Support Care Cancer (2013) 21:2899–2911 DOI 10.1007/s00520-013-1897-1

REVIEW ARTICLE

Cancer-related fatigue in the elderly A. Giacalone & D. Quitadamo & E. Zanet & M. Berretta & M. Spina & U. Tirelli

Received: 1 October 2012 / Accepted: 26 June 2013 / Published online: 13 July 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract Purpose Cancer is a disease of the elderly: 60 % of tumours occur in patients aged 65 years or older. Cancer-related fatigue is a common symptom experienced by cancer patients and cancer survivors that profoundly affects all aspects of the quality of life. Although it has been estimated that up to 70 % of elderly with cancer experience fatigue, this symptom is still largely ignored in ageing population. Methods We performed a systematic review of the literature identified by MEDLINE. Results The relationship between ageing process and pathogenesis of cancer-related fatigue is still not fully understood. Conclusions Ageing is associated with an increased prevalence of chronic diseases, decreased functional reserve in multiple organ systems and enhanced susceptibility to stress. Ageing and the concomitant presence of a condition of frailty may predispose to the presence of fatigue. Nevertheless, only few studies have to date specifically assessed the impact of fatigue in the geriatric population. Since cancer-related fatigue is a peculiarly debilitating condition characteristic of elderly cancer patient population, we suggest the early recognition and thorough evaluation of the symptom fatigue, its co-existing causes (i.e. anaemia, mood disorders and sleep disturbances) and co-morbidities (i.e., endocrine disorders, metabolic, cardiovascular and liver diseases). A. Giacalone (*) : E. Zanet : M. Berretta : M. Spina : U. Tirelli Medical Oncology Department, National Cancer Institute—IRCCS, via Franco Gallini 2, 33081 Aviano, Pordenone, Italy e-mail: [email protected] A. Giacalone e-mail: [email protected] D. Quitadamo Scientific Directorate, National Cancer Institute—IRCCS, Aviano, Pordenone, Italy

Keywords Ageing . Cancer . Cancer-related fatigue . Elderly . Fatigue . Immunosenescence

Introduction Fatigue is defined as a sense of physical, emotional and/or cognitive tiredness/exhaustion related to cancer or cancer treatments that does not recover with adequate rest [1–3]. It has been described as the most distressing symptom both by patients still under cancer treatment and by survivors, which seriously compromises the quality of life (QOL) and ability to function on a daily basis [3–10]. In the general cancer population, the estimates of incidence range from 20 to 95 % throughout the course of disease [11–13]. Cancer is a disease of the elderly, with 60 % of tumours occurring in patients over 65 years of age. Elderly patients are more vulnerable to side effects of cancer therapy and often present age-related changes in multiple organ systems and increasing comorbidities, which predispose to fatigue. This condition is often underestimated by clinicians or not communicated by patients, who often consider fatigue to be part of the usual course of ageing. To give an up-to-date overview of the state of the science about cancer-related fatigue (CRF) in elderly patients, we performed a computer-based literature search on MEDLINE database identifying articles about CRF in elderly patients published between January 2000 and June 2012. The search terms we used included fatigue, cancer, elderly, cancer-related fatigue and immunosenescence. The search was restricted to published original or review articles that met the following criteria: (a) published in a scientific peer-reviewed journal in a full manuscript form; (b) published in a scientific book; (c) written in English language; (d) that included patients with at least 65 years of age, with a cancer diagnosis (any type and stage), either during or at a distance from treatment; and (e)

2900

that presented a specific fatigue assessment (including related symptoms, the mechanism that have contributed to its development, its measurement and related treatments). Since only a few of selected manuscripts specifically evaluated the impact of CRF in an elderly population, we decided to include in the review also some reports of peculiar importance in understanding CRF pathogenetic mechanisms, measurement and treatment interventions that have been observed in a younger population. In Appendix, we listed the mean age and the number of patients included in the main clinical articles reviewed.

Factors associated with CRF Fatigue rarely is an isolated symptom. More often than not, fatigue is one symptom within a cluster of other symptoms. In elderly cancer patients, fatigue may be accompanied by conditions that may contribute to the development of CRF (i.e. anaemia, depression and sleep disorders). Moreover, the elderly are often affected by several co-morbidities (i.e. endocrine disorders, metabolic disorders, cardiovascular and liver diseases), which may cause fatigue. These clinical conditions should be promptly recognised and treated (Table 1). The incidence and prevalence of anaemia increase with age [14]. Anaemia has serious consequences on older individuals’ functional dependence (i.e. the ability to live by themselves) [15], chemotherapy tolerance (a reduction in haemoglobin is associated with increased concentration of circulating free drug and related toxicity concerns) [16] and fatigue appearance. It is an independent risk factor for mortality in the elderly [17]. The mechanism by which anaemia might cause fatigue in patients with cancer is largely unknown, but hypoxia-related impairment of organ function has been suggested [18]. Anaemia (defined as haemoglobin level below 12 g/dl) may occur as a result of either cancer (i.e. neoplasm that involves bone marrow and cancer-related chronic bleeding) or cancer treatment. However, the elderly may present other common causes of anaemia, which often co-exist with a cancer diagnosis and should be ruled out. The research of anaemia causes in the elderly should take into account also the peculiar physiopathological aspects of this population. A reduced sensibility of erythropoietic precursors to erythropoietin in the elderly, due to age-related chronic inflammation and/or an erythropoietin production deficit secondary to renal insufficiency were found by some authors [19]. Iron deficiency anaemia may follow, especially in the elderly, a decreased absorption of iron, due to gastric achylia, or to increased circulating concentrations of hepcidin [20]. B12 vitamin deficit anaemia may be due to inability to digest B12 due to decreased gastric secretion of hydrochloridic acid and of pepsin [21]. Ferrucci et al. [22] highlighted a type of

Support Care Cancer (2013) 21:2899–2911

anaemia secondary to hypogonadism. Low testosterone circulating levels resulted in anaemia in three quarters of older anaemic men and women. As regards treatment, for hypo-proliferative anaemia, a replenishment of nutritional deficiencies including iron, cobalamin and folates is indicated. The use of erythropoietin-stimulating agents (ESAs) epoietin and darbepoietin is indicated for chemotherapyassociated anaemia and should be adopted only in patients with haemoglobin 35, sleep apnoea, waist circumference, microvascular diabetic complications, cognitive impairment

Exertional dyspnoea, fever, fatigue and weakness, abdominal symptoms (nausea, vomit, pain, fullness, lack of appetite), headache, insomnia, malaise, tachycardia, weight loss/gain, cognitive disorders (confusion, lack of concentration, loss of memory), mood alteration (anxiety, hunger, depression)

Neurologic dysfunction Infections

disorders. This resulted in increased inflammation and fatigue in the presence of cancer and/or cancer treatment and/or cancer related psychological stress.

