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Muscle dysfunction in cancer patients
Annals of Oncology Advance Access published January 8, 2014
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Annals of Oncology 00: 1–12, 2014 doi:10.1093/annonc/mdt551
Muscle dysfunction in cancer patients J. F. Christensen1,2, L. W. Jones3, J. L. Andersen4,5, G. Daugaard2, M. Rorth2 & P. Hojman6* 1 The University Hospitals Centre for Health Care Research (UCSF); 2Department of Oncology, Copenhagen University Hospital, Copenhagen, Denmark; 3Duke Cancer Institute, Durham, USA; 4Department of Orthopaedic Surgery M, Institute of Sports Medicine, Bispebjerg Hospital, Copenhagen; 5Centre for Healthy Ageing, Faculty of Health Sciences, University of Copenhagen, Copenhagen; 6Centre for Inflammation and Metabolism, Copenhagen University Hospital, Copenhagen, Denmark
Received 27 May 2013; revised 18 July 2013 and 4 October 2013; accepted 12 November 2013
introduction Skeletal muscle is the largest organ in the human body, constituting 40%–50% of total body mass in healthy nonobese humans [1]. Skeletal muscle function is classically defined as the ability to perform muscular contractions, generating external mechanical force, which enables physical activities of daily living and exercise. In addition, skeletal muscle plays a vital role in primary and secondary disease prevention as an essential regulator of metabolic and inflammatory homeostasis [2]. Indeed, substantial evidence shows that muscle function, defined as strength or muscle composition (muscle mass or size), in healthy individuals is a strong independent predictor of all-cause-, cancer- and cardiovascular disease (CVD) mortality risk [3].
*Correspondence to: Dr Pernille Hojman, Centre for Inflammation and Metabolism, Copenhagen University Hospital, Blegdamsvej 9, 7641, DK-2100 Copenhagen, Denmark. Tel: +45-35-45-75-44; Fax: +45-35-45-75-41; E-mail: phojman@inflammationmetabolism.dk
Within oncology, interest in muscle function has traditionally been confined to the clinical entity of cancer cachexia, which is characterized by severe muscle wasting, systemic inflammation [4] and malnutrition [5] in patients with advanced stage disease [6]. But emerging evidence shows that decreased muscle mass (sarcopenia [7]) is a prevalent condition in cancer patients regardless of disease stage [8] and nutritional status [9], and is associated with higher mortality rates in both advanced stage [10, 11] and early-stage patients [12]. The reports of skeletal muscle as a prognostic factor emphasize the need for a better understanding of the complex etiology of muscle dysfunction in the oncology setting, and the need for effective therapeutic countermeasures in clinical practice. Exercise training constitutes a potent modulator of skeletal muscle function, and growing evidence suggests that exercise is a safe, feasible and effective therapeutic strategy with the capacity to mitigate and/or reverse muscle dysfunction in patients with cancer. Here, we review the current evidence describing the degree, causes and clinical implications of muscle dysfunction in cancer
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Background: Muscle dysfunction is a prevalent phenomenon in the oncology setting where patients across a wide range of diagnoses are subject to impaired muscle function regardless of tumor stage and nutritional state. Here, we review the current evidence describing the degree, causes and clinical implications of muscle dysfunction in cancer patients. The efficacy of exercise training to prevent and/or mitigate cancer-related muscle dysfunction is also discussed. Design: We identified 194 studies examining muscular outcomes in cancer patients by searching PubMed and EMBASE databases. Results: Muscle dysfunction is evident across all stages of the cancer trajectory. The causes of cancer-related muscle dysfunction are complex, but may involve a wide range of tumor-, therapy- and/or lifestyle-related factors, depending on the clinical setting of the individual patient. The main importance of muscle dysfunction in cancer patients lies in the correlation to vital clinical end points such as cancer-specific and all-cause mortality, therapy complications and quality of life (QoL). Such associations strongly emphasize the need for effective therapeutic countermeasures to be developed and implemented in oncology practice. Significant progress has been made over the last decade in the field of exercise oncology, indicating that exercise training constitutes a potent modulator of skeletal muscle function in patients with cancer. Conclusion: There are clear associations between muscle dysfunction and critical clinical end points. Yet there is a discrepancy between timing of exercise intervention trials, which can improve muscle function, and study populations in whom muscle function are proven prognostic important for clinical end points. Thus, future exercise trials should in earlystage patients, be powered to evaluate clinical outcomes associated with improvements in muscle function, or be promoted in advanced stage settings, aiming to reverse cancer-related muscle dysfunction, and thus potentially improve time-to-progression, treatment toxicity and survival. Key words: skeletal muscle, muscle strength, muscle mass, cancer, exercise
review patients. Moreover, we will discuss the potential of exercise training to mitigate or reverse muscle dysfunction.
search strategy A comprehensive search of the literature was conducted in the PubMed (NIH), Medline and EMBASE databases (January 1966 to March 2013) using keyword combinations of the medical subject headings (MeSH) ‘body composition’, ‘muscle, skeletal’, ‘muscular atrophy’, ‘muscle function’, ‘muscle strength’, ‘exercise’, ‘cancer’, ‘neoplasms’. Relevant reference lists were also manually searched. The search was confined to include independent studies in adults diagnosed with solid malignancies, thus studies on childhood cancers and hematological diseases were excluded (Table 1).
Muscle contraction is a central feature of muscle function, enabling locomotor activity and metabolic control through the production of external force and induction of glucose uptake and other metabolic processes in the contracting muscles [13]. The exertion of muscle contraction is measured as muscle strength. Muscles are composed of individual muscle fibers, which are characterized by their size, twitch velocity and metabolic phenotype. Together the composition plays a central role for regulation of voluntary function (muscle contraction) and nonvoluntary functions (e.g. muscle metabolism). Against this background, we adopt the following organizing framework to evaluate the available evidence of muscle function defined by (i) muscle strength and (ii) muscle composition. The latter may be evaluated on three levels: (I) whole-body level (whole-body muscle mass), (II) single muscle (group) level (muscle/muscle group size or volume) and (III) muscle fiber level ( phenotypic characteristics; i.e. morphology, cellular signaling and gene expression profile). Accordingly, we define ‘cancer-related muscle dysfunction’, as any measurable impairment in muscle strength or muscle composition independent of the underlying cause in patients diagnosed with cancer. Table 2 provides a summary of commonly applied methods, which directly assess muscle strength or composition in humans. In brief, contractile muscle function can be measured by isometric or isokinetic force/torque or more pragmatic methods including repetition maximum (RM) tests or handgrip strength. Wholebody muscle mass can be measured by body composition assessments including dual-energy X-ray absorptiometry (DXA) scans or bioelectrical impendence. Single muscle (or muscle group) size or volume is measured via cross-sectional area (CSA) assessments by imaging modalities, i.e. computerized topography (CT), magnetic resonance imaging (MRI) or ultrasonography. For assessment of cellular muscle structure, muscle tissue biopsying is a valuable method allowing for detailed assessment of muscle fiber morphology, biochemical indices and gene expression profiles.
muscle dysfunction in cancer patients In total, we identified 194 independent clinical studies (supplementary appendix, available at Annals of Oncology online,
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Table 1), which reported measures of muscle function in adult cancer patients across more than 15 diagnoses, and different disease phases (before-, during- or after primary cancer therapy) and tumor stages (early- or advanced stage disease). Below we summarize these studies, focusing on the degree, causes and clinical implications of muscle dysfunction in cancer patients.
degree of muscle dysfunction muscle strength. The majority of studies reporting muscle strength have used one RM measurement ( predominantly in exercise intervention trials) or assessment of handgrip strength. Collectively, the studies indicate that cancer patients have significant impairments in muscle strength regardless of disease stage, when compared with healthy controls matched by age, sex, BMI and/or physical activity level. For example Burden et al. [14] found that 54% of newly diagnosed early-stage colorectal patients had a handgrip strength, which was below 85% of the age-matched reference range. In accordance, patients with locally advanced prostate cancer undergoing androgen deprivation therapy (ADT), which lowers bioavailable testosterone, had 29% lower handgrip strength compared with healthy controls [15]. Furthermore, breast cancer survivors evaluated after completion of primary therapy displayed consistently lower muscle strength (20%–30%) in seven different upper body exercises compared with healthy individuals [16]. Finally, evidence of late effects on muscle strength has been shown in adult survivors of childhood cancers. For example Ness et al. [17] found that 18% survivors of extracranial solid tumors, assessed a median of 25 years after diagnosis, displayed muscle weakness, defined as the dorsiflexion torque within the lowest 10th percentile compared with healthy age-matched reference subjects. muscle composition. Consistent with the reports of decreased muscle strength, putative evidence demonstrates changes in muscle composition across diagnoses and disease phases. whole-body level: The vast majority of studies identified by our search, reported data on whole-body muscle mass assessed by DXA scan or bioelectrical impendence. For example a crosssectional study of 714 newly diagnosed patients with mixed diagnoses (i.e. lung, gastric, esophagus, colorectal or pancreas cancer) found that cancer patients had 0.9 kg lower muscle mass compared with healthy controls [18], before initiation of antineoplastic therapy. Moreover, during the course of adjuvant chemotherapy early-stage breast cancer patients lost 1.3 kg lean body mass, and continued to lose lean body mass after therapy completion [19]. In comparison, early-stage prostate cancer patients on long-term (>6 months) ADT had ∼2.5 kg lower muscle mass (reported as 4.5% lower lean body mass) compared with healthy BMI-matched controls [20], while metastatic prostate cancer patients, who were weight stabile during 12 months of ADT, lost 11.8 kg lean body mass [21]. single muscle level: Most studies reporting muscle composition at the single muscle/muscle group level have used diagnostic CT scans to measure ‘muscle index’ (muscle area in the third lumbar [L3] vertebrae region normalized by height). By such method, Prado et al. [8] evaluated prevalence of sarcopenia among 441 newly diagnosed obese patients with cancer of
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Table 1. Characteristics of reviewed studies All studies (N = 194)
Number of cancer patients and mean age All patients Female patients Male patients Sex not reported Age Number of patients by cancer site Breast cancer Prostate cancer Colorectal cancer Gastric cancer Lung cancer Pancreas cancer Head and neck cancer Liver cancer Esophagus cancer Gynecological cancer Genitourinary cancer Renal cell cancer Primary glioma Other cancers Number of patients by setting Point of diagnosis (before cancer therapy) During systemic therapy Off systemic therapy/palliation
Intervention studies (N = 74)
38 59 28 16 13 12 11 5 4 2 2 4
22 24 20 16 8 10 8 3 3 1 2 3
16 35 8 0 5 2 3 2 1 1 0 1
37 86 14 41 16
37 52 6 10 15
0 34 8 31 1
108 50 31 5
59 29 27 5
49 21 4 0
125 69
52 68
74 0
145 49
73 47
72 2
16 307 8400 6610 1297 60.1 ± 7.8
9988 4097 4660 1231 61.3 ± 7.4
6319 4303 1950 66 58.2 ± 8.1
5196 2414 1996 1525 1524 1144 485 382 359 299 119 100 64 700
1940 1963 1590 1160 1009 723 290 256 322 90 97 20 59 469
3256 451 406 365 515 421 195 126 37 209 22 80 5 231
3696 5501 2705
3696 2959 1446
0 2542 1259 Continued
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Number of studies by cancer site Mixed cancer population Breast cancer Prostate cancer Cancer of the upper gastrointestinal tract Lung cancer Colorectal cancer Pancreas cancer Head and neck cancer Gynecological cancer Genitourinary cancer Primary glioma Others cancers Number of studies by setting Point of diagnosis (before cancer therapy) During systemic therapy Off systemic therapy/palliation Post-therapy survivors Mixed Number of studies by disease stage Early-stage/operable Advanced stage/inoperable Mixed Not reported Cross-sectional or longitudinal assessments Longitudinal Cross-sectional Healthy/noncancer reference group included No Yes
Observational studies (N = 120)
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Table 1. Continued All studies (N = 194) Post-therapy survivors Mixed Number of patients by disease stage Early-stage/operable Advanced stage/inoperable Not reported
Observational studies (N = 120)
Intervention studies (N = 74)
3479 926
983 904
2496 22
8886 6166 1255
5082 3745 1161
3804 2421 94
Data includes the accumulated number of studies or number of patients for each parameter except for age, which is predicted as mean ± standard deviation for all studies.
