infiltration of the tumour or treatment toxicity 39 . It is considered a contributing factor to the development of CRF 3 because it affects the patient's appetite, sleep quality, treatment adherence, mood 38 , and level of activity to such an extent as to produce kinesiophobia 41 .
Although pain hinders PE adherence 42 , regular physical activity is known to help relieve it in various diseases, including those involving chronic pain 42,43 . Though different analgesia pathways are associated with exercise 43 , it is held that the effects achieved are proportionally related to the length and intensity of the exercise, and the isometric contractions 43 associated with the modulation of the nervous system with respect to pain 42 .
In BCS, it has been observed that combined PE protocols (aerobic, resistance, and flexibility) 44 , Pilates 45 , Qigong 46 , specific exercises mobilising the arm on the affected side 47 , and simply a higher level of physical activity (even while under treatment) 48 reduce the intensity of pain and its impact on daily life. Similarly, lumbopelvic stabilisation exercises in colon cancer survivors can lead to improvements in pain perception, CRF, and mood 49 .

Nutritional disturbances
− Malnutrition: The presence of a tumour increases protein catabolism, lipolysis, insulin resistance, and energy expenditure in CS 28 . We also know that when the digestive system is affected or when patients are undergoing treatment, caloric intake falls 2,28 . If malnutrition ensues, the competition between the tumour and healthy cells for nutrients triggers hypermetabolism, leading to loss of efficiency in replenishing ATP and reducing the level of complete blood protein 30 . Malnutrition has consequences related to CRF: dysfunctional breathing patterns due to respiratory muscle atrophy, inactivity as a result of reduced functional capacity, heart muscle disorders, reduced glomerular filtration, depression, increased toxicity of the treatments 28 , and damage to the peripheral nervous system 50 . Anaemia 31,51 , cachexia 2,28,30,31 , and electrolyte imbalances 28 may also develop. Finally, vitamin D deficiency influences the intensity of muscle pain and arthralgia, typical of hormonal treatment with aromatase inhibitors in BCS 52 , while iron deficiency is associated with restless legs syndrome 53 , related to CRF 3 . − Electrolyte imbalances: The most common alterations in CS are decreases in sodium and magnesium, and increases in potassium, phosphates, and calcium 54 . Chemotherapy, however, especially with cisplatin, can reduce the levels of all the minerals mentioned 55 . Some of the consequences of these imbalances affect CRF. Magnesium deficiency has a negative effect on fatigue, neuromuscular excitability 55 , cardiovascular health, energy production in cells, and inflammatory response 56 . Hyponatremia causes fatigue, cognitive impairment and, in severe cases, pulmonary oedema and increased risk of bone fracture 54 . Finally, hypercalcemia increases bone resorption and affects bone health 55 . On this point, the positive effect of combined exercise and nutrition protocols for improving CRF in PCS 57 and maintaining muscle mass in BCS 58 has been reported. However, there is no evidence that PE might influence appetite in CS 59 .

Stress, anxiety and depression
Some authors suggest that depression predisposes patients to chronic fatigue and that it shares a common aetiology with CRF 2 . Psychoemotional health, which is highly variable between patients, influences the level of fatigue 1,60 ; to such an extent that there are studies which suggest that interventions to treat psychological and emotional disturbances could reduce its intensity 60 . Depression also affects adherence to medical treatment, particularly hormone therapy in BCS, with the consequences this might have on a patient's prognosis 61 .
The effectiveness of PE to improve the emotional state of CS is recognised by the National Comprehensive Cancer Network (NCCN) for its ability to reduce anxiety, perceived stress, and cortisol release 62 . Improvements in psycho-emotional health during chemotherapy in BCS are also greater when physical and psychological interventions are combined, especially when the physical interventions are supervised 63 . Specifically, aerobic exercise interventions (AE) 12 and yoga 64 reduce emotional symptoms in BCS although no significant improvements in physiological parameters have been observed through yoga 64 .

Sleep problems
Commonly associated with emotional issues 4 , insomnia, daytime sleepiness, and night-time awakening are directly related to fatigue in CS 1,9 . They are produced in part by disruption of the natural circadian cycle, which leads, precisely, to increased susceptibility to emotional disorders 2 . They are also the result of serotonin dysregulation and HPA-axis dysfunction, due to the increase in cortisol, which negatively influences non-REM sleep 2 . Finally, the increased level of cytokines due to chronic inflammation in CS 65 also influences CRF, given their effect on daytime sleepiness, narcolepsy, and idiopathic insomnia 2 . In the case of head and neck CS, radiotherapy favours the onset of sleep apnoea, although the relationship between this sequela and CRF could be due to a higher level of cytokines 65 .
Sleep problems, together with pain and CRF, significantly predict the functional decline of CS 66,67 , and although not all the research conducted has found a correlation between PE and improved quality of sleep, bene-fits have been confirmed in BCS, especially after treatment 68 . Although more research is needed, the moderate AE protocols tested with CS 69,70 and the RT protocols tested with BCS during radiotherapy have shown clear benefits regarding this problem compared to relaxation protocols 71 .