Pathogenetic hypotheses The pathogenesis of CRF is not well understood yet. Besides, a variety of mechanisms may contribute to its development. The scenario is even more complex in elderly patients. Ageing affects the immune system (low-grade chronic, systemic up-regulation of the inflammatory response, decreased immunity to exogenous antigens and increased autoreactivity) and causes neuroendocrine dysregulation (decreased growth hormone along with cortisol dysregulation and increased sympathetic tone), involving frequently a physiological decline in several organ systems (i.e. decreased heart rate and cardiac output with consequent decreased organ perfusion and increased systolic blood pressure, decreased lung vital capacity and expiratory reserve volume along with increased residual volumes,

decreased gastric emptying and absorption in the gastrointestinal tract, an overall reduction in haematopoiesis, decreased sex hormones and decreased muscle mass and strength) [35]. The ageing process and its consequences seem to promote cancer incidence, development and progression. Two main components of fatigue have been proposed: the peripheral and the central [36, 37]. Peripheral fatigue relates to dysfunction at the neuromuscular junction and muscle tissues levels, results in the inability to perform a task in response to central stimulation and is clinically manifested by weakness. Central fatigue develops within the central nervous system and is characterised by a difficulty in performing physical (often mental) activities, which require self-motivation and responses to internal cues. Central fatigue is often associated with a higher perceived effort when undertaking tasks. Moreover, by definition, central fatigue directly results from altered neurotransmission within the brain. Proposed mechanisms of CRF include serotonin dysregulation, hypothalamic–pituitary–adrenal (HPA) axis dysfunction, circadian rhythm disruption, muscle metabolism

2902

Support Care Cancer (2013) 21:2899–2911

dysregulation, disorders in energy balance, and cytokine dysregulation (Fig. 1). Serotonin dysregulation One proposed mechanism for CRF in cancer patients, based on research in the field of exercise-induced fatigue and chronic fatigue syndrome (CFS) [38], relies on an increase in brain serotonin (5-HT) levels and/or an upregulation of a population of 5-HT receptors. Serotonin has numerous functions including control of appetite, sleep, memory, learning, temperature regulation, mood, behaviour, cardiovascular function, muscle contraction and endocrine regulation, with an increasing evidence for a role in the genesis of the central fatigue [39]. Previous studies have shown that during prolonged exercise, an increased in plasma levels of free tryptophan (the amino acid precursor of 5-HT) followed by an increased neuronal synthesis of 5-HT in patients affected by CFS result in physical and mental fatigue [40, 41]. The rate-limiting step for synthesis of 5-HT in the brain is the transport of tryptophan into the brain. Tryptophan and branched-chain amino acids (BCAAs) compete for entry into the brain via a transporter [42]. During exercise, BCAAs are taken up by muscle cells. One hypothesis suggests that increased levels of central 5-HT during exercise are caused by a reduction in circulating BCAAs, which allows more tryptophan to enter the brain [43]. In addition, exercise increases the concentration of plasma free fatty acids that displace tryptophan form albumin, thus generating more available unbound tryptophan in plasma [44]. Reports in humans

show that supplementation with BCAAs before and during exercise was associated with improved physical and mental performance [45, 46]. Alterations in central serotoninergic transmission are associated with fatigue during exercise. In several human studies, administration of selective serotonin reuptake inhibitors has been shown to reduce the capacity to perform exercise [47, 48]. Other data from CFS suggest a disruption of the interaction between the HPA axis and the serotoninergic system, explained through a decreased responsiveness of 5-HT1A receptors at hypothalamic–pituitary level [49]. There is increasing evidence of the role of pro-inflammatory systemic cytokines in the dysregulation of central 5-HT metabolism and the resulting CRF. In particular, some authors postulated the existence of a feedback loop between peripheral cytokines and central 5-HT metabolism dysregulated in cancer or by cancer therapies [50]. Systemic cytokines seem to influence 5-HT synthesis, release in the synaptic space [51], and 5HT reuptake [52]. Conversely, 5-HT can influence cytokine synthesis. This feedback loop may become dysregulated by cancer and/or cancer related therapies. HPA axis dysfunction Another possible mechanism involved in the pathogenesis of CRF is the disturbance of the HPA axis by cancer and/or cancer treatment. The HPA axis is the central regulatory system involved in the control of the release of cortisol in response to physical and

Fig. 1 Interplay among potential causative agents of CRF AGING

DEPRESSION

CANCER Cytotoxic therapies/ RT/OT/Surgery

Muscle metabolism dysregulation

Cytokines dysregulation 5-TH dysregulation HPA-axis dysfunction Circadian rhythms disruption

Anaemia

Co-morbidities

FATIGUE

Energy dysregulation

?

b

a

Spatis et al. [111] N=20 NSCLCa; median age of 74, range of 53–81 Cruciani et al. N=29 various advanced cancer; [112] mean age of 67 (SD=13) Esquedo et al. N=00 various solid tumours; mean [113] age of 63 (SD=12)

Erythropoiesis-stimulating agents

AMPA receptor modulators

Paroxetine

Etarnecept

Etarnecept

Etarnecept

Drug

5 mg up to 20 mg daily

18 mg daily (starting dose), 54 mg (goal dose)

Darbopoietin

Levo-carnitine

Modafinil

Chemotherapy-related fatigue Chemotherapy-related fatigue Severe baseline CRF

Severe baseline CRF

Severe baseline CRF

100 mg daily (starting dose), Severe baseline CRF 200 mg daily (goal dose) 1 g twice daily Energy dysregulation related fatigue 1 every 3 weeks CRF due to chemotherapy associated anaemia

100 mg daily (starting dose), Severe baseline CRF 200 mg daily (goal dose)

Dexmethylphenidate 5 mg up to 10 mg twice daily Modafinil 200 mg daily Modafinil

Indication

Cytokine mediated fatigue Cytokine mediated fatigue Cytokine mediated fatigue Inflammation mediated fatigue Cytokine related fatigue: object of research 2,5-5 mg daily or twice daily Severe baseline CRF

25 mg subcutaneous twice weekly 25 mg subcutaneous twice weekly 25 mg subcutaneous twice weekly 20 mg once daily

Dosage

Dexmethylphenidate 10 mg up to 50 mg daily

Methylphenidate

N=30 various cancer; median age of Methylphenidate 74, range of 51–90 N=148 various cancer; mean age of Methylphenidate 59 (SD=11)

Yennurajalingam N=82 advanced various cancer; et al. [106] median age of 55 Lower et al. N=52 various cancer; mean age of [107] 53 (SD=9) Mar Fan [108] N=57 breast cancer; median age of 50, range of 36–74 Jean-Pierre et al. N=631 various cancer; mean age of [109] 61, range of 18–90 Blackhall et al. N=27 various cancer; mean age of [110] 60

Moraska et al. [105]

Kerr et al. [104]

Non-small cell lung cancer

Nutritional supplements ESAb

Neurotransmitter inhibitors Regulators of synaptic plasticity Psychostimulants

Madhusudan N=30 advanced ovarian cancer; age et al. [99] range of 35–76 Madhusudan N=16 metastatic breast cancer; et al. [100] median age of 53, range of 34–74 Monk et al. [101] N=28 various advanced cancer; median age of 56, range of 25–83 Morrow et al. N=479 various cancer; mean age of [102] 56, range of 23–87 Kuipers et al. [103]