muscle fiber level: Evaluation of dysfunctional features at the cellular level can be carried out through histological or molecular analyses of muscle biopsies. In newly diagnosed cancer patients undergoing intrathoracic surgery, primarily for GI cancer, muscle biopsies show significant upregulation of muscle degradation pathways such as ubiquitin ligases [23], calpain activity [24] and myostatin [25] compared with patients, who were operated for nonmalignant diseases. In advanced stage patients, Weber et al. [26] found severe reductions (40%–50%) in myofiber size primarily in Type IIx fibers.
causes of muscle dysfunction Whether muscle dysfunction should be considered an intrinsic part of a cancer disease or a generalized response to multiple atrophic stimuli can be debated. Commonly, all cancer patients are subjected to a wide range of cancer-specific and noncancerspecific degenerative factors, which are all potent causes of muscle dysfunction including aging, malnutrition, physical inactivity and factors directly related to disease pathophysiology and therapy toxicity. age and co-morbidities. The incidence of cancer increases with age, and more than 50% of all newly diagnosed cancer patients are older than 65 years [27]. An age-related decline in muscle mass is observed from the end of the fifth decade and has been estimated to 1.9 kg per decade for men and 1.1 kg per decade for women [28]. Biopsy studies have shown that the age-related loss in muscle mass is primarily driven by selective loss of Type II muscle fibers [29], possibly caused by progressive denervation and motorneuron failure [30]. Depending on diagnosis between 30% and 80% of all patients present with other age-related co-morbidities (e.g. Type II diabetes or CVD), which may
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contribute to the aging effects through low-grade inflammation, impaired metabolism and deconditioning [31]. malnutrition. Malnutrition is a major problem, particularly in patients diagnosed with head and neck, GI tract, pancreas and lung cancer. A recent study in 1453 oncology outpatients with mixed diagnoses, reported that 32% were at ‘high nutritional risk’ (a score ≥ 3 on The Nutritional Risk Screening [NRS 2002]) [32]. The underlying causes may include decreased central drive to eat, chemosensory disturbances (taste and smell), decreased upper GI motility, nausea and constipation. In an energy-depleted state, muscle protein serves as the primary reservoir of circulating amino acids, resulting in net release from the muscles [33]. In accordance, progressive muscle dysfunction has been reported in malnourished colorectal cancer patients, who had 29% lower handgrip strength and 12.2 kg lower wholebody muscle mass, but the same level of fat mass compared with well-nourished patients [14]. physical inactivity. Patients diagnosed with cancer often reduce their daily physical activity. Most profoundly following major surgery, where prolonged bed rest can cause muscle dysfunction as seen in elderly men, whom following 10 days bed rest had a 16% decline in isokinetic muscle strength and a loss of 1.5 kg whole-body muscle mass, including 1 kg from the lower extremities [34]. Adverse effects like pain, physical weakness or therapy toxicity can furthermore reduce daily physical activity. A recent study found that patients receiving neoadjuvant chemotherapy or radiotherapy walked ∼4000 steps per day, compared with 9000 steps in healthy controls [35]. In accordance, breast cancer patients undergoing adjuvant chemotherapy reduced their daily energy expenditure from 514 to 461 kcal during therapy, which was associated with a loss of 0.4 kg muscle mass [36]. tumor-derived factors. The direct tumor-derived impact on muscle tissue has been extensively studied in preclinical models demonstrating roles for tumor-induced inflammation and altered metabolism (reviewed in [37–39]). Studies in mice with large tumor burden show that proinflammatory cytokines like TNF-α, IL1-β and IFN-γ are derived from the tumor, resulting in increased systemic inflammation. This systemic inflammation can activate NF-κβ signaling in muscles, inducing transcription
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gastrointestinal (GI) or respiratory tracts, and found that 15.2% of all patients were sarcopenic [8]. Interestingly, these patients did not report a prediagnostic weight loss, and presence of sarcopenia was not associated with disease stage. In a prospective study of patients with esophagus or gastric cancer, 100 days of neoadjuvant chemotherapy resulted in a 10-cm2 reduction in L3 muscle area [22], increasing the prevalence of sarcopenia from 57% to 78% in this population.
Measurement Muscle contraction Muscle strength
Muscle composition Whole-body levelc
Data outcome
Defined cutoff points
Advantages
Limitations
• •
Isokinetic/isometric Maximum voluntary contraction test
• •
Force (Newton) Torque (Newton meter)
•
•
•
Expensive test equipment
•
Repetition maximum (RM) tests
•
Mass (kg)
•
Gold standard strength testing procedure Possible use of interpolation twitch technique (for assessment of central fatigue) Can be carried out for most muscle/muscle groups
•
Strong risk of praxis adaptation
•
Handgrip strength test
• •
Mass (kg) Force (Newton)
•
Mobile equipment (dynamometer)
•
Limited muscle mass activated
•
DXA scan
• • • • • • • •
Muscle mass (kg) Fat mass (kg) Fat percentage (% body mass) Bone density (g/cm2) Bone mass (kg) Muscle mass (kg) Fat mass (kg) Bone mass (kg)
Sarcopenia defined by handgrip strengthb: Male < 30 kg Female < 20 kg • Sarcopenia defined by appendicular skeletal muscle mass normalized by height$b: Men < 7.26 kg/m2 Women < 5.45 kg/m2
•
•
•
Gold standard method for whole-body composition assessment Precise bone-density measure
Extracellular fluid overestimate muscle mass Radiation dose (minor)
•
Sarcopenia defined by wholebody muscle mass normalized by heightb: Men < 8.87 kg/m2 Women < 6.42 kg/m2
• • •
Inexpensive, mobile equipment Easy procedure No radiation
•
Less accurate compared with DXA scan
• •
CSA (cm2) Muscle index (cm2/m2)—CSA in third lumbar vertebrae (L3) region normalized by height
•
Sarcopenia defined by Muscle indexa:Male < 55.4 cm2/ m2Female < 38.9 cm2/m2
•
Gold standard segmental assessment Diagnostic procedure Distinction between muscle, fat, bone and other organs.
• •
Estimated whole-body measure Expensive, immobile equipment γ-Radiation
CSA (cm2)
•
Not defined
•
Gold standard segmental assessment Distinction between muscle, fat, bone, other organs No radiation Less expensive, more mobile than MRI scan Distinction between muscle and fat
• •
Estimated whole-body measure Expensive, immobile equipment
•
Less accurate compared with MRI scan
•
Single muscle/ muscle group level
•
•
Bioelectrical impendence
CT scan
MRI scan
•
Not defined
• Not defined
•
• •
• Ultrasonography
•
Muscle volume (cm3)
•
Not defined
• • •
•
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•
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Table 2. Common assessments methods for evaluation of muscle function in clinical and research praxis
Sampling errors Invasive procedure: discomfort/ pain Risk of infections
b
a
Morphology Enzyme activity Transport proteins Intracellular signaling Gene expression Muscle biopsy
• Muscle fiber-level composition
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Cutoff values from Prado et al. [59]. Cutoff values from Cruz-Jentoft et al. [7]. c Other indirect methods including assessment of ‘Total Body Nitrogen (TBN)’, ‘air-displacement plethysmography’ and ‘skin-fold thickness’ are not described here. DXA, dual-energy X-ray absorptiometry; CT, computerized topography; MRI, magnetic resonance imaging; CSA, cross-sectional area.