Cytokine dysregulation
Chronic inflammation causes different symptoms related to CRF 2,72 , such as anaemia, depression, and cachexia 51 . The most direct relationship between cytokines and fatigue is caused by the amounts of tumour necrosis factor (TNF) receptor 1 (sTNF-r1), C-reactive protein (CRP), and interleukin IL-6, the latter being of greatest importance when it comes to symptoms such as sleep problems and depression in BCS 5,72 . The AIS protein (Anaemia-Inducing Factor) secreted by cancer tissue depresses the production of erythrocytes and the immune capacity of healthy cells, causes endothelial damage, and increases vascular permeability and the leakage of clotting factors 18 , encouraging the development of anaemia. The AIS protein also stimulates lipolytic activity, playing a part in the development of anorexia and cachexia 30 .
The development of cachexia depends on catabolic and proinflammatory cytokines (IL-1, TNF-α, IL-6) and anti-inflammatory cytokines (IL-4, IL-10 and IL-12), and their ability to stop or reverse the cachectic process 30 . During exercise, muscle tissue is the main source of cytokine production. However, regular muscle contraction produces myokines (anti-inflammatory) both in muscle tissue and at more distant sites which could suppress proinflammatory activity, meaning that habitual training would reduce their plasma concentration 9 . In fact, more active people, with or without a history of cancer, have lower levels of inflammatory markers (especially TNF-α, IL-6, and CPR) 6,9 . Continued PE is known to cause changes in myokine production. On the one hand, the reduction in myostatin permits less inhibition of the mammalian target-of-rapamycin (mTOR), thereby allowing increased tissue synthesis, less insulin resistance, and a reduction in sarcopenia 73 . On the other, increased secretion of IL-6 due to increased muscle mass recruitment and exercise intensity and duration induces a better response of anti-inflammatory cytokines such as IL-1Ra, IL-10, and sTNF-R, and inhibits the effects of TNF-α 73 .
The release of pro-inflammatory cytokines during exercise, therefore, would be balanced by the production of anti-inflammatory cytokines and inflammatory response inhibitors 9 . Although the exact mechanisms through which exercise reduces systemic inflammation are unknown, other contributing factors, such as reduced body weight, increased insulin sensitivity, and improved endothelial function, have been suggested 9 , not only at a general level but also in relation to CRF 72,74 .

Anaemia
According to the NCCN, anaemia is one of the CRF factors which may be treatable 2,75,76 . Although it depends on the type of cancer and stage, its prevalence is very high, reaching 30-80% of patients 77 . It may result from nutritional problems, erythropoiesis inhibition 2 , the progression of the disease, or the treatment applied 78 . Although in some cases it can cause dyspnoea on exertion, chest pain, tachycardia, depression, anorexia, and sleep disturbances 78 , anaemia chiefly manifests as fatigue 76.78 . Additionally, it is important to consider that in some CS, it affects QoL and is associated with a worse prognosis and less effective treatment 78 .
Treatment with erythropoiesis-stimulating agents 51,76,77 or packed red blood cell transfusions 76 yields positive results in terms of patient energy levels 75 , haemoglobin concentration, QoL, and prognosis 78 , although, of course, such treatment entails certain risks 76 . There is, therefore, evidence to suggest that QoL improves when the haemoglobin value improves 78 .
PE in the case of anaemia would, therefore, be effective because it stimulates the production of erythrocytes 9 . Specifically, moderateintensity AE, as occurs in healthy populations, increases blood volume through an early increase in plasma volume and a later increase in erythrocyte volume, normalising the haematocrit 10.79 . This not only improves oxygen transport (by increasing the total haemoglobin mass) but also improves cardiac output by increasing preload during diastole 10 , both fundamental in reducing CRF. However, if the anaemia is severe (Hb <6 g/dL), it is advisable to put off exercise until it improves 50 , although patients can still perform daily life activities.