Cytokine blockers

Participants

Study

Drug classes

Table 2 Pharmacological agents for the treatment of cancer-related fatigue (CRF) according to recent literature

Yes

Yes

Yes

Yes

Yes

NO

Yes

Yes

NO

Yes

NO

Yes

NO

Yes

Risk of thromboembolic events

Diarrhoea, nausea

Well tolerated

Nervousness, appetite loss, dizziness, insomnia Nausea, dizziness, insomnia, anorexia Headache, nausea, dry mouth Anxiety, insomnia, dizziness Dyspnoea, headache, allergic reaction Mild (dizziness, nausea, diarrhoea, heartburn)

None

Somnolence, asthenia

None

Nausea, headache

None

Fatigue Side effects improvement

Support Care Cancer (2013) 21:2899–2911 2903

2904

psychological stress. Cortisol exerts several biological effects, including regulation of blood pressure, cardiovascular function, carbohydrate metabolism and immune function. Serum cortisol concentrations show diurnal variations, which are typically at their highest after walking followed by a decline through the day. Data obtained from multiple clinical conditions in humans such as CFS and cancer show a reduced HPA axis activity in response to stress expressed by reduced corticotropin-releasing hormone (CRH) synthesis and released from the hypothalamus, and consequent hypocortisolemia [53]. At present, the exact mechanism by which cancer and/or cancer related treatment may cause a dysregulation of the HPA axis resulting in fatigue is unclear. Cancer therapies such as glucocorticoids, radiotherapy and some forms of chemotherapy may directly suppress the HPA axis [54–56]. A decreased responsiveness of the 5-HT1A receptors responsible for controlling the HPA axis at the hypothalamic level, resulting in defective central CRH release and consequent hypocortisolemia, has also been suggested [49, 57]. Moreover, reduced cortisol levels allow pro-inflammatory cytokines to rise, with a consequent influence on HPA axis function [58]. Furthermore, co-morbid conditions such as sleep disorders [59] and depression [60] (that is associated with hypercortisolemia) have a role in HPA axis dysregulation.

Circadian rhythm disruption Another possible mechanism by which cancer and/or its treatment may cause CRF is through circadian rhythm (CR) disruption. CRs are endogenous genetically and physiologically based patterns that regulate endocrine hormones secretion (i.e. cortisol, melatonin and prolactin), metabolic processes (i.e. body temperature and circulating protein levels), the immune system (i.e. levels of circulating leucocytes and neutrophils) and rest–activity rhythms [61]. Cortisol secretion rhythms and rest–activity patterns are the most investigated mechanisms. Bower et al. [62] have reported on change in salivary cortisol levels between morning after awakening and late evening in women surviving breast cancer and have showed a significant flatter diurnal cortisol slope in the group of patients experiencing fatigue. Berger [63] and Mormont et al. [64] in their investigation of the rest–activity CR in patients affected by a colon and breast cancer have demonstrated a positive relationship between fatigue and restless sleep at night. Moreover, they observed an association between inconsistent and/or dampened CR and greater fatigue. Among the reported causes of CRs disruption, genetic, psychosocial and environmental neuroimmunologic factors may have a role. In fact, possible relationships among diurnal changes of cortisol, cortisol effects on immune cells and pro-inflammatory cytokines have been reported [58].

Support Care Cancer (2013) 21:2899–2911

Muscle metabolism dysregulation A peculiar aspect of CRF reported by patients, which they described as a sense of “weakness” and “lack of energy”, can be better explained with a muscle reduced capacity for contraction and ability to perform mechanical tasks. This CRF feature is at least in part related to a kind of peripheral fatigue and depends on a reduced capacity to regenerate adenosine triphosphate (ATP), which is the major source of energy for contraction of skeletal muscle [39]. In patients with cancer, ATP depletion may be explained by a reduced energy intake (due to altered appetite or cancer and/or cancer treatment related events such as anorexia–cachexia), by increased levels of uncoupling proteins or altered muscle protein metabolism with consequent reduced levels of ATP [65]. Moreover, evidence suggests that the number and function of mitochondria (the energetic machines of all animal cells) decline with age, along with an increased susceptibility to mutation and damage from reactive oxygen species. The efficiency of the process by which the chemical energy provided by carbohydrate and lipid metabolism is translated into ATP and heat decreases with age due to the accumulation of mutation at mitochondrial DNA level. This process results in fatigue and exercise intolerance [66]. Age has an influence on muscle changes both as regards anatomy (i.e. smaller size, fewer motor units and greater fat content) and function (lower strength and power, slower contractile properties and greater oxidative energy utilisation). This situation may explain the differences in muscle fatigue resistance (i.e. the ability to maintain force and power as a result of prolonged or repetitive muscular activity, until fatigue appears) between young and old adults. Recent studies suggest an increased resistance to fatigue in older adults’ muscles than in the younger counterpart, particularly during isometric contractions [67]. In contrast, dynamic contractions, which rely on velocity and power generation, can result in relatively higher fatigue in older adults [68]. Energy utilisation and fatigue Another proposed fatigue model investigates fatigue as a disorder of energy balance [69]. The total amount of energy potentially used by an individual within 24 h may be divided into portions. A small amount of energy is necessary to process food during digestion and avoid excessive fluctuation in body temperature. A bigger energy portion (from 40 to 60 % of total daily energy used) is represented by the theoretical minimum energy requirement for homeostasis at rest or resting metabolic rate. In the presence of pathology, an extra-portion of energy is required to maintain the homeostatic equilibrium. The remaining portion of energy is the energy used daily for physical and cognitive activities. In older adults, reduction in fitness, need for extra energy necessary

Support Care Cancer (2013) 21:2899–2911

for homeostasis due to pathologies and reduction in biomechanical efficiency were noted and thus the performance of basic daily activities may require near maximum energy available. This reduction in energy is perceived by brain as an “alarm” that leads to “generating” fatigue. In the attempt to spare energy, patients reduce physical activity thus lowering the total energy available and generating more severe fatigue, in a vicious circle. This model may encourage interventions aimed at reducing sedentary behaviour, increasing fitness and energy availability and reducing fatigue as a consequence.

Cytokine dysregulation Increasing data correlate increased inflammatory responses with pathways known to be involved in the regulation of behaviour and confer to cytokine dysregulation model a unifying role among proposed mechanisms for CRF [70]. Surgery, chemotherapy and radiation are all associated with significant tissue damage and destruction, which in turn are related to the activation of innate immune responses. Moreover, the data at our disposal show a direct induction of nuclear factor kappa B (NF-kB) and its downstream proinflammatory gene products by cancer treatments [71]. Receiving a diagnosis of cancer is one of the greatest imaginable stressors. Stress, in turn, may activate inflammatory cytokines and their signalling pathways (i.e. NF-kB) both in the periphery and in the brain [72]. There is compelling evidence of the role of innate immune cytokines in the induction of behavioural alterations. Cytokineinduced behavioural changes have been associated with: (1) alterations in the metabolism of relevant neurotransmitters within the brain (i.e. 5-TH, norepinephrine and dopamine) [73]; (2) with the dysregulated synthesis of neuropeptides (i.e. CRH, a key regulatory of HPA axis) [53]; (3) with the activation of the sympathetic nervous system and the release of catecholamines, which bind to alpha and beta adrenergic receptors on relevant cells [74]; (4) with changes in the circadian cortisol rhythm and the disruption of glucocorticoid receptor function which, in turn, results in a reduction of neuroendocrine capacity to limit inflammatory responses [59]; and (5) with disrupted sleep–wake cycles [59]. Since ageing involves inflammation, older individuals are at higher risk for developing fatigue symptoms [35]. A recent study [75], utilising genome-wide expression microarrays, identified an increased transcription of inflammation-related genes, particularly the genes responsive to the pro-inflammatory NF-kB transcription control pathway, along with a concomitant decreased transcription of glucocorticoid-responsive genes, in leucocytes from persistent fatigued breast cancer survivors. These data provide confirmation of an inflammatory model for CRF and suggest possible fields of intervention.