• • Single myofiber assessment
• • • • • • •
Not defined
Defined cutoff points Data outcome Methods Measurement
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of the ubiquitin ligases, Atrogin-1 and Murf1 and muscle protein degradation [40, 41]. Induction of these pathways has also been reported in muscle biopsies from newly diagnosed cancer patients. The mRNA levels correlated with tumor stage but not preillness weight loss [42], indicating that tumor burden directly initiates early phases of muscle degradation, which is present before muscle wasting is detectable [43]. In addition to tumor-derived inflammation, most tumors are highly metabolically active with glycolysis as the main energygenerating pathway [44]. To meet the substrate need for the high glycolytic rate, tumors take up large amounts of glucose, competing directly for the energy availability with other glucosedependent tissues [45]. Moreover, recent studies have shown that tumors are also largely dependent on supply of glutamine. This requirement for amino acids might through unidentified mechanisms accelerate protein degradation in the muscles. cancer therapy. Cancer management typically involves combinations of locoregional and/or systemic therapies, which potentially impact nontargeted tissues [46]. Very few studies have investigated the direct effects of cancer therapy on muscle function, least of all compared the effects of different treatment regimens. Nonetheless, surgery and/or radiotherapy can affect the structural integrity of skeletal musculature in the anatomical treated regions. For example women treated for early-stage breast cancer experience markedly impaired muscle strength in the affected side compared with the nonaffected side [47]. Moreover, systemic cancer therapies greatly influence muscle composition. For example Hamilton et al. [48] found that prostate cancer patients receiving ADT lost 1.8 kg muscle mass during the first 6 months of therapy despite an overall weight gain. Advanced stage colorectal cancer patients treated with the VEGF receptor inhibitor Bevacizumab for 3 months reduced L3 muscle area by 3 cm2/m2 equivalent to ∼1 kg muscle mass [49], which was independent of tumor progression. Likewise, biopsies taken before and after a 50-day period of chemotherapy with doxorubicin (DOX) or melphalan in patients with melanoma or sarcoma showed severe reductions in myofiber size, neurogenic alterations and mitochondria-related damages [50]. In line with this, preclinical studies show that DOX decrease maximal twitch force and impair relaxation, associated with intracellular Ca2+ accumulation in the muscles [51]. supportive care medication. Supportive care medications like glucocorticoids are frequently administrated concomitant to systemic antineoplastic therapy. These drugs counteract therapy-induced adverse events like nausea and pain through anti-inflammatory effects, but they also have considerable impact on muscle composition and metabolism. Eight days of prednisone use in healthy young men caused significant insulin resistance, evident by a 65% lower insulin-stimulated glucose uptake compared with placebo users [52]. Moreover, long-term use of glucocorticoids is associated with muscle wasting and weakness [53].
clinical implications of muscle dysfunction Muscle function is a strong independent predictor of all-cause, CVD- and cancer mortality [3], morbidity [54] and QoL [55] in
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Advantages
Limitations
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noncancer populations. Although not as thoroughly investigated, similar associations exist for cancer patients, as summarized in the following and in Table 3.
exercise therapy countermeasures Exercise training is well established as a cornerstone of primary and secondary disease prevention in multiple clinical settings [65, 66]. Of importance, exercise constitutes a pleiotropic therapeutic strategy with the capacity to directly modify skeletal muscle and potentially reverse dysfunction [67]. The repeated episodic bouts of muscle contraction associated with exercise training stimulate a wide range of physiological adaptations, including changes in the contractile apparatus, mitochondrial function, metabolic regulation and intracellular signaling [68]. In the following, we will discuss the mechanisms and efficacy of exercise training as a countermeasure of cancer-related muscle dysfunction.
mechanisms of exercise adaptations therapy complications. Significant associations between muscle function and treatment complications are emerging from recent studies. In advanced stage breast cancer patients treated with capecitabine, 50% of the patients presenting with sarcopenia experienced dose-limiting toxicity, compared with 19.5% of the non-sarcopenic patients [57]. In accordance, presence of sarcopenia was associated with dose-limiting toxicity in advanced stage renal cell [58] and colon cancer patients [59]. Following hepatic resection of colorectal metastasis, sarcopenia was associated with increased risk of major postsurgical complications (OR = 3.12) [60], and low handgrip strength predicted longer hospital stay in patients undergoing esophagectomy with reconstruction for esophageal cancer [61].
Resistance and aerobic training represent two different exercise modalities with distinct potential for modifying muscles [68]. In brief, resistance training is characterized by short periods of high contractile muscle performance against heavy external load [69]. Known adaptations to chronic resistance training are increased muscle strength, increased muscle CSA by myofiber hypertrophy, expression of glycolytic enzymes and regulation of basal metabolic rate. Aerobic training, in comparison, is characterized by prolonged periods of low contractile muscle performance, which causes an acute rise in muscle ATP turnover, increased blood flow and substrate uptake. By stimulating oxidative capacity, aerobic training improves overall muscle metabolism including insulin sensitivity and intramuscular energy stores [68].
patient-reported outcomes. Consistent reports have found associations between muscle function and patient-reported outcomes, in particular fatigue, in early- and advanced stage cancer patients. For example a study in patients with low-grade primary glioma showed that thigh muscle CSA predicted fatigue (r = −0.74, P < 0.05) [62]. In accordance, in breast cancer survivors evaluated after adjuvant treatment, handgrip strength was associated with several patient-reported outcomes including fatigue, pain and QoL [63]. Moreover, Kilgour et al. [64] found several measures of muscle function; handgrip strength, quadriceps strength and skeletal muscle index correlated with fatigue in advanced stage cancer patients. In summary, the evidence reviewed here show that cancerrelated muscle dysfunction is a broad clinical challenge, which is not confined to palliative/advanced stage patients but also found in newly diagnosed patients with low tumor burden. As such, this phenomenon may go undetected in clinical practice for cancer populations, who do not constitute traditional risk groups. The etiology of cancer-related muscle dysfunction is highly complex, comprising a wide range of catabolic stimuli, which are very difficult to separate and which impact depends on the clinical setting of the individual patient. The clinical importance of muscle dysfunction in cancer patients is evident from recent studies showing strong associations to vital clinical end points, including survival, treatment toxicity and
effect of exercise on muscle function in the oncology setting Over the last decade, there have been considerable advances in the field of exercise oncology [70], with more than 70 published exercise trials, primarily evaluating safety and feasibility of moderate intensity exercise along with the effect on fitness, QoL and fatigue [71, 72]. The majority of exercise trials reporting effects on muscle function have included early-stage breast cancer patients during or after adjuvant chemotherapy or prostate cancer patients during ADT [73]. muscle strength. Numerous randomized, controlled trials in early-stage cancer patients have shown that resistance training improves muscle strength. For example prostate cancer patients improved upper and lower body strength by 22% and 24%, respectively, following 24 weeks of resistance training [74], and early-stage breast cancer patients enhanced muscle strength by 25%–35% after 17 weeks resistance training compared with usual care control [75]. The latter study furthermore showed that the resistance training group had a higher chemotherapy completion rate, improved QoL and lower fatigue level [75]. As expected, aerobic training did not result in similar muscle strength improvements, but improved aerobic fitness, body fat content and self-esteem [75]. Considerably, fewer studies have investigated the effect of exercise in advanced stage cancer
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mortality and disease progression. The importance of muscle dysfunction as a predictor of prognosis was recently reported in patients with early-stage breast cancer. Survivors diagnosed with sarcopenia, assessed on average 12 months after diagnosis, had almost three-fold higher all-cause mortality rate (HR = 2.86) compared with nonsarcopenic survivors [12]. Of importance, this study was the first in early-stage patients to report what several prior studies have found in patients with advanced disease. For example sarcopenia is associated with poorer prognosis in patients with advanced cancer of colon [11], respiratory and GI tracts [8] and melanoma [56]. In line with this, Prado et al. [57] found that sarcopenic patients with metastatic breast cancer had shorter time-to-tumor progression (101 days) relative to nonsarcopenic patients (173 days).
patients-reported outcomes, thus emphasizing the need for effective counteracting strategies in oncology practice.