Alterations in muscle metabolism
There are several theories about the relationship between muscle metabolism and CRF which could explain, at least in part, the feeling of tiredness that patients describe 2 . One is ATP dysregulation, produced by the damage that the cancer or its treatment causes to the sarcoplasmic reticulum of cells, which increases intracellular calcium levels. This phenomenon has several possible consequences: lower protein synthesis; alterations in calcium release, and reduced calcium sensitivity of actin and myosin 31 . Together with this, most tumours degenerate the muscle tissue, leading to tissue loss (cachexia) and different alterations in the metabolism of its nutrients 30 . In this case, it has been observed that CS have less muscle strength than healthy subjects and that those with greater muscular strength are those with lower levels of CRF 6 . Therefore, it would appear that RT could improve muscle strength and function in CS 6 by improving motor unit synchronisation, central nervous system activity, and motor neuron excitability 44 . AE, meanwhile, produces an increase in mitochondrial volume, density, and enzyme activity, which changes muscle morphology towards a phenotype which is more oxidative and, therefore, better able to synthesise ATP 10 .

Treatments
Each treatment applied can influence the onset of symptoms related to CRF (Table 1). It is known that the prevalence and duration of CRF is greater in patients who have undergone chemotherapy compared to those who have not 80 ; the effects of radiotherapy on vital organs, sleep disorders, and hot flashes are widely described; and arthralgias are specific to hormonal treatments.
Increases in cytokine levels are considered one of the most determining factors for CRF as a result of treatment 2,9 . Analgesics or medication for comorbidities, such as β-blockers, antidepressants, or antiemetics, can also contribute to increases in the perception of fatigue 1 .
Among the effects of treatment directly related to CRF, it is found that: − Surgery may compromise the nutritional status of patients 28 and damage peripheral or muscle nerves, favouring the onset of pain 23,81 . − Chemotherapy increases the risk of developing heart disease 12,19,82 , pulmonary toxicity 83 ; and ovarian failure, which accelerates bone loss in BCS 24 , and reduces the protective effect of oestrogen on cytokines 52 . It can also cause nervous disturbances which affect muscle force-generating capacity, initiating atrophy and functional decline 12 . Finally, it affects the digestive system, which has nutritional consequences 23 . − Radiotherapy is also related to heart disease 13,18 , lung damage 22 , nerve damage, due to its effects on blood vessels and tissue fibrosis 81 , anaemia 78 , and nutritional disturbances 28 . − Finally, hormonal treatment with tamoxifen increases the risk of cardiovascular disease 13 , pulmonary toxicity, and hot flashes 84,85 . When aromatase inhibitors are used, there is a higher incidence of hypercholesterolemia 13 (and, therefore, a greater risk of myocardial infarction 86 ), joint pain, and increased bone loss and fracture risk 52 .
Taking certain considerations into account before planning the training programme 14 , PE, even high-intensity exercise 35,87 , during chemotherapy has proven to be both safe and beneficial for cancer patients 14,24,88 . We also know that exercise induces the release of anti-inflammatory cytokines 9 , and various studies report improvements in cardiorespiratory level 13,14 , functionality 14,89 , muscle strength, fatigue 14 , body composition, and QoL 89 .
During radiotherapy, the effect of exercise on CRF is equally significant; interventions which centred exclusively on resistance in BCS 90 and PCS 91 reduced the level of fatigue or prevented the decline that the subjects in the control groups suffered 90,91 .

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction
Cancer and/or its treatment have a direct effect on the HPA axis, altering the release of cortisol 2 and androgens 51 . For example, lower decreases in cortisol levels during the day and high concentrations at night 6 have been observed in breast and ovarian CS suffering from CRF, and low testosterone levels related to fatigue have been observed in male CS 75 . Cortisol is also released in situations of psychological or physical stress 2 , but when stress becomes chronic, the production of proinflammatory cytokines increases and the functioning of the HPA axis is disrupted, reducing the release of cortisol and leading to symptoms compatible with CRF 31 . Based on the research conducted, we know that the hormone release which takes place in healthy subjects during AE could be altered in BCS 92 , it having been observed that the reduction in cortisol that PE produces is less pronounced in BCS compared to healthy women following a single session of moderate-intensity AE 92 . We also know that there is no significant difference in cortisol levels between active and inactive BCS 93 . However, interference with the endocrine system caused by medication, sleep disturbance, psychological stress, and other factors means it is not possible to clearly describe the relationship between PE and cortisol, and further research into the subject is needed 93 .