2905

Evaluation of the patient Ageing is associated with the loss of functional reserve of multiple organ systems, increased prevalence of chronic diseases, enhanced susceptibility to stress and predisposition to develop fatigue [76, 77]. Frailty is a peculiar physiological state that may lead to disability, which is the loss of a function necessary for independence, following minimal stress. In geriatrics, frailty is often considered as a combination of signs and symptoms such as weakness, fatigue, weight loss, decreased balance, physical inactivity, slowed motor processing and performance, social withdrawal, mild cognitive changes and increased vulnerability to stressors [78, 79]. The prevalence of frailty is usually estimated to be around 10–25 % in subjects aged 65 years or older [80]. According to the National Comprehensive Cancer Network guidelines, each patient, especially if elderly [76, 77], should be screened for the presence of fatigue at their initial visit and during the routine visits, and treated promptly [3]. Elderly patients are often reluctant to report fatigue to their clinicians, mainly because they consider fatigue as an unavoidable side effect [81, 82]. Therefore, health care providers should help elderly patients to disclose and describe the tiredness they are experiencing, the intensity and pervasiveness of fatigue, the factors that exacerbate or relieve it, its course over time and its impact on functioning. The adoption of an assessment tool may help patients to talk about their fatigue. Even if literature reports more than 20 instruments for the assessment of fatigue, to date, none has been specifically developed for elderly cancer patients [83, 84]. However, one-dimensional scales, which contain 3–13 items and are easy and brief to administer, should be recommended in elderly patients. Some examples are the Functional Assessment of Cancer Therapy Fatigue subscale [85] (we suggest its use for research purposes for the scores that significantly correspond to different clinical conditions) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Fatigue subscale (QLQ-C30) [86, 87] (less sensitive in the identification of changes in fatigue and less able to assess differences between groups, but easier to use in everyday practice).

Treatments There is an increasing trend of treating older patients with several drugs. More than 40 % of older people (age, >65 years) take five or more different medications per week, and 12 % take 10 or more different medications [88]. When clinicians assess patients for CRF, they should carefully check what drugs patients are taking and their influence on CRF appearance. In

2906

fact, there are several drugs used as adjuvant in cancer therapy or drugs used in the treatment of possible multiple comorbidities that may cause fatigue. For example, opioids, which are drugs commonly used in the control of acute or chronic pain, can cause fatigue through an increase in the inhibitory activity of the central nervous system, although the mechanism by which determine a depression of the central nervous system is not well defined. Open communication among the patient, family and health care team about the experience of fatigue and its effects on daily life should be favoured [89], in particular before starting a potential fatigueinducing treatment. The modern approach to CRF treatment advocates the use of both pharmacological and non-pharmacological interventions. Unfortunately, clinical trials involving older patients are still poor in number. Several drugs have been studied, such as drugs targeting cytokine signaling pathway, psycho-stimulants and erythropoiesis-stimulating agents, with mixed results (see Table 2). There is preliminary evidence for the use of psycho-stimulants to treat CRF [90]. However, further confirmation is needed before firm recommendations on their usage and safety have to be made in the treatment of CRF with the old patient, due to their side effects. Among the educational general strategies useful in coping with fatigue, the teaching of strategies based on the principles of energy conservation [91], which may help patients examine their routine activities, reduce the amount of effort needed to perform certain tasks eliminate other tasks and balance adequately periods of rest and activity, could be of a certain importance. Moreover, an indication for activities designed to distract [92] (i.e. games, music, reading, socialising) could be helpful in decreasing fatigue. Interventions aimed at enhancing physical activity and their impact upon CRF have been explored in several studies. Exercise is thought to reduce cancer and cancer-related treatment inflammation and consequently gradually restore HPA axis dysfunction, circadian rhythm disruption and revert behavioural abnormalities such as central fatigue or depression-related fatigue. A 2008 Cochrane analysis [93] reported on 28 randomised controlled trials investigating the effects of exercise on CRF. Overall, physical activity was superior to control in relieving CRF, both during and after therapy. At this time, it is unknown what the optimal amount, type or frequency of physical activity should be for the elderly cancer population. However, some studies have suggested at least 3–5 h of moderate activity per week to experience fewer side effects of therapy, including fatigue [94, 95]. Some patients, especially those with co-morbidities or that had recently undergone major surgery or with specific functional or anatomical defects should be referred to exercise specialists for individualised prescription based on age, gender, type of cancer and physical fitness level.

Support Care Cancer (2013) 21:2899–2911

Caution in exercise prescription should be paid in patients with bone metastases, thrombocytopenia, anaemia, fever or active infection. As regards psychosocial interventions on CRF, three recent meta-analyses [96–98] explored the state of the art. In particular, many of the studies in the field are not addressed to evaluate fatigue as the primary outcome parameter, but as a secondary measure of a general emotional distress and/or an impaired quality of life. Moreover, patients are not included on the basis of their fatigue severity scores, the fatigue outcomes are often self-reported and the impact of fatigue on function is often missing. Nevertheless, cognitive behavioural therapies or psychoeducational therapies aimed at reducing subsequent stress-mediated inflammation, restoring regular circadian cycles (i.e. sleep patterns) or dealing with fatigue-associated depression are especially relevant. Even therapies such as massage therapy, acupuncture, yoga, muscle relaxation or stress reduction based on mindfulness have been reported to be effective in reducing CRF.

Conclusion The number of elderly persons living with/surviving cancer is increasing. Ageing is associated with an increased prevalence of chronic diseases, decreased functional reserve in multiple organ systems and enhanced susceptibility to stress. Ageing and the concomitant presence of a condition of frailty may predispose to the presence of fatigue. CRF is a peculiarly debilitating condition characteristic of elderly cancer patient population and should be thoroughly investigated. First, an open communication among the older patient, family and health care team about CRF experience should be stimulated. Second, a regular monitoring of fatigue levels during and after cancer treatment should be advocated. Third, well-known causes of fatigue should be ruled out and treated. Fourth, a better understanding of the possible mechanisms involved in the genesis of CRF should guide tailored interventions. Fifth, further research concerning the specific role and effects of CRF in the elderly population should be strongly encouraged. Finally, an additional effort to refine the diagnostic criteria for CRF should be made. The criteria for cancer-related fatigue are based on the clinical experience of the members of the Fatigue Coalition. These criteria do not readily evaluate the chronic and persistent fatigue possibly experienced by persons prior to the diagnosis of cancer or by long-term cancer survivors. Acknowledgments The authors wish to thank Mrs Anna Vallerugo, MA, for her linguistic help in preparing the text. Conflict of interest The authors have declared no conflicts of interest.