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Table 3. Summary of reported associations between muscle function assessments and clinical end points Muscle assessment (method)
Population, N
Main finding
Handgrip strength (MVC)
Esophageal cancer, stages I–IV, N = 61
Handgrip strength below 25 kg associated with • Surgical mortality rate (within 6 months), 35% versus 4.8%: OR ≈8 [no CI reported, P < 0.05]
Villasenor et al. [12]
Muscle mass (DXA scan)
Breast cancer, stages I–IIIa, N = 471
•
van Vledder et al. [11]
Muscle index (CT scan)
Colon cancer, stages I–IV, N = 196
•
Prado et al. [8]
Muscle index (CT scan)
Lung and GI cancer, stages I–IV, N = 250
•
Muscle index (CT scan)
Breast cancer, stage IV, N = 55
Sabel et al. [56]
Psoas muscle density (CT scan)
Melanoma, stage III, N = 101
van Vledder et al. [11]
Muscle index (CT scan)
Colon cancer, stages I–IV, N = 196
Handgrip strength (MVC)
Esophageal cancer, stages I–IV, N = 61
Prado et al. [57]
Muscle index (CT scan)
Breast cancer, stage IV, N = 55
Antoun et al. [58]
Muscle index (CT scan)
Renal cell cancer, stage IV, N = 37 (males only)
Clinical end point References Mortality Chen et al. [61]
Therapy complications Chen et al. [61]
Sarcopenia associated with 5-year survival rate, 20.0% versus 49.9%, HR = 2.53 [95% CI 1.60–4.01, P < 0.001] Sarcopenia associated with Survival, 21.6 versus 11.3 months, HR = 4.2 [95% CI 2.4–7.2, P < 0.001]
Sarcopenia associated with Time to progression, 173 versus 101 days, HR = 2.6 [95% CI 1.2–5.6, P < 0.01]
•
Decreasing psoas muscle density correlated with • Disease-free survival: Cox regression estimate = −0.09, HR = 0.39 [95% CI 0.20–0.80, P < 0.01] • Distant disease-free survival Cox regression estimate = −0.06, HR = 0.55 [95% CI 0.35–0.87, P < 0.01] Sarcopenia associated with 5-year recurrence-free survival, 15.0% versus 28.5%, HR = 1.88 [95% CI 1.25– 2.82; P < 0.01]
•
Handgrip strength below 25 kg associated with. • Surgery complication rate, 85% versus 30% [no CI reported, P < 0.001] • Duration to start regular oral intake, 22 versus 12 days [no CI reported, P < 0.01] • Hospital stay, 32.3 versus 21.4 days [no CI reported, P < 0.01] • Intensive care unit stay, 12.7 days versus 4.1 days [nO CI reported, P < 0.01] Sarcopenia associated with Dose-limiting toxicity, 50% versus 19%, HR:4.1 [Fisher’s exact test, P < 0.05]
•
Sarcopenia associated with Dose-limiting toxicity, 37% versus 5% [no HR/CI reported, P < 0.05]
•
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Time-to-tumor progression Prado et al. [57]
Sarcopenia associated with 5-year survival rate, 83.8% versus 92.9%, HR = 02.86 [95% CI 1.67–4.89, P < 0.001]
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Annals of Oncology Table 3. Continued Muscle assessment (method)
Population, N
Main finding
Prado et al. [59]
Muscle index (CT scan)
Colon cancer, stages II–III, N = 30 (females only)
Low lean body mass = Chemotherapy dose higher than 20 mg 5-FU/kg LBM associated with • Presence of toxicity, Yes/no (National Cancer Institute Common Toxicity Criteria, version 2.0), OR = 16.73 [Student’s t-test, P < 0.05]
Peng et al. [60]
Muscle index (CT scan)
Colon cancer, stage IV, N = 259
Sabel et al. [56]
Psoas muscle density (CT scan)
Melanoma, stage III, N = 101
Handgrip strength (dynanometer)
Breast cancer, stages I–IIIa, N = 95
Kilgour et al. [64]
Handgrip and Quadriceps strength (MVC) Skeletal muscle index (DXA scan)
NSCLC, GI cancer, stages III– IV, N = 84
Jones et al. [62]
Thigh CSA (MRI scan)
Primary glioma, stage I–II, N = 10
Clinical end point References
Psoas muscle density correlated with Major surgical complications (Yes/No), OR = 1.08 [95% CI 1.02–1.15, P < 0.01]
•
Handgrip strength correlated with Depression Scale (and subscales: anger, fatigue, confusion), Profile Mood States, r = −0.23 [P < 0.05] • Pain, VAS scale shoulder, r = −0.37 [P < 0.001]
•
Handgrip strength (HGS), Quadriceps strength (QS) and Skeletal Muscle index (SMMI) correlated with • Fatigue (Brief Fatigue Inventory), for HGS r = −0.71 [P < 0.01]; for QS, r = −0.55 [P < 0.05]; for SMMI, r = −0.86 [P < 0.01] Thigh muscle CSA was correlated with Fatigue, FACT Brain Scale, r = −0.74 [P < 0.05]
•
DXA, dual-energy X-ray absorptiometry; CT, computerized topography; MRI, magnetic resonance imaging; CSA, cross-sectional area; MVC, maximum voluntary contraction; CI, confidence intervals; OR, odds ratio; HR, hazard ratio.
patients, but initial findings indicate that exercise is safe and feasible in this setting. A recent study showed that 8 weeks of circuit training in advanced stage patients with mixed diagnoses, improved handgrip strength by 2.0 kg compared with a usual care control group [76]. In accordance, 6 weeks of high intensity combined aerobic and resistance exercise in inoperable lung cancer patient increased muscle strength by 17% (average increase in two upper and two lower body exercises) [77]. muscle composition. In line with the improvements in muscle strength, resistance training in cancer patients increases muscle
mass. For instance, prostate cancer patients gained between 0.8 and 1.7 kg lean body mass after 12–24 weeks of resistance training [75, 78], and breast cancer patients performing resistance training gained 0.8 kg muscle mass during chemotherapy [75]. Only two studies have, to our knowledge, reported exercise effects in muscle composition on a single muscle level, both of which investigated the effect of 12-week resistance training. LaStayo et al. [79] found a 4% increase in quadriceps muscle area following resistance training in a group of cancer survivors with mixed diagnoses. In accordance, Hanson et al. [78] found that prostate cancer patients undergoing ADT increased quadriceps
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Patient-reported end points Cantarero-Villanueva et al. [63]
Sarcopenia associated with Major post-surgery complications, Yes/ No, OR = 3.12 [95% CI 1.14–8.49, P < 0.05] • Hospital stays, 6.6 versus 5.4 days [no CI reported, P < 0.05] • Intensive care unit stay (>2 days), 15% versus 4% [no CI reported; P < 0.01]
•
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Annals of Oncology
muscle volume by 6.4%. To our knowledge, no studies so far have reported effects of exercise on the muscle fiber level in cancer patients, but at least four randomized exercise trials are currently ongoing, collecting muscle biopsies from testicular [80], prostate [81], lung [82] and breast [83] cancer patients, respectively. The evidence reviewed here shows that exercise, in particular resistance training, is a potent strategy to improve muscle strength and composition in patients with cancer. To this end, resistance training should be promoted as a potential therapeutic countermeasure, alone or in combination with nutritional and/or pharmacological supplements in appropriate populations, such as elderly patients, patients with poor functional status and patients undergoing toxic therapies causing severe muscle degradation. Aerobic exercise, in comparison, is a powerful moderator of other risk factors of cancer-related and overall mortality including fitness, cardiotoxicity and circulating angiogenic biomarkers [84]. Thus, aerobic training should be promoted in cancer populations, who experience substantial risk of developing morbidities such as CVD and metabolic disorders, e.g. breast cancer survivors [85].
with the capacity to maintain and/or improve muscle mass, strength and metabolism during and after cancer treatment.
future directions
1. Ehrenborg E, Krook A. Regulation of skeletal muscle physiology and metabolism by peroxisome proliferator-activated receptor delta. Pharmacol Rev 2009; 61: 373–393. 2. Pedersen BK. Exercise-induced myokines and their role in chronic diseases. Brain Behav Immun 2011; 25: 811–816. 3. Ruiz JR, Sui X, Lobelo F et al. Association between muscular strength and mortality in men: prospective cohort study. BMJ 2008; 337: a439. 4. Argiles JM, Busquets S, Toledo M et al. The role of cytokines in cancer cachexia. Curr Opin Support Palliat Care 2009; 3: 263–268. 5. Argiles JM. Cancer-associated malnutrition. Eur J Oncol Nurs 2005; 9 Suppl 2: S39–S50. 6. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev 2009; 89: 381–410. 7. Cruz-Jentoft AJ, Baeyens JP, Bauer JM et al. Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010; 39: 412–423. 8. Prado CM, Lieffers JR, McCargar LJ et al. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol 2008; 9: 629–635. 9. Martin L, Birdsell L, MacDonald N et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol 2013; 31: 1539–1547. 10. Tan BH, Birdsell LA, Martin L et al. Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer. Clin Cancer Res 2009; 15: 6973–6979. 11. van Vledder MG, Levolger S, Ayez N et al. Body composition and outcome in patients undergoing resection of colorectal liver metastases. Br J Surg 2012; 99: 550–557. 12. Villasenor A, Ballard-Barbash R, Baumgartner K et al. Prevalence and prognostic effect of sarcopenia in breast cancer survivors: the HEAL Study. J Cancer Surviv 2012; 6: 398–406. 13. Wojtaszewski JF, Nielsen JN, Richter EA. Invited review: effect of acute exercise on insulin signaling and action in humans. J Appl Physiol 2002; 93: 384–392. 14. Burden ST, Hill J, Shaffer JL et al. Nutritional status of preoperative colorectal cancer patients. J Hum Nutr Diet 2010; 23: 402–407. 15. Soyupek F, Soyupek S, Perk H et al. Androgen deprivation therapy for prostate cancer: effects on hand function. Urol Oncol 2008; 26: 141–146. 16. Harrington S, Padua D, Battaglini C et al. Comparison of shoulder flexibility, strength, and function between breast cancer survivors and healthy participants. J Cancer Surviv 2011; 5: 167–174. 17. Ness KK, Jones KE, Smith WA et al. Chemotherapy-related neuropathic symptoms and functional impairment in adult survivors of extracranial solid tumors of
conclusion This review highlights the considerable clinical extent and importance of muscle dysfunction in cancer patients across all stages and diagnoses. The causes include a range of tumor, therapy- and/or lifestyle-related factors, yet more work is needed to explore the individual and interacting effects of these on muscle function in cancer patients. Against this multifactorial background, exercise training may be a potent intervention
| Christensen et al.
JFC is supported by the Beckett Foundation and Centre for Integrated Rehabilitation of Cancer Patients (CIRE); a center established and supported by the Danish Cancer Society and the Novo Nordic Foundation. The Centre of Inflammation and Metabolism (CIM) is supported by a grant from the Danish National Research Foundation (DNRF55). PH was further supported by grants from the Copenhagen University Hospital (RH961507529).
disclosure The authors have declared no conflicts of interest.
references
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Accumulating data emphasize the broad clinical challenge of muscle dysfunction in cancer patients; however, considerable limitations remain. First, although evidence of muscle dysfunction can be found across all diagnoses, as reviewed here, the actual sequelae of cancer-related muscle dysfunction remain poorly described, due to lack of longitudinal and/or comparative data. Second; the causes remain difficult to separate and may vary greatly depending on the clinical setting. Therefore, to improve the understanding of the etiology of cancer-related muscle dysfunction, a better molecular understanding of the mechanisms behind the muscle dysfunction is warranted. Third; exercise training constitutes a promising therapeutic countermeasure to cancer-related muscle dysfunction; however, there is currently a discrepancy between the clinical setting (timing and study population) of exercise intervention trials (mainly in early-stage breast and prostate cancer patients) and the observational studies, showing muscle function as a predictor of clinical end points (mainly shown in advanced stage GI patients). Thus, future exercise trials in early-stage patients should be powered to evaluate long-term beneficial effects of improved muscle function on clinical outcomes. Also, future exercise trials should be promoted in advanced stage settings, where patients experience the highest incidence and degree of muscle function impairments, aiming to reverse cancerrelated muscle dysfunction and thus potentially improve timeto-progression, treatment toxicity and mortality.
funding
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Annals of Oncology
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Annals of Oncology 00: 1–12, 2014 doi:10.1093/annonc/mdt551
Muscle dysfunction in cancer patients J. F. Christensen1,2, L. W. Jones3, J. L. Andersen4,5, G. Daugaard2, M. Rorth2 & P. Hojman6* 1 The University Hospitals Centre for Health Care Research (UCSF); 2Department of Oncology, Copenhagen University Hospital, Copenhagen, Denmark; 3Duke Cancer Institute, Durham, USA; 4Department of Orthopaedic Surgery M, Institute of Sports Medicine, Bispebjerg Hospital, Copenhagen; 5Centre for Healthy Ageing, Faculty of Health Sciences, University of Copenhagen, Copenhagen; 6Centre for Inflammation and Metabolism, Copenhagen University Hospital, Copenhagen, Denmark
Received 27 May 2013; revised 18 July 2013 and 4 October 2013; accepted 12 November 2013
introduction Skeletal muscle is the largest organ in the human body, constituting 40%–50% of total body mass in healthy nonobese humans [1]. Skeletal muscle function is classically defined as the ability to perform muscular contractions, generating external mechanical force, which enables physical activities of daily living and exercise. In addition, skeletal muscle plays a vital role in primary and secondary disease prevention as an essential regulator of metabolic and inflammatory homeostasis [2]. Indeed, substantial evidence shows that muscle function, defined as strength or muscle composition (muscle mass or size), in healthy individuals is a strong independent predictor of all-cause-, cancer- and cardiovascular disease (CVD) mortality risk [3].