Serotonin dysregulation
Serotonin (5-HT) regulates processes such as the circadian cycle, mood, pain, appetite, and cardiovascular and muscle functions 2 , processes which influence the intensity of CRF 3 . It has been described that in cancer patients, the increase in serotonin in the brain appears to decrease the nerve impulse to the muscle fibres 2,3 and affects vagal afferent nerve activation, reducing the ability to carry out PE 2 . The HPA axis is also directly affected by serotonin, with an increased release of corticotropin releasing hormone (CRH), antidiuretic hormone (ADH), and adrenocorticotropic hormone (ACTH) 2 .
When healthy subjects perform PE, two mechanisms influence the increase in brain serotonin content and, consequently, the acute increase in fatigue 94 . Firstly, the depletion of glycogen reserves (should it occur), and secondly, the increase in the brain of the concentration of tryptophan, the precursor of 5-HT synthesis 94 . However, decreases in cortisol and serotonin have been reported in older female BCS after 12 weeks of AE (four weekly walking sessions), with a consequent improvement in sleep quality, but not in the level of CRF 95 . Even so, it is not known whether exercise could normalise the metabolism of serotonin in CS in the long term 6 .

Vagal afferent nerve activation
It has been studied that a healthy vagus nerve could inhibit the inflammation caused by cancer and that its activity, reflected in the basal heart rhythm, is associated with the prognosis of various types of cancer 96 . For example, a high basal heart rhythm and recovery heart rate (HR rec) are associated with a worse prognosis for people who have been operated on for lung cancer 97 . When there is inflammation, caused by the disease and its treatment, a peripheral release of cytokines occurs, activating vagal afferent nerves signals. This leads, among other things, to suppression of somatic muscle activity, sickness behaviour 2,31 , and changes in the hypothalamus 31 .
It is known that AE improves the aerobic capacity of cancer patients, their HR rec , and autonomic control of cardiac muscle both during and af-ter treatment, especially in patients with lesser cardiovascular capacity 98 . Although these results are not reflected in the level of CRF, improved vagal tone may also reduce the risk of cardiac arrhythmias, which could have a positive impact on the survival of CS 98 .

Vasomotor symptoms: hot flashes
Typical during menopause, these mainly affect survivors who have received hormone therapy, such as BCS 99 and PCS 100 . They are considered fatigue triggers because they are a bothersome symptom which affects daily activities 84 , QoL 84,101 , treatment adherence 101 , and rest 84,101,102 , and may augment the perception of pain and fatigue 84 .
Although PE is beneficial for controlling hot flashes in healthy women 103 , it is generally advised that BCS avoid any increases in body temperature 99 . In these women, breathing exercises and progressive relaxation seem to be effective ways of reducing the frequency of this event 100,104 .

Conclusions
Having reviewed the triggers of CRF, it is possible not only to appreciate the complexity of this side effect but also to recognise that it presents a significant number of physiological alterations which also have effects on other processes and increase the risk of developing comorbidities. Similarly, it can be observed that there are fatigue triggers inherent in the disease and, from there, unavoidable triggers and other factors which could be tackled. In this light, it would be appropriate to assess the advisability of applying preventive therapies for CRF, such as physical exercise.
One of the conclusions of this review is that decreased activity and physical deconditioning are not only CRF triggers in themselves but that they are also greatly aggravated by a great many of the factors related to this side effect ( Figure 1A). Perhaps the most important conclusion of this review is that physical exercise is capable of reversing these two factors (being directly related to them) and that it also has positive effects on many other CRF triggers.
This review also concludes which CRF triggers could be improved through physical exercise, either during or after treatment. In addition to improving CRF directly as the main outcome, there is evidence that physical exercise improves CRF through its positive effects on organ dysfunctions, musculoskeletal problems, pain, and the effects of treatment (Table 2). There is also evidence that physical exercise has positive effects on other triggers, such as psycho-emotional disturbances, sleep problems, cytokine dysregulation, alterations in muscle metabolism, sleep dysregulation, and vagal afferent nerve activation. The action of physical exercise on CRF in these cases would be indirect but equally effective in reducing their overall intensity. Only in three of the fifteen CRF triggers is there no evidence of physical exercise having a positive effect.
In all, the findings of this review clearly describe the therapeutic value, at least as a coadjuvant, of physical exercise on the different side effects of cancer, making the inclusion of exercise programmes highly recommendable as preventive therapy for CRF. Cytokine dysregulation CS: ↑ inflammatory cytokines and myokines 9 Anaemia CS: ↑ erythrocyte production 9 , → normalisation of haematocrit 10,79 Alterations in muscle metabolism CS: RT → motor unit synchronisation, CNS activity 44