Support Care Cancer (2013) 21:2899–2911

2907

Appendix

Table 3 List of CRF clinical studies Study

Sample

Age, years

Object of the study

De Jong et al. (2004) Prue et al. (2006) Wu and McSweeney (2007) Yavuzsen et al. (2009) Guralnik et al. (2004)

157 5,214 10

20–70; mean 47.3( SD 8.8) 20–89; 2266 pts were aged ≥60 30–73; mean 51.6

CRF prevalence CRF prevalence CRF assessment

16

48–82; median 62.5

CRF assessment

1,955

mean 75

Kuhnt et al. (2009) Denny et al. (2006) Extermann et al. (2002) Ferrucci et al. (2005) Ferrucci et al. (2006) Bohlius et al. (2009) Mohile et al. (2011) Mitchell et al. (2011) Morrow et al. (2003) Stockler et al. (2007) Spiegel et al. (1999) Caufriez et al. (2002) Badawy et al. (2005) Dinan et al. (1997)

646 1,744 59

22–89; mean 62.3 71–102; mean 78 (SD 5.42) 70–87; median 75

1,235 905 13,933 12,480 14,078 479 189 11 8 23 14

20–70; mean >67.5 Mean >73.8 Median 60.6 ≥65 Mean ≥60 in 4442 pts 23–87 132 patients were aged ≥60 18–27 21–33 21–55; mean 41 (SD 8.9) Mean 38 (SD 6.2)

Anaemia prevalence in the elderly population CRF prevalence Anaemia in CRF pathogenesis Predictors of tolerance to chemotherapy in the elderly population Anaemia in CRF pathogenesis Anaemia in CRF pathogenesis Anaemia in CRF pathogenesis Geriatric syndromes Depression and cancer: epidemiology Fatigue and depression Depression in CRF pathogenesis Sleep disorders in CRF pathogenesis Sleep disorders in CRF pathogenesis CFS CFS

Capuron et al. (2007) 12

Mean 49 (SD 9)

Del Priore et al. (1995) Morrow et al. (2002) Schmiegelow et al. (2003) Bower et al. (2005)

9

Not reported

Serotonin dysregulation in CRF pathogenesis HPA axis dysfunction in CRF pathogenesis

23 73

34–72; median 61 6.2–43.5; median 21.6

HPA axis dysfunction in CRF pathogenesis HPA axis dysfunction in CRF pathogenesis

29

Berger (1998)

72

Mean 58.2 (SD 7.3); mean 61.8 (SD 9.2) control group 30–69

Mormont et al. (1998) Petersen et al. (2003) Allman and Rice (2002) Petrella et al. (2005)

37

35–78

28 691

18–24 20–91

28 young patients 24 older patients Bierhaus et al. (2003) 19 Bower et al. (2011) 11 fatigued patients 10 no fatigued patients

Mean 26.9 (SD 0.7) 63.6 (SD 0.8) Mean 24.8 (SD 4.8) Mean 51.2 Mean 62.2

Circadian rhythm disruption in CRF pathogenesis Circadian rhythm disruption in CRF pathogenesis Circadian rhythm disruption in CRF pathogenesis Mitochondrial dysfunction Muscle metabolism dysregulation in CRF pathogenesis Muscle metabolism dysregulation in CRF pathogenesis Cytokine dysregulation in CRF pathogenesis Cytokine dysregulation in CRF pathogenesis

Luciani et al. (2008) Butt et al. (2010) Siegel et al. (2012) Giacalone et al. (2007)

214 738 35 122 elderly patients 52 young patients

70–89; mean 78 (SD 4.73) Mean 58.7 (SD 13.6) 56–88; mean 67 65–93; mean 72 18–40; mean 33

Functional dependence Fatigue prevalence Patient–clinician communication Patient–clinician communication

2908

Support Care Cancer (2013) 21:2899–2911

Table 3 (continued) Study

Sample

Age, years

Object of the study

Yellen et al. (1997) Aaronson et al. (1993) Knobel et al. (2003) Kaufman et al. (2002) Giacalone et al. (2008) Madhusudan et al. (2005) Madhusudan et al. (2004) Monk et al. (2006) Morrow et al. (2003) Kerr et al. (2012) Moraska et al. (2010) Yennurajalingam et al. (2011) Lower et al. (2009) Mar Fan et al. (2008)

50 Not reported

18–83; median 56 ≥18

Fatigue assessment scales Fatigue assessment scales

366 2,590

16–90 594 patients were aged ≥65

Fatigue assessment scales Patterns of medication use

112

65–93; mean 72

Patient–clinician–family communication

30

35–76

Pharmacological treatment

16

34–74

Pharmacological treatment

28 479 30 139 82

25–83; median 56 23–87 51–90 Mean 60 Median 55

Pharmacological treatment Pharmacological treatment Pharmacological treatment Pharmacological treatment Pharmacological treatment

152 57

Mean 52.8 (SD 9.3) 36–74

Pharmacological treatment Pharmacological treatment

Jean-Pierre et al. (2010) Blackhall et al. (2009) Spatis et al. (2009)

877

18–90; mean 60.5

Pharmacological treatment

27

Mean 60

Pharmacological treatment

20

53–81; median 74

Pharmacological treatment

Cruciani et al. (2009) Esquedo et al. (2011) Minton et al. (2011) Barsevick (2004) Graydon (1995) Cramp and Daniel (2008) Mock et al. (2005) Kangas et al. (2008)

39 100 426 396 99 2,083

Mean >66.5 Mean 62.7 (SD 12.1) Mean age range 50–71 18–83; mean 56.3 (SD 12.5) 25–77 Mean age range 39–69

Pharmacological treatment Pharmacological treatment Non-pharmacological interventions Non- pharmacological interventions Non-pharmacological interventions Non-pharmacological interventions

Goedendorp et al. (2009) Jacobsen et al. (2007)

234 30–69; mean 52 Not reported. A total of 248 studies Not reported were reviewed 3,324 Mean age range 40–70>55 in 1,840 patients 1,827 Not reported

Non-pharmacological interventions Fatigue non-pharmacological interventions Non-pharmacological interventions Non-pharmacological interventions

Focus on number of patients included and mean age at study recruitment CRF cancer-related fatigue, CFS chronic fatigue syndrome

References 1. Cella D, Peterman A, Passik S, Jacobsen P, Breitbart W (1998) Progress toward guidelines for the management of fatigue. Oncology 12:369–377 2. Portenoy RK, Itri LM (1999) Cancer-related fatigue: guidelines for evaluation and management. Oncologist 4:1–10 3. National Comprehensive Cancer Network: Cancer-related fatigue, version 1.2012. http://www.nccn.org/professionals/physicians/ PDF/fatigue.pdf. Accessed 4 Apr 2012 4. de Jong N, Candel MJ, Schouten HC, Abu-Saad HH, Courtens AM (2004) Prevalence and course of fatigue in breast cancer patients receiving adjuvant chemotherapy. Ann Oncol 15:896–905