*Correspondence to: Dr Pernille Hojman, Centre for Inflammation and Metabolism, Copenhagen University Hospital, Blegdamsvej 9, 7641, DK-2100 Copenhagen, Denmark. Tel: +45-35-45-75-44; Fax: +45-35-45-75-41; E-mail: phojman@inflammationmetabolism.dk
Within oncology, interest in muscle function has traditionally been confined to the clinical entity of cancer cachexia, which is characterized by severe muscle wasting, systemic inflammation [4] and malnutrition [5] in patients with advanced stage disease [6]. But emerging evidence shows that decreased muscle mass (sarcopenia [7]) is a prevalent condition in cancer patients regardless of disease stage [8] and nutritional status [9], and is associated with higher mortality rates in both advanced stage [10, 11] and early-stage patients [12]. The reports of skeletal muscle as a prognostic factor emphasize the need for a better understanding of the complex etiology of muscle dysfunction in the oncology setting, and the need for effective therapeutic countermeasures in clinical practice. Exercise training constitutes a potent modulator of skeletal muscle function, and growing evidence suggests that exercise is a safe, feasible and effective therapeutic strategy with the capacity to mitigate and/or reverse muscle dysfunction in patients with cancer. Here, we review the current evidence describing the degree, causes and clinical implications of muscle dysfunction in cancer
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Background: Muscle dysfunction is a prevalent phenomenon in the oncology setting where patients across a wide range of diagnoses are subject to impaired muscle function regardless of tumor stage and nutritional state. Here, we review the current evidence describing the degree, causes and clinical implications of muscle dysfunction in cancer patients. The efficacy of exercise training to prevent and/or mitigate cancer-related muscle dysfunction is also discussed. Design: We identified 194 studies examining muscular outcomes in cancer patients by searching PubMed and EMBASE databases. Results: Muscle dysfunction is evident across all stages of the cancer trajectory. The causes of cancer-related muscle dysfunction are complex, but may involve a wide range of tumor-, therapy- and/or lifestyle-related factors, depending on the clinical setting of the individual patient. The main importance of muscle dysfunction in cancer patients lies in the correlation to vital clinical end points such as cancer-specific and all-cause mortality, therapy complications and quality of life (QoL). Such associations strongly emphasize the need for effective therapeutic countermeasures to be developed and implemented in oncology practice. Significant progress has been made over the last decade in the field of exercise oncology, indicating that exercise training constitutes a potent modulator of skeletal muscle function in patients with cancer. Conclusion: There are clear associations between muscle dysfunction and critical clinical end points. Yet there is a discrepancy between timing of exercise intervention trials, which can improve muscle function, and study populations in whom muscle function are proven prognostic important for clinical end points. Thus, future exercise trials should in earlystage patients, be powered to evaluate clinical outcomes associated with improvements in muscle function, or be promoted in advanced stage settings, aiming to reverse cancer-related muscle dysfunction, and thus potentially improve time-to-progression, treatment toxicity and survival. Key words: skeletal muscle, muscle strength, muscle mass, cancer, exercise
review patients. Moreover, we will discuss the potential of exercise training to mitigate or reverse muscle dysfunction.
search strategy A comprehensive search of the literature was conducted in the PubMed (NIH), Medline and EMBASE databases (January 1966 to March 2013) using keyword combinations of the medical subject headings (MeSH) ‘body composition’, ‘muscle, skeletal’, ‘muscular atrophy’, ‘muscle function’, ‘muscle strength’, ‘exercise’, ‘cancer’, ‘neoplasms’. Relevant reference lists were also manually searched. The search was confined to include independent studies in adults diagnosed with solid malignancies, thus studies on childhood cancers and hematological diseases were excluded (Table 1).
Muscle contraction is a central feature of muscle function, enabling locomotor activity and metabolic control through the production of external force and induction of glucose uptake and other metabolic processes in the contracting muscles [13]. The exertion of muscle contraction is measured as muscle strength. Muscles are composed of individual muscle fibers, which are characterized by their size, twitch velocity and metabolic phenotype. Together the composition plays a central role for regulation of voluntary function (muscle contraction) and nonvoluntary functions (e.g. muscle metabolism). Against this background, we adopt the following organizing framework to evaluate the available evidence of muscle function defined by (i) muscle strength and (ii) muscle composition. The latter may be evaluated on three levels: (I) whole-body level (whole-body muscle mass), (II) single muscle (group) level (muscle/muscle group size or volume) and (III) muscle fiber level ( phenotypic characteristics; i.e. morphology, cellular signaling and gene expression profile). Accordingly, we define ‘cancer-related muscle dysfunction’, as any measurable impairment in muscle strength or muscle composition independent of the underlying cause in patients diagnosed with cancer. Table 2 provides a summary of commonly applied methods, which directly assess muscle strength or composition in humans. In brief, contractile muscle function can be measured by isometric or isokinetic force/torque or more pragmatic methods including repetition maximum (RM) tests or handgrip strength. Wholebody muscle mass can be measured by body composition assessments including dual-energy X-ray absorptiometry (DXA) scans or bioelectrical impendence. Single muscle (or muscle group) size or volume is measured via cross-sectional area (CSA) assessments by imaging modalities, i.e. computerized topography (CT), magnetic resonance imaging (MRI) or ultrasonography. For assessment of cellular muscle structure, muscle tissue biopsying is a valuable method allowing for detailed assessment of muscle fiber morphology, biochemical indices and gene expression profiles.
muscle dysfunction in cancer patients In total, we identified 194 independent clinical studies (supplementary appendix, available at Annals of Oncology online,
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Table 1), which reported measures of muscle function in adult cancer patients across more than 15 diagnoses, and different disease phases (before-, during- or after primary cancer therapy) and tumor stages (early- or advanced stage disease). Below we summarize these studies, focusing on the degree, causes and clinical implications of muscle dysfunction in cancer patients.
degree of muscle dysfunction muscle strength. The majority of studies reporting muscle strength have used one RM measurement ( predominantly in exercise intervention trials) or assessment of handgrip strength. Collectively, the studies indicate that cancer patients have significant impairments in muscle strength regardless of disease stage, when compared with healthy controls matched by age, sex, BMI and/or physical activity level. For example Burden et al. [14] found that 54% of newly diagnosed early-stage colorectal patients had a handgrip strength, which was below 85% of the age-matched reference range. In accordance, patients with locally advanced prostate cancer undergoing androgen deprivation therapy (ADT), which lowers bioavailable testosterone, had 29% lower handgrip strength compared with healthy controls [15]. Furthermore, breast cancer survivors evaluated after completion of primary therapy displayed consistently lower muscle strength (20%–30%) in seven different upper body exercises compared with healthy individuals [16]. Finally, evidence of late effects on muscle strength has been shown in adult survivors of childhood cancers. For example Ness et al. [17] found that 18% survivors of extracranial solid tumors, assessed a median of 25 years after diagnosis, displayed muscle weakness, defined as the dorsiflexion torque within the lowest 10th percentile compared with healthy age-matched reference subjects. muscle composition. Consistent with the reports of decreased muscle strength, putative evidence demonstrates changes in muscle composition across diagnoses and disease phases. whole-body level: The vast majority of studies identified by our search, reported data on whole-body muscle mass assessed by DXA scan or bioelectrical impendence. For example a crosssectional study of 714 newly diagnosed patients with mixed diagnoses (i.e. lung, gastric, esophagus, colorectal or pancreas cancer) found that cancer patients had 0.9 kg lower muscle mass compared with healthy controls [18], before initiation of antineoplastic therapy. Moreover, during the course of adjuvant chemotherapy early-stage breast cancer patients lost 1.3 kg lean body mass, and continued to lose lean body mass after therapy completion [19]. In comparison, early-stage prostate cancer patients on long-term (>6 months) ADT had ∼2.5 kg lower muscle mass (reported as 4.5% lower lean body mass) compared with healthy BMI-matched controls [20], while metastatic prostate cancer patients, who were weight stabile during 12 months of ADT, lost 11.8 kg lean body mass [21]. single muscle level: Most studies reporting muscle composition at the single muscle/muscle group level have used diagnostic CT scans to measure ‘muscle index’ (muscle area in the third lumbar [L3] vertebrae region normalized by height). By such method, Prado et al. [8] evaluated prevalence of sarcopenia among 441 newly diagnosed obese patients with cancer of
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Table 1. Characteristics of reviewed studies All studies (N = 194)
Number of cancer patients and mean age All patients Female patients Male patients Sex not reported Age Number of patients by cancer site Breast cancer Prostate cancer Colorectal cancer Gastric cancer Lung cancer Pancreas cancer Head and neck cancer Liver cancer Esophagus cancer Gynecological cancer Genitourinary cancer Renal cell cancer Primary glioma Other cancers Number of patients by setting Point of diagnosis (before cancer therapy) During systemic therapy Off systemic therapy/palliation
Intervention studies (N = 74)
38 59 28 16 13 12 11 5 4 2 2 4
22 24 20 16 8 10 8 3 3 1 2 3
16 35 8 0 5 2 3 2 1 1 0 1
37 86 14 41 16
37 52 6 10 15
0 34 8 31 1
108 50 31 5
59 29 27 5
49 21 4 0
125 69
52 68
74 0
145 49
73 47
72 2
16 307 8400 6610 1297 60.1 ± 7.8
9988 4097 4660 1231 61.3 ± 7.4
6319 4303 1950 66 58.2 ± 8.1
5196 2414 1996 1525 1524 1144 485 382 359 299 119 100 64 700
1940 1963 1590 1160 1009 723 290 256 322 90 97 20 59 469
3256 451 406 365 515 421 195 126 37 209 22 80 5 231
3696 5501 2705
3696 2959 1446
0 2542 1259 Continued
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Number of studies by cancer site Mixed cancer population Breast cancer Prostate cancer Cancer of the upper gastrointestinal tract Lung cancer Colorectal cancer Pancreas cancer Head and neck cancer Gynecological cancer Genitourinary cancer Primary glioma Others cancers Number of studies by setting Point of diagnosis (before cancer therapy) During systemic therapy Off systemic therapy/palliation Post-therapy survivors Mixed Number of studies by disease stage Early-stage/operable Advanced stage/inoperable Mixed Not reported Cross-sectional or longitudinal assessments Longitudinal Cross-sectional Healthy/noncancer reference group included No Yes
Observational studies (N = 120)
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Table 1. Continued All studies (N = 194) Post-therapy survivors Mixed Number of patients by disease stage Early-stage/operable Advanced stage/inoperable Not reported
Observational studies (N = 120)
Intervention studies (N = 74)
3479 926
983 904
2496 22
8886 6166 1255
5082 3745 1161
3804 2421 94
Data includes the accumulated number of studies or number of patients for each parameter except for age, which is predicted as mean ± standard deviation for all studies.