5. Prue G, Rankin J, Allen J, Gracey J, Cramp F (2006) Cancerrelated fatigue: a critical appraisal. Eur J Cancer 42:846–863 6. Wu HS, McSweeney M (2007) Cancer-related fatigue: “It’s so much more than just being tired”. Eur J Oncol Nurs 11:117–125 7. Yavuzsen T, Davis MP, Ranganathan VK, Walsh D, Siemionow V, Kirkova J et al (2009) Cancer-related fatigue: central or peripheral? J Pain Symptom Manage 38:587–596 8. Butt Z, Rosenbloom SK, Abernethy AP, Beaumont JL, Paul D, Hampton D et al (2008) Fatigue is the most important symptom for advanced cancer patients who have had chemotherapy. J Natl Compr Canc Netw 6:448–455 9. Kuhnt S, Ernst J, Singer S, Rüffer JU, Kortmann RD, Stolzenburg JU et al (2009) Fatigue in cancer survivors: prevalence and correlates. Onkologie 32:312–317

Support Care Cancer (2013) 21:2899–2911 10. Giacalone A, Spina M, Berretta M, Tirelli U (2012) Two types of fatigue in cancer patients. BJC 106:424 11. Curt GA (2001) Fatigue in cancer. Brit Med J 322:1560 12. Wagner LI, Cella D (2004) Fatigue and cancer: causes, prevalence and treatment approaches. Br J Cancer 91:822–828 13. Nail LM (2004) My get up and go up and went: fatigue in people with cancer. JNCI Monogr 32:72–75 14. Guralnik JM, Eisenstaedt RS, Ferrucci L, Klein HG, Woodman RC (2004) Prevalence of anaemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anaemia. Blood 104:2263–2268 15. Denny SD, Kuchibhatla MN, Cohen HJ (2006) Impact of anaemia on mortality, cognition, and function in community-dwelling elderly. Am J Med 119:327–334 16. Extermann M, Chen H, Cantor AB, Corcoran MB, Meyer J, Grendys E et al (2002) Predictors of tolerance to chemotherapy in older cancer patients: a prospective pilot study. Eur J Cancer 38:1466–1473 17. Balducci L (2010) Anemia, fatigue and aging. Transfus Clin Biol 17:375–381 18. Mercuriali F, Inghilleri G (2001) Treatment of anaemia in cancer patients: transfusion of rHuEPO. In: Marty M, Pecorelli S (eds) Fatigue and cancer. European School of Oncology Scientific Updates, 5. Elsevier, Amsterdam, pp 185–200 19. Ferrucci L, Guralnik JM, Woodman RC, Bandinelli S, Lauretani F, Corsi AM et al (2005) Proinflammatory state and circulating erythropoietin in persons with and without anemia. Am J Med 118:1288 20. Nemeth E, Tuttle MS, Powelson J, Donovan A, Ward DM, Ganz T et al (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090– 2093 21. Stabler SP (2008) Prevalence and mechanisms of B12 deficiency. In: Balducci L, Ershler WH, DeGaetano G (eds) Blood disorders in the elderly. University Press, Cambridge, pp 181–191 22. Ferrucci L, Maggio M, Bandinelli S, Basaria S, Lauretani F, Ble A et al (2006) Low testosterone levels and the risk of anemia in older men and women. Arch Intern Med 166:1380–1388 23. Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J et al. (2009) Erythropoietin or darbepoetin for patients with cancer—meta-analysis based on individual patient data. Cochrane Database Syst Rev CD007303 24. Raison CL, Miller AH (2003) Depression in cancer: new developments regarding diagnosis and treatment. Biol Psychiatry 54:283–294 25. Mohile SG, Fan L, Reeve E, Mustian K, Peppone L, Janelsins M et al (2011) Association of cancer with geriatric syndromes in older Medicare beneficiaries. J Clin Oncol 29:1458–1464 26. Mitchell AJ, Chan M, Bhatti H, Halton M, Grassi L, Johansen C et al (2011) Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: a meta-analysis of 94 interview-based studies. Lancet Oncol 12:160–174 27. American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-Text Revision), 4th edn. APA, Washington 28. Cohen-Cole SA, Brown FW, McDaniel JS (1993) Diagnostic assessment of depression in the medically ill. In: Stoudemire A, Fogel B (eds) Psychiatric care of the medical patient. Oxford University Press, New York, pp 53–70 29. Reuter K, Härter M (2004) The concepts of fatigue and depression in cancer. Eur J Cancer Care 13:127–134 30. Morrow GR, Hickok JT, Roscoe JA, Raubertas RF, Andrews PL, Flynn PJ et al (2003) Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Centre Community Clinical Oncology Program. J Clin Oncol 21:4635–4641

2909 31. Stockler MR, O'Connell R, Nowak AK, Goldstein D, Turner J, Wilcken NR et al (2007) Effect of sertraline on symptoms and survival in patients with advanced cancer, but without major depression: a placebo-controlled double-blind randomised trial. Lancet Oncol 8:603–612 32. Fiorentino L, Ancoli-Israel S (2006) Insomnia and its treatment in women with breast cancer. Sleep Med Rev 10:419–429 33. Spiegel K, Leproult R, Van Cauter E (1999) Impact of sleep debt on metabolic and endocrine function. Lancet 354:1435–1439 34. Caufriez A, Moreno-Reyes R, Leproult R, Vertongen F, Van Cauter E, Copinschi G (2002) Immediate effects of an 8-h advance shift of the rest-activity cycle on 24-h profiles of cortisol. Am J Physiol Endocrinol Metab 282:E1147–E1153 35. Rao A, Cohen HJ (2004) Symptom management in the elderly cancer patient: fatigue, pain, and depression. J Natl Cancer Inst Monogr 32:150–157 36. Chaudhuri A, Behan PO (2004) Fatigue in neurological disorders. Lancet 363:978–988 37. Swain MG (2000) Fatigue in chronic disease. Clin Sci 99:1–8 38. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A (1994) The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 121:953–959 39. Andrews PL, Morrow GR, Hickok JT (2004) Mechanisms and models of fatigue associated with cancer and its treatment: Evidence of pre-clinical and clinical studies. In: Armes J, Krishnasamy M, Higginson I (eds) Fatigue in cancer. Oxford University Press, Oxford, pp 51–87 40. Fernstrom JD, Fernstrom MH (2006) Exercise, serum free tryptophan, and central fatigue. J Nutr 136:553S–559S 41. Badawy AA, Morgan CJ, Llewelyn MB, Albuquerque SR, Farmer A (2005) Heterogeneity of serum tryptophan concentration and availability to the brain in patients with the chronic fatigue syndrome. J Psychopharmacol 19:385–391 42. Blomstrand E (2006) A role for branched-chain amino acids in reducing central fatigue. J Nutr 136(2):544S–547S 43. Newsholme EA, Blomstrand E (1995) Tryptophan, 5hydroxytryptamine and a possible explanation for central fatigue. Adv Exp Med Biol 384:315–320 44. Chaouloff F, Elghozi JL, Guezennec Y, Laude D (1985) Effects of conditioned running on plasma, liver and brain tryptophan and on brain 5-hydroxytryptamine metabolism of the rat. Br J Pharmacol 86:33–41 45. Blomstrand E, Hassmén P, Newsholme EA (1991) Effect of branched-chain amino acid supplementation on mental performance. Acta Physiol Scand 143:225–226 46. Mittleman KD, Ricci MR, Bailey SP (1998) Branched-chain amino acids prolong exercise during heat stress in men and women. Med Sci Sports Exerc 30:83–91 47. Strüder HK, Hollmann W, Platen P, Donike M, Gotzmann A, Weber K (1998) Influence of paroxetine, branched-chain amino acids and tyrosine on neuroendocrine system responses and fatigue in humans. Horm Metab Res 30:188–194 48. Davis JM, Bailey SP (1997) Possible mechanisms of central nervous system fatigue during exercise. Med Sci Sports Exerc 29:45–57 49. Dinan TG, Majeed T, Lavelle E, Scott LV, Berti C, Behan P (1997) Blunted serotonin-mediated activation of the hypothalamic–pituitary– adrenal axis in chronic fatigue syndrome. Psychoneuroendocrinology 22:261–267 50. Morrow GR, Andrews PL, Hickok JT, Roscoe JA, Matteson S (2002) Fatigue associated with cancer and its treatment. Support Care Cancer 10:389–398 51. Capuron L, Pagnoni G, Demetrashvili MF, Lawson DH, Fornwalt FB, Woolwine B et al (2007) Basal ganglia hypermetabolism and