muscle fiber level: Evaluation of dysfunctional features at the cellular level can be carried out through histological or molecular analyses of muscle biopsies. In newly diagnosed cancer patients undergoing intrathoracic surgery, primarily for GI cancer, muscle biopsies show significant upregulation of muscle degradation pathways such as ubiquitin ligases [23], calpain activity [24] and myostatin [25] compared with patients, who were operated for nonmalignant diseases. In advanced stage patients, Weber et al. [26] found severe reductions (40%–50%) in myofiber size primarily in Type IIx fibers.
causes of muscle dysfunction Whether muscle dysfunction should be considered an intrinsic part of a cancer disease or a generalized response to multiple atrophic stimuli can be debated. Commonly, all cancer patients are subjected to a wide range of cancer-specific and noncancerspecific degenerative factors, which are all potent causes of muscle dysfunction including aging, malnutrition, physical inactivity and factors directly related to disease pathophysiology and therapy toxicity. age and co-morbidities. The incidence of cancer increases with age, and more than 50% of all newly diagnosed cancer patients are older than 65 years [27]. An age-related decline in muscle mass is observed from the end of the fifth decade and has been estimated to 1.9 kg per decade for men and 1.1 kg per decade for women [28]. Biopsy studies have shown that the age-related loss in muscle mass is primarily driven by selective loss of Type II muscle fibers [29], possibly caused by progressive denervation and motorneuron failure [30]. Depending on diagnosis between 30% and 80% of all patients present with other age-related co-morbidities (e.g. Type II diabetes or CVD), which may
| Christensen et al.
contribute to the aging effects through low-grade inflammation, impaired metabolism and deconditioning [31]. malnutrition. Malnutrition is a major problem, particularly in patients diagnosed with head and neck, GI tract, pancreas and lung cancer. A recent study in 1453 oncology outpatients with mixed diagnoses, reported that 32% were at ‘high nutritional risk’ (a score ≥ 3 on The Nutritional Risk Screening [NRS 2002]) [32]. The underlying causes may include decreased central drive to eat, chemosensory disturbances (taste and smell), decreased upper GI motility, nausea and constipation. In an energy-depleted state, muscle protein serves as the primary reservoir of circulating amino acids, resulting in net release from the muscles [33]. In accordance, progressive muscle dysfunction has been reported in malnourished colorectal cancer patients, who had 29% lower handgrip strength and 12.2 kg lower wholebody muscle mass, but the same level of fat mass compared with well-nourished patients [14]. physical inactivity. Patients diagnosed with cancer often reduce their daily physical activity. Most profoundly following major surgery, where prolonged bed rest can cause muscle dysfunction as seen in elderly men, whom following 10 days bed rest had a 16% decline in isokinetic muscle strength and a loss of 1.5 kg whole-body muscle mass, including 1 kg from the lower extremities [34]. Adverse effects like pain, physical weakness or therapy toxicity can furthermore reduce daily physical activity. A recent study found that patients receiving neoadjuvant chemotherapy or radiotherapy walked ∼4000 steps per day, compared with 9000 steps in healthy controls [35]. In accordance, breast cancer patients undergoing adjuvant chemotherapy reduced their daily energy expenditure from 514 to 461 kcal during therapy, which was associated with a loss of 0.4 kg muscle mass [36]. tumor-derived factors. The direct tumor-derived impact on muscle tissue has been extensively studied in preclinical models demonstrating roles for tumor-induced inflammation and altered metabolism (reviewed in [37–39]). Studies in mice with large tumor burden show that proinflammatory cytokines like TNF-α, IL1-β and IFN-γ are derived from the tumor, resulting in increased systemic inflammation. This systemic inflammation can activate NF-κβ signaling in muscles, inducing transcription
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gastrointestinal (GI) or respiratory tracts, and found that 15.2% of all patients were sarcopenic [8]. Interestingly, these patients did not report a prediagnostic weight loss, and presence of sarcopenia was not associated with disease stage. In a prospective study of patients with esophagus or gastric cancer, 100 days of neoadjuvant chemotherapy resulted in a 10-cm2 reduction in L3 muscle area [22], increasing the prevalence of sarcopenia from 57% to 78% in this population.
Measurement Muscle contraction Muscle strength
Muscle composition Whole-body levelc
Data outcome
Defined cutoff points
Advantages
Limitations
• •
Isokinetic/isometric Maximum voluntary contraction test
• •
Force (Newton) Torque (Newton meter)
•
•
•
Expensive test equipment
•
Repetition maximum (RM) tests
•
Mass (kg)
•
Gold standard strength testing procedure Possible use of interpolation twitch technique (for assessment of central fatigue) Can be carried out for most muscle/muscle groups
•
Strong risk of praxis adaptation
•
Handgrip strength test
• •
Mass (kg) Force (Newton)
•
Mobile equipment (dynamometer)
•
Limited muscle mass activated
•
DXA scan
• • • • • • • •
Muscle mass (kg) Fat mass (kg) Fat percentage (% body mass) Bone density (g/cm2) Bone mass (kg) Muscle mass (kg) Fat mass (kg) Bone mass (kg)
Sarcopenia defined by handgrip strengthb: Male < 30 kg Female < 20 kg • Sarcopenia defined by appendicular skeletal muscle mass normalized by height$b: Men < 7.26 kg/m2 Women < 5.45 kg/m2
•
•
•
Gold standard method for whole-body composition assessment Precise bone-density measure
Extracellular fluid overestimate muscle mass Radiation dose (minor)
•
Sarcopenia defined by wholebody muscle mass normalized by heightb: Men < 8.87 kg/m2 Women < 6.42 kg/m2
• • •
Inexpensive, mobile equipment Easy procedure No radiation
•
Less accurate compared with DXA scan
• •
CSA (cm2) Muscle index (cm2/m2)—CSA in third lumbar vertebrae (L3) region normalized by height
•
Sarcopenia defined by Muscle indexa:Male < 55.4 cm2/ m2Female < 38.9 cm2/m2
•
Gold standard segmental assessment Diagnostic procedure Distinction between muscle, fat, bone and other organs.
• •
Estimated whole-body measure Expensive, immobile equipment γ-Radiation
CSA (cm2)
•
Not defined
•
Gold standard segmental assessment Distinction between muscle, fat, bone, other organs No radiation Less expensive, more mobile than MRI scan Distinction between muscle and fat
• •
Estimated whole-body measure Expensive, immobile equipment
•
Less accurate compared with MRI scan
•
Single muscle/ muscle group level
•
•
Bioelectrical impendence
CT scan
MRI scan
•
Not defined
• Not defined
•
• •
• Ultrasonography
•
Muscle volume (cm3)
•
Not defined
• • •
•
Continued
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•
•
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Table 2. Common assessments methods for evaluation of muscle function in clinical and research praxis
Sampling errors Invasive procedure: discomfort/ pain Risk of infections
b
a
Morphology Enzyme activity Transport proteins Intracellular signaling Gene expression Muscle biopsy
• Muscle fiber-level composition
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Cutoff values from Prado et al. [59]. Cutoff values from Cruz-Jentoft et al. [7]. c Other indirect methods including assessment of ‘Total Body Nitrogen (TBN)’, ‘air-displacement plethysmography’ and ‘skin-fold thickness’ are not described here. DXA, dual-energy X-ray absorptiometry; CT, computerized topography; MRI, magnetic resonance imaging; CSA, cross-sectional area.
• • Single myofiber assessment
• • • • • • •
Not defined
Defined cutoff points Data outcome Methods Measurement
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of the ubiquitin ligases, Atrogin-1 and Murf1 and muscle protein degradation [40, 41]. Induction of these pathways has also been reported in muscle biopsies from newly diagnosed cancer patients. The mRNA levels correlated with tumor stage but not preillness weight loss [42], indicating that tumor burden directly initiates early phases of muscle degradation, which is present before muscle wasting is detectable [43]. In addition to tumor-derived inflammation, most tumors are highly metabolically active with glycolysis as the main energygenerating pathway [44]. To meet the substrate need for the high glycolytic rate, tumors take up large amounts of glucose, competing directly for the energy availability with other glucosedependent tissues [45]. Moreover, recent studies have shown that tumors are also largely dependent on supply of glutamine. This requirement for amino acids might through unidentified mechanisms accelerate protein degradation in the muscles. cancer therapy. Cancer management typically involves combinations of locoregional and/or systemic therapies, which potentially impact nontargeted tissues [46]. Very few studies have investigated the direct effects of cancer therapy on muscle function, least of all compared the effects of different treatment regimens. Nonetheless, surgery and/or radiotherapy can affect the structural integrity of skeletal musculature in the anatomical treated regions. For example women treated for early-stage breast cancer experience markedly impaired muscle strength in the affected side compared with the nonaffected side [47]. Moreover, systemic cancer therapies greatly influence muscle composition. For example Hamilton et al. [48] found that prostate cancer patients receiving ADT lost 1.8 kg muscle mass during the first 6 months of therapy despite an overall weight gain. Advanced stage colorectal cancer patients treated with the VEGF receptor inhibitor Bevacizumab for 3 months reduced L3 muscle area by 3 cm2/m2 equivalent to ∼1 kg muscle mass [49], which was independent of tumor progression. Likewise, biopsies taken before and after a 50-day period of chemotherapy with doxorubicin (DOX) or melphalan in patients with melanoma or sarcoma showed severe reductions in myofiber size, neurogenic alterations and mitochondria-related damages [50]. In line with this, preclinical studies show that DOX decrease maximal twitch force and impair relaxation, associated with intracellular Ca2+ accumulation in the muscles [51]. supportive care medication. Supportive care medications like glucocorticoids are frequently administrated concomitant to systemic antineoplastic therapy. These drugs counteract therapy-induced adverse events like nausea and pain through anti-inflammatory effects, but they also have considerable impact on muscle composition and metabolism. Eight days of prednisone use in healthy young men caused significant insulin resistance, evident by a 65% lower insulin-stimulated glucose uptake compared with placebo users [52]. Moreover, long-term use of glucocorticoids is associated with muscle wasting and weakness [53].
clinical implications of muscle dysfunction Muscle function is a strong independent predictor of all-cause, CVD- and cancer mortality [3], morbidity [54] and QoL [55] in
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Advantages
Limitations
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noncancer populations. Although not as thoroughly investigated, similar associations exist for cancer patients, as summarized in the following and in Table 3.
exercise therapy countermeasures Exercise training is well established as a cornerstone of primary and secondary disease prevention in multiple clinical settings [65, 66]. Of importance, exercise constitutes a pleiotropic therapeutic strategy with the capacity to directly modify skeletal muscle and potentially reverse dysfunction [67]. The repeated episodic bouts of muscle contraction associated with exercise training stimulate a wide range of physiological adaptations, including changes in the contractile apparatus, mitochondrial function, metabolic regulation and intracellular signaling [68]. In the following, we will discuss the mechanisms and efficacy of exercise training as a countermeasure of cancer-related muscle dysfunction.
mechanisms of exercise adaptations therapy complications. Significant associations between muscle function and treatment complications are emerging from recent studies. In advanced stage breast cancer patients treated with capecitabine, 50% of the patients presenting with sarcopenia experienced dose-limiting toxicity, compared with 19.5% of the non-sarcopenic patients [57]. In accordance, presence of sarcopenia was associated with dose-limiting toxicity in advanced stage renal cell [58] and colon cancer patients [59]. Following hepatic resection of colorectal metastasis, sarcopenia was associated with increased risk of major postsurgical complications (OR = 3.12) [60], and low handgrip strength predicted longer hospital stay in patients undergoing esophagectomy with reconstruction for esophageal cancer [61].
Resistance and aerobic training represent two different exercise modalities with distinct potential for modifying muscles [68]. In brief, resistance training is characterized by short periods of high contractile muscle performance against heavy external load [69]. Known adaptations to chronic resistance training are increased muscle strength, increased muscle CSA by myofiber hypertrophy, expression of glycolytic enzymes and regulation of basal metabolic rate. Aerobic training, in comparison, is characterized by prolonged periods of low contractile muscle performance, which causes an acute rise in muscle ATP turnover, increased blood flow and substrate uptake. By stimulating oxidative capacity, aerobic training improves overall muscle metabolism including insulin sensitivity and intramuscular energy stores [68].
patient-reported outcomes. Consistent reports have found associations between muscle function and patient-reported outcomes, in particular fatigue, in early- and advanced stage cancer patients. For example a study in patients with low-grade primary glioma showed that thigh muscle CSA predicted fatigue (r = −0.74, P < 0.05) [62]. In accordance, in breast cancer survivors evaluated after adjuvant treatment, handgrip strength was associated with several patient-reported outcomes including fatigue, pain and QoL [63]. Moreover, Kilgour et al. [64] found several measures of muscle function; handgrip strength, quadriceps strength and skeletal muscle index correlated with fatigue in advanced stage cancer patients. In summary, the evidence reviewed here show that cancerrelated muscle dysfunction is a broad clinical challenge, which is not confined to palliative/advanced stage patients but also found in newly diagnosed patients with low tumor burden. As such, this phenomenon may go undetected in clinical practice for cancer populations, who do not constitute traditional risk groups. The etiology of cancer-related muscle dysfunction is highly complex, comprising a wide range of catabolic stimuli, which are very difficult to separate and which impact depends on the clinical setting of the individual patient. The clinical importance of muscle dysfunction in cancer patients is evident from recent studies showing strong associations to vital clinical end points, including survival, treatment toxicity and
effect of exercise on muscle function in the oncology setting Over the last decade, there have been considerable advances in the field of exercise oncology [70], with more than 70 published exercise trials, primarily evaluating safety and feasibility of moderate intensity exercise along with the effect on fitness, QoL and fatigue [71, 72]. The majority of exercise trials reporting effects on muscle function have included early-stage breast cancer patients during or after adjuvant chemotherapy or prostate cancer patients during ADT [73]. muscle strength. Numerous randomized, controlled trials in early-stage cancer patients have shown that resistance training improves muscle strength. For example prostate cancer patients improved upper and lower body strength by 22% and 24%, respectively, following 24 weeks of resistance training [74], and early-stage breast cancer patients enhanced muscle strength by 25%–35% after 17 weeks resistance training compared with usual care control [75]. The latter study furthermore showed that the resistance training group had a higher chemotherapy completion rate, improved QoL and lower fatigue level [75]. As expected, aerobic training did not result in similar muscle strength improvements, but improved aerobic fitness, body fat content and self-esteem [75]. Considerably, fewer studies have investigated the effect of exercise in advanced stage cancer
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mortality and disease progression. The importance of muscle dysfunction as a predictor of prognosis was recently reported in patients with early-stage breast cancer. Survivors diagnosed with sarcopenia, assessed on average 12 months after diagnosis, had almost three-fold higher all-cause mortality rate (HR = 2.86) compared with nonsarcopenic survivors [12]. Of importance, this study was the first in early-stage patients to report what several prior studies have found in patients with advanced disease. For example sarcopenia is associated with poorer prognosis in patients with advanced cancer of colon [11], respiratory and GI tracts [8] and melanoma [56]. In line with this, Prado et al. [57] found that sarcopenic patients with metastatic breast cancer had shorter time-to-tumor progression (101 days) relative to nonsarcopenic patients (173 days).
patients-reported outcomes, thus emphasizing the need for effective counteracting strategies in oncology practice.