2910

52.

53.

54.

55.

56.

57. 58.

59.

60.

61.

62.

63. 64.

65.

66.

67. 68.

69. 70. 71.

72.

Support Care Cancer (2013) 21:2899–2911 symptoms of fatigue during interferon-alpha therapy. Neuropsychopharmacology 32:2384–2392 Zhu CB, Blakely RD, Hewlett WA (2006) The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology 31:2121– 2131 Shanks N, Harbuz MS, Jessop DS, Perks P, Moore PM, Lightman SL (1998) Inflammatory disease as chronic stress. Ann N Y Acad Sci 840:599–607 Del Priore G, Gurski KJ, Warshal DP, Angel C, Dubeshter B (1995) Adrenal function following high-dose steroids in ovarian cancer patients. Gynecol Oncol 59:102–104 Morrow GR, Hickok JT, Andrews PL, Stern RM (2002) Reduction in serum cortisol after platinum based chemotherapy for cancer: a role for the HPA axis in treatment-related nausea? Psychophysiology 39:491–495 Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, Lange M, Poulse HS, Müller J (2003) Assessment of the hypothalamuspituitary-adrenal axis in patients treated with radiotherapy and chemotherapy for childhood brain tumour. J Clin Endocrinol Metab 88:3149–3154 Cleare AJ (2003) The neuroendocrinology of chronic fatigue syndrome. Endocr Rev 24:236–252 Petrovsky N, McNair P, Harrison LC (1998) Diurnal rhythms of proinflammatory cytokines: regulation by plasma cortisol and therapeutic implications. Cytokine 10:307–312 Vgontzas AN, Chrousos GP (2002) Sleep, the hypothalamic-pituitaryadrenal axis, and cytokines: multiple interactions and disturbances in sleep disorders. Endocrinol Metab Clin North Am 31:15–36 McDaniel JS, Musselman DL, Porter MR, Reed DA, Nemeroff CB (1995) Depression in patients with cancer. Diagnosis, biology, and treatment. Arch Gen Psychiatry 52:89–99 Sephton S, Spiegel D (2003) Circadian disruption in cancer: a neuroendocrine-immune pathway from stress to disease? Brain Behav Immun 17:321–328 Bower JE, Ganz PA, Dickerson SS, Dickerson SS, Petersen L, Aziz N et al (2005) Diurnal cortisol rhythm and fatigue in breast cancer survivors. Psychoneuroendocrinology 30:92–100 Berger AM (1998) Patterns of fatigue and activity and rest during adjuvant breast cancer chemotherapy. Oncol Nurs Forum 25:51–62 Mormont MC, Hecquet B, Bogdan A, Benavides M, Touitou Y, Levi F (1998) Non-invasive estimation of the circadian rhythm in serum cortisol in patients with ovarian or colorectal cancer. Int J Cancer 78:421–424 Giordano A, Calvani M, Petillo O, Carteni' M, Melone MR, Peluso G (2003) Skeletal muscle metabolism in physiology and in cancer disease. J Cell Biochem 90:170–186 Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL et al (2003) Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300:1140–1142 Allman BL, Rice CL (2002) Neuromuscular fatigue and aging: central and peripheral factors. Muscle Nerve 25:785–796 Petrella JK, Kim JS, Tuggle SC, Hall SR, Bamman MM (2005) Age differences in knee extension power, contractile velocity, and fatigability. J Appl Physiol 98:211–220 Wilson MM, Morley JE (2003) Invited review: aging and energy balance. J Appl Physiol 95:1728–1736 Dantzer R (2001) Cytokine-induced sickness behavior: mechanisms and implications. Ann N Y Acad Sci 933:222–234 Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G (2006) Inflammation and cancer: how hot is the link? Biochem Pharmacol 72:1605–1621 Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D et al (2003) A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci USA 100:1920–1925

73. Dunn AJ, Wang J, Ando T (1999) Effects of cytokines on cerebral neurotransmission. Comparison with the effects of stress. Adv Exp Med Biol 461:117–127 74. Johnson JD, Campisi J, Sharkey CM, Kennedy SL, Nickerson M, Greenwood BN et al (2005) Catecholamine mediate stressinduced increases in peripheral and central inflammatory cytokines. Neuroscience 135:1295–1307 75. Bower JE, Ganz PA, Irwin MR, Arevalo JM, Cole SW (2011) Fatigue and gene expression in human leukocytes: increased NFκB and decreased glucocorticoid signalling in breast cancer survivors with persistent fatigue. Brain Behav Immun 25:147–150 76. Luciani A, Jacobsen PB, Extermann M, Foa P, Marussi D, Overcash JA et al (2008) Fatigue and functional dependence in older cancer patients. Am J Clin Oncol 31:424–430 77. Butt Z, Rao AV, Lai JS, Abernethy AP, Rosenbloom SK, Cella D (2010) Age-associated differences in fatigue among patients with cancer. J Pain Symptom Manage 40:217–223 78. Bergman H, Ferrucci L, Guralnik J, Hogan DB, Hummel S, Karunananthan S et al (2007) Frailty: an emerging research and clinical paradigm—issues and controversies. J Gerontol A Biol Sci Med Sci 62:731–737 79. Buchner DM, Wagner EH (1992) Preventing frail health. Clin Geriatr Med 8:1–17 80. Fried LP, Walston J (2003) Frailty and failure to thrive. In: Hazzard WR, Blass JP, Ettinger WH (eds) Principles of geriatric medicine and gerontology. McGraw-Hill, New York, pp 1487–1502 81. Siegel K, Lekas HM, Maheshwari D (2012) Causal attributions for fatigue by older adults with advanced cancer. J Pain Symptom Manage 44:52–63 82. Giacalone A, Blandino M, Talamini R, Bortolus R, Spazzapan S, Valentini M et al (2007) What elderly cancer patients want to know? Differences among elderly and young patients. PsychoOncology 16:365–370 83. Wu HS, McSweeney M (2001) Measurement of fatigue in people with cancer. Oncol Nurs Forum 28:1371–1384 84. Minton O, Stone P (2009) A systematic review of the scales used for the measurement of cancer-related fatigue (CRF). Ann Oncol 20:17–25 85. Yellen SB, Cella DF, Webster K, Webster K, Blendowski C, Kaplan E (1997) Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 13:63–74 86. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ et al (1993) The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365–376 87. Knobel H, Loge JH, Brenne E, Fayers P, Hjermstad MJ, Kaasa S (2003) The validity of EORTC QLQ-C30 fatigue scale in advanced cancer patients and cancer survivors. Palliat Med 17:664–672 88. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA (2002) Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 287:337–344 89. Giacalone A, Talamini R, Spina M, Fratino L, Spazzapan S, Tirelli U (2008) Can the caregiver replace his/her elderly cancer patient in the physician–patient line of communication? Support Care Cancer 16:1157–1162 90. Minton O, Richardson A, Sharpe M, Hotopf M, Stone PC (2011) Psycho-stimulants for the management of cancer-related fatigue: a systematic review and meta-analysis. J Pain Symptom Manage 41:761–767 91. Barsevick AM, Dudley W, Beck S, Sweeney C, Whitmer K, Nail L (2004) A randomized clinical trial of energy conservation for patients with cancer-related fatigue. Cancer 100:1302–1310

Support Care Cancer (2013) 21:2899–2911 92. Graydon JE, Bubela N, Irvine D, Vincent L (1995) Fatiguereducing strategies used by patients receiving treatment for cancer. Cancer Nurs 18:23–28 93. Cramp F, Daniel J (2008) Exercise for the management of cancerrelated fatigue in adults. Cochrane Database Syst Rev CD006145 94. Dimeo FC (2001) Effects of exercise on cancer-related fatigue. Cancer 92:1689–1693 95. Mock V, Frangakis C, Davidson NE, Ropka ME, Pickett M, Poniatowski B et al (2005) Exercise manages fatigue during breast cancer treatment: a randomized controlled trial. Psychooncol 14:464–477 96. Kangas M, Bovbjerg DH, Montgomery GH (2008) Cancerrelated fatigue: a systematic and meta-analytic review of non-pharmacological therapies for cancer patients. Psychol Bull 134:700–741 97. Goedendorp MM, Gielissen MF, Verhagen CA, Bleijenberg G (2009) Psychosocial interventions for reducing fatigue during cancer treatment in adults. Cochrane Database Syst Rev CD006953 98. Jacobsen PB, Donovan KA, Vadaparampil ST, Small BJ (2007) Systematic review and meta-analysis of psychological and activity-based interventions for cancer-related fatigue. Health Psychol 26:660–667 99. Madhusudan S, Muthuramalingam SR, Braybrooke JP, Wilner S, Kaur K, Han C et al (2005) Study of etanercept, a tumour necrosis factor-alpha inhibitor, in recurrent ovarian cancer. J Clin Oncol 23:5950–5959 100. Madhusudan S, Foster M, Muthuramalingam SR, Braybrooke JP, Wilner S, Kaur K et al (2004) A phase II study of etanercept (Enbrel), a tumour necrosis factor alpha inhibitor in patients with metastatic breast cancer. Clin Cancer Res 10:6528–6534 101. Monk JP, Phillips G, Waite R, Kuhn J, Schaaf LJ, Otterson GA et al (2006) Assessment of tumour necrosis factor alpha blockade as an intervention to improve tolerability of dose-intensive chemotherapy in cancer patients. J Clin Oncol 24:1852–1859 102. Morrow GR, Hickok JT, Roscoe JA, Raubertas RF, Andrews PL, Flynn PJ et al (2003) Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Centre Community Clinical Oncology Program. J Clin Oncol 21:4635–4641 103. Kuipers SD, Bramham CR (2006) Brain-derived neurotrophic factor mechanisms and function in adult synaptic plasticity: new insights and implications for therapy. Curr Opin Drug Discov Devel 9:580–586

2911 104. Kerr CW, Drake J, Milch RA, Brazeau DA, Skretny JA, Brazeau GA et al (2012) Effects of methylphenidate on fatigue and depression: a randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage 43:68–77 105. Moraska AR, Sood A, Dakhil SR, Sloan JA, Barton D, Atherton PJ et al (2010) Phase III, randomized, double-blind, placebocontrolled study of long-acting methylphenidate for cancerrelated fatigue: North Central Cancer Treatment Group NCCTGNo5C7 Trial. J Clin Oncol 28:3673–3679 106. Yennurajalingam S, Palmer JL, Chacko R, Bruera E (2011) Factor associated with response to methylphenidate in advanced cancer patients. Oncologist 16:246–253 107. Lower EE, Fleishman S, Cooper A, Zeldis J, Faleck H, Yu Z et al (2009) Efficacy of dexmethylphenidate for the treatment of fatigue after cancer chemotherapy: a randomized clinical trial. J Pain Symptom Manage 38:650–662 108. Mar Fan HG, Clemons M, Xu W, Chemerynsky I, Beunis H, Braganza S et al (2008) A randomized, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer. Support Care Cancer 16:577–583 109. Jean-Pierre P, Morrow GR, Roscoe JA, Heckler C, Mohile S, Janelsins M et al (2010) A phase 3 randomized, placebocontrolled, double-blind, clinical trial of the effect of modafinil on cancer-related fatigue among 631 patients receiving chemotherapy: a University of Rochester Cancer Center Community Clinical Oncology Program Research base study. Cancer 116:3513–3520 110. Blackhall L, Petroni G, Shu J, Baum L, Farace E (2009) A pilot study evaluating the safety and efficacy of modafinil for cancerrelated fatigue. J Palliat Med 12:433–439 111. Spatis A, Dhillan R, Booden D, Forbes K, Vrotsou K, Fife K (2009) Modafinil for the treatment of fatigue in lung cancer: a pilot study. Palliat Med 23:325–331 112. Cruciani RA, Dvorkin E, Homel P, Culliney B, Malamud S, Lapin J et al (2009) L-carnitine supplementation in patients with advanced cancer and carnitine deficiency: a double-blind, placebocontrolled study. J Pain Symptom Manage 37:622–631 113. Esquedo G, Llorca C, Cervera JM, Orts D, Juárez A, Carrato A (2011) Effectiveness of darbepoetin alfa in a color of oncology patients with chemotherapy-induced anemia. Relationship between variation in three fatigue-specific quality of life questionnaire scores and change in hemoglobin level. Clin Transl Oncol 13:341–347