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Table 3. Summary of reported associations between muscle function assessments and clinical end points Muscle assessment (method)
Population, N
Main finding
Handgrip strength (MVC)
Esophageal cancer, stages I–IV, N = 61
Handgrip strength below 25 kg associated with • Surgical mortality rate (within 6 months), 35% versus 4.8%: OR ≈8 [no CI reported, P < 0.05]
Villasenor et al. [12]
Muscle mass (DXA scan)
Breast cancer, stages I–IIIa, N = 471
•
van Vledder et al. [11]
Muscle index (CT scan)
Colon cancer, stages I–IV, N = 196
•
Prado et al. [8]
Muscle index (CT scan)
Lung and GI cancer, stages I–IV, N = 250
•
Muscle index (CT scan)
Breast cancer, stage IV, N = 55
Sabel et al. [56]
Psoas muscle density (CT scan)
Melanoma, stage III, N = 101
van Vledder et al. [11]
Muscle index (CT scan)
Colon cancer, stages I–IV, N = 196
Handgrip strength (MVC)
Esophageal cancer, stages I–IV, N = 61
Prado et al. [57]
Muscle index (CT scan)
Breast cancer, stage IV, N = 55
Antoun et al. [58]
Muscle index (CT scan)
Renal cell cancer, stage IV, N = 37 (males only)
Clinical end point References Mortality Chen et al. [61]
Therapy complications Chen et al. [61]
Sarcopenia associated with 5-year survival rate, 20.0% versus 49.9%, HR = 2.53 [95% CI 1.60–4.01, P < 0.001] Sarcopenia associated with Survival, 21.6 versus 11.3 months, HR = 4.2 [95% CI 2.4–7.2, P < 0.001]
Sarcopenia associated with Time to progression, 173 versus 101 days, HR = 2.6 [95% CI 1.2–5.6, P < 0.01]
•
Decreasing psoas muscle density correlated with • Disease-free survival: Cox regression estimate = −0.09, HR = 0.39 [95% CI 0.20–0.80, P < 0.01] • Distant disease-free survival Cox regression estimate = −0.06, HR = 0.55 [95% CI 0.35–0.87, P < 0.01] Sarcopenia associated with 5-year recurrence-free survival, 15.0% versus 28.5%, HR = 1.88 [95% CI 1.25– 2.82; P < 0.01]
•
Handgrip strength below 25 kg associated with. • Surgery complication rate, 85% versus 30% [no CI reported, P < 0.001] • Duration to start regular oral intake, 22 versus 12 days [no CI reported, P < 0.01] • Hospital stay, 32.3 versus 21.4 days [no CI reported, P < 0.01] • Intensive care unit stay, 12.7 days versus 4.1 days [nO CI reported, P < 0.01] Sarcopenia associated with Dose-limiting toxicity, 50% versus 19%, HR:4.1 [Fisher’s exact test, P < 0.05]
•
Sarcopenia associated with Dose-limiting toxicity, 37% versus 5% [no HR/CI reported, P < 0.05]
•
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Time-to-tumor progression Prado et al. [57]
Sarcopenia associated with 5-year survival rate, 83.8% versus 92.9%, HR = 02.86 [95% CI 1.67–4.89, P < 0.001]
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Annals of Oncology Table 3. Continued Muscle assessment (method)
Population, N
Main finding
Prado et al. [59]
Muscle index (CT scan)
Colon cancer, stages II–III, N = 30 (females only)
Low lean body mass = Chemotherapy dose higher than 20 mg 5-FU/kg LBM associated with • Presence of toxicity, Yes/no (National Cancer Institute Common Toxicity Criteria, version 2.0), OR = 16.73 [Student’s t-test, P < 0.05]
Peng et al. [60]
Muscle index (CT scan)
Colon cancer, stage IV, N = 259
Sabel et al. [56]
Psoas muscle density (CT scan)
Melanoma, stage III, N = 101
Handgrip strength (dynanometer)
Breast cancer, stages I–IIIa, N = 95
Kilgour et al. [64]
Handgrip and Quadriceps strength (MVC) Skeletal muscle index (DXA scan)
NSCLC, GI cancer, stages III– IV, N = 84
Jones et al. [62]
Thigh CSA (MRI scan)
Primary glioma, stage I–II, N = 10
Clinical end point References
Psoas muscle density correlated with Major surgical complications (Yes/No), OR = 1.08 [95% CI 1.02–1.15, P < 0.01]
•
Handgrip strength correlated with Depression Scale (and subscales: anger, fatigue, confusion), Profile Mood States, r = −0.23 [P < 0.05] • Pain, VAS scale shoulder, r = −0.37 [P < 0.001]
•
Handgrip strength (HGS), Quadriceps strength (QS) and Skeletal Muscle index (SMMI) correlated with • Fatigue (Brief Fatigue Inventory), for HGS r = −0.71 [P < 0.01]; for QS, r = −0.55 [P < 0.05]; for SMMI, r = −0.86 [P < 0.01] Thigh muscle CSA was correlated with Fatigue, FACT Brain Scale, r = −0.74 [P < 0.05]
•
DXA, dual-energy X-ray absorptiometry; CT, computerized topography; MRI, magnetic resonance imaging; CSA, cross-sectional area; MVC, maximum voluntary contraction; CI, confidence intervals; OR, odds ratio; HR, hazard ratio.
patients, but initial findings indicate that exercise is safe and feasible in this setting. A recent study showed that 8 weeks of circuit training in advanced stage patients with mixed diagnoses, improved handgrip strength by 2.0 kg compared with a usual care control group [76]. In accordance, 6 weeks of high intensity combined aerobic and resistance exercise in inoperable lung cancer patient increased muscle strength by 17% (average increase in two upper and two lower body exercises) [77]. muscle composition. In line with the improvements in muscle strength, resistance training in cancer patients increases muscle
mass. For instance, prostate cancer patients gained between 0.8 and 1.7 kg lean body mass after 12–24 weeks of resistance training [75, 78], and breast cancer patients performing resistance training gained 0.8 kg muscle mass during chemotherapy [75]. Only two studies have, to our knowledge, reported exercise effects in muscle composition on a single muscle level, both of which investigated the effect of 12-week resistance training. LaStayo et al. [79] found a 4% increase in quadriceps muscle area following resistance training in a group of cancer survivors with mixed diagnoses. In accordance, Hanson et al. [78] found that prostate cancer patients undergoing ADT increased quadriceps
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Patient-reported end points Cantarero-Villanueva et al. [63]
Sarcopenia associated with Major post-surgery complications, Yes/ No, OR = 3.12 [95% CI 1.14–8.49, P < 0.05] • Hospital stays, 6.6 versus 5.4 days [no CI reported, P < 0.05] • Intensive care unit stay (>2 days), 15% versus 4% [no CI reported; P < 0.01]
•
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muscle volume by 6.4%. To our knowledge, no studies so far have reported effects of exercise on the muscle fiber level in cancer patients, but at least four randomized exercise trials are currently ongoing, collecting muscle biopsies from testicular [80], prostate [81], lung [82] and breast [83] cancer patients, respectively. The evidence reviewed here shows that exercise, in particular resistance training, is a potent strategy to improve muscle strength and composition in patients with cancer. To this end, resistance training should be promoted as a potential therapeutic countermeasure, alone or in combination with nutritional and/or pharmacological supplements in appropriate populations, such as elderly patients, patients with poor functional status and patients undergoing toxic therapies causing severe muscle degradation. Aerobic exercise, in comparison, is a powerful moderator of other risk factors of cancer-related and overall mortality including fitness, cardiotoxicity and circulating angiogenic biomarkers [84]. Thus, aerobic training should be promoted in cancer populations, who experience substantial risk of developing morbidities such as CVD and metabolic disorders, e.g. breast cancer survivors [85].
with the capacity to maintain and/or improve muscle mass, strength and metabolism during and after cancer treatment.
future directions
1. Ehrenborg E, Krook A. Regulation of skeletal muscle physiology and metabolism by peroxisome proliferator-activated receptor delta. Pharmacol Rev 2009; 61: 373–393. 2. Pedersen BK. Exercise-induced myokines and their role in chronic diseases. Brain Behav Immun 2011; 25: 811–816. 3. Ruiz JR, Sui X, Lobelo F et al. Association between muscular strength and mortality in men: prospective cohort study. BMJ 2008; 337: a439. 4. Argiles JM, Busquets S, Toledo M et al. The role of cytokines in cancer cachexia. Curr Opin Support Palliat Care 2009; 3: 263–268. 5. Argiles JM. Cancer-associated malnutrition. Eur J Oncol Nurs 2005; 9 Suppl 2: S39–S50. 6. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev 2009; 89: 381–410. 7. Cruz-Jentoft AJ, Baeyens JP, Bauer JM et al. Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010; 39: 412–423. 8. Prado CM, Lieffers JR, McCargar LJ et al. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol 2008; 9: 629–635. 9. Martin L, Birdsell L, MacDonald N et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol 2013; 31: 1539–1547. 10. Tan BH, Birdsell LA, Martin L et al. Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer. Clin Cancer Res 2009; 15: 6973–6979. 11. van Vledder MG, Levolger S, Ayez N et al. Body composition and outcome in patients undergoing resection of colorectal liver metastases. Br J Surg 2012; 99: 550–557. 12. Villasenor A, Ballard-Barbash R, Baumgartner K et al. Prevalence and prognostic effect of sarcopenia in breast cancer survivors: the HEAL Study. J Cancer Surviv 2012; 6: 398–406. 13. Wojtaszewski JF, Nielsen JN, Richter EA. Invited review: effect of acute exercise on insulin signaling and action in humans. J Appl Physiol 2002; 93: 384–392. 14. Burden ST, Hill J, Shaffer JL et al. Nutritional status of preoperative colorectal cancer patients. J Hum Nutr Diet 2010; 23: 402–407. 15. Soyupek F, Soyupek S, Perk H et al. Androgen deprivation therapy for prostate cancer: effects on hand function. Urol Oncol 2008; 26: 141–146. 16. Harrington S, Padua D, Battaglini C et al. Comparison of shoulder flexibility, strength, and function between breast cancer survivors and healthy participants. J Cancer Surviv 2011; 5: 167–174. 17. Ness KK, Jones KE, Smith WA et al. Chemotherapy-related neuropathic symptoms and functional impairment in adult survivors of extracranial solid tumors of
conclusion This review highlights the considerable clinical extent and importance of muscle dysfunction in cancer patients across all stages and diagnoses. The causes include a range of tumor, therapy- and/or lifestyle-related factors, yet more work is needed to explore the individual and interacting effects of these on muscle function in cancer patients. Against this multifactorial background, exercise training may be a potent intervention
| Christensen et al.
JFC is supported by the Beckett Foundation and Centre for Integrated Rehabilitation of Cancer Patients (CIRE); a center established and supported by the Danish Cancer Society and the Novo Nordic Foundation. The Centre of Inflammation and Metabolism (CIM) is supported by a grant from the Danish National Research Foundation (DNRF55). PH was further supported by grants from the Copenhagen University Hospital (RH961507529).
disclosure The authors have declared no conflicts of interest.
references
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Accumulating data emphasize the broad clinical challenge of muscle dysfunction in cancer patients; however, considerable limitations remain. First, although evidence of muscle dysfunction can be found across all diagnoses, as reviewed here, the actual sequelae of cancer-related muscle dysfunction remain poorly described, due to lack of longitudinal and/or comparative data. Second; the causes remain difficult to separate and may vary greatly depending on the clinical setting. Therefore, to improve the understanding of the etiology of cancer-related muscle dysfunction, a better molecular understanding of the mechanisms behind the muscle dysfunction is warranted. Third; exercise training constitutes a promising therapeutic countermeasure to cancer-related muscle dysfunction; however, there is currently a discrepancy between the clinical setting (timing and study population) of exercise intervention trials (mainly in early-stage breast and prostate cancer patients) and the observational studies, showing muscle function as a predictor of clinical end points (mainly shown in advanced stage GI patients). Thus, future exercise trials in early-stage patients should be powered to evaluate long-term beneficial effects of improved muscle function on clinical outcomes. Also, future exercise trials should be promoted in advanced stage settings, where patients experience the highest incidence and degree of muscle function impairments, aiming to reverse cancerrelated muscle dysfunction and thus potentially improve timeto-progression, treatment toxicity and mortality.
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18. 19.
20.
21.
22.
23.
25. 26.
27. 28. 29. 30. 31. 32. 33. 34. 35.
36.
37.
38. 39. 40.
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Annals of Oncology