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Muscoloskeletal aging, sarcopenia and cancer
JGO-00644; No. of pages: 6; 4C: Journal of Geriatric Oncology xxx (xxxx) xxx
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Journal of Geriatric Oncology
Muscoloskeletal aging, sarcopenia and cancer Colloca Giuseppe a,⁎, Di Capua Beatrice b, Bellieni Andrea b, Cesari Matteocenzo c, Valentini Vincenzo a, Marzetti Emanuele b, Calvani Riccardo b a Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Istituto di Radiologia, Fondazione Policlinico A. Gemelli IRCCS - Università Cattolica Sacro Cuore, Largo A. Gemelli, 8, 00168, Rome, Italy b Università Cattolica del Sacro Cuore, Rome 00168, Italy c Unit of Epidemiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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Article history: Received 3 February 2018 Received in revised form 26 August 2018 Accepted 20 November 2018 Available online xxxx
a b s t r a c t In the context of the management of the elderly patient with cancer, currently, a key topic may be expressed by sarcopenia. Sarcopenia in its various definitions and ambiguities in the older adult is always related to negative outcomes. A close correlation between sarcopenia and adverse outcomes such as treatment response or toxicity has also been shown in the patient with cancer. For these reasons, it becomes increasingly important to try to understand and therefore differentiate conditions such as the loss of muscle mass linked to normal aging, an independent pathological condition such as sarcopenia and finally a sometimes confusing pathologic condition called cachexia. © 2018 Elsevier Ltd. All rights reserved.
1. Introduction In the scenario of the general population, aging and the increasing number of diagnosed and treated cancer in the older adult, it has become more and more important to identify, understand and assess the so-called geriatric syndromes in the elderly patient with cancer. Among these more attention is being placed on sarcopenia. For this reason, it has become important to know the differences between sarcopenia and the loss of muscle mass related to the normal process of muscle aging, but also how to differentiate them from an overlapping pathological condition called cachexia (both cancer and no-cancer related cachexia). Cachexia has similar clinical features to sarcopenia but is deeply different in terms of pathophysiological and etiological characteristics. 2. Muscle Aging Muscle is a major component of lean body mass (LBM) and plays a vital role in maintaining health “Fig.1”. It has been shown that there is a direct or indirect relationship between muscle and strength, energy, mobility, skeletal support, balance, wound healing, immune function, digestive function, and skin health. Furthermore, decreasing muscle strength and age-related muscle loss, are currently considered the most common changes that accompany aging [1,2]. The decrease in muscle mass and strength represent the most relevant descriptor of physiological aging, considered by some as the basis ⁎ Corresponding author. E-mail address: [email protected] (G. Colloca).
for understanding the aging process “Fig. 2”. Moreover an accentuated muscle loss can lead to adverse health outcomes (e.g., mobility disability, physical frailty, falls and fractures, mortality) and worse survival in older adults [3]. Muscle wasting can affect the risk of developing cancer, as muscle tissue is a major regulator of metabolic and inflammatory pathways [4–6], and in adults with cancer it has been associated with increased chemotherapy toxicity, postoperative complications, and higher mortality rates [7], independent of disease stage. (Table 1). The muscle tissue is a complex organ system, an organ, with an enormous plasticity able to regulate its functional, structural and metabolic properties in order to adapt to varying physiological demands. The muscle decline has a multifactorial origin, involving lifestyle habits, disease triggers, and age-dependent biological changes. This phenomenon is part of the geriatric literature and is starting to disseminate into other specialties dealing with the complexity of frail older persons. Muscle tissue changes with aging and specific alterations include: a reduction in cell number, decreased sarcoplasmic reticulum volume and calcium pumping capacity, unorganized sarcomere spacing, reduced excitability of the muscle plasma membrane, increases in fat storage within and around the muscle cells, decreased muscle twitch time and twitch force, a lower number of motor neurons, and a reduced regenerative abilities of the nervous tissue. Testosterone concentrations gradually decrease which may cause lower muscle protein synthesis and muscle mass [8]. The Growth hormone and insulin-like growth factor exhibit a gradual and progressive decline during normal aging, this is related to a decrease in muscle mass but not on muscle strength [9,10]. A mitochondrial DNA deletion mutation subsequent to oxidative
https://doi.org/10.1016/j.jgo.2018.11.007 1879-4068/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: G. Colloca, B. Di Capua, A. Bellieni, et al., Muscoloskeletal aging, sarcopenia and cancer, J Geriatr Oncol, https://doi.org/ 10.1016/j.jgo.2018.11.007
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Fig. 1. Percentage of body composition by weight.
damage and a slight reduction in overall metabolic rate has been reported [11,12]. Moreover, the most striking aspect is a reduction in protein synthesis, with a closely related progressive decrease in muscle mass [13,14]. The basal metabolic rate falls during the normal aging process, after the age of 30 years decrease at the rate of 3–8% per decade, and it is entirely due to involuntary loss of muscle (the metabolic rate corrected for muscle mass does not decline). After the age of 50, approximately 1–2% per year of muscle mass is lost, which accelerates to 3% per year past the age of 60, in conjunction with decline in strength of 1.5% annual [15,16]. A completely different topic but closely related to muscle aging is muscle inactivity [17]. A controversial study showed that prolonged inactivity can cause a significant decrease in muscle protein synthesis, whole body lean mass, lower extremity lean mass, and strength, even if an equicaloric diet is consumed and the recommended amount of protein is consumed (0.8 g/kg of protein per day), in this study the researchers held in bed twelve men and woman continuously for ten days, except for toileting [18].
Physical exercise is currently considered to be equivalent to medications and special attention is devoted to the design and standardization of recommendations for its prescription [19]. Thus physical inactivity it could be considered as one of the strongest predictors of disability in older adults [20]. Evidence shows an inverse relation between mortality/morbidity and physical activity [21]. Longitudinal studies have demonstrated that regular physical activity extends longevity and reduces the risk of physical disability, improves muscle twitch time and twitch force [22], reduces osteoporosis, induces a release of neuro-hormonal mediators as endorphins and serotonin, reduces the risk of sudden death related to cardiovascular diseases [23], reduces the development metabolic disorders, and delays cognitive function decline [24]. The research of the Leveille group [25] of The National Institute of Aging is an excellent example of what exercise can do for physical disability; they found that those who perform regular physical activity are twice as likely to be disability-free at death [26,27]. Consistent findings have also been reported from similar studies conducted in smaller groups of patients with cancer showing the beneficial effects of exercise [28,29].
3. Sarcopenia Etiological Factors and Mechanisms The term sarcopenia was coined by Rosenberg in 1989 to describe the age-related reduction of muscle mass that occurs with advancing age [30]. However, the important changes in muscle quality [31] and structure not just mass, necessitate a functional measurement to establish the true power of muscles mass [32]. Thus currently, sarcopenia can be defined as: a pathological loss of skeletal muscle mass characterized Table 1 Associated complications to loss of lean body mass. % Loss of LBM
Associated complications
10%
• • • • • • • •
20% 30% Fig. 2. Loss of muscle mass and strength: After the age of 40, healthy adults can lose 8% of muscle mass every 10 years, between the age of 40 to 70 years old, healthy adults lose an average of 24% of muscle mass.
40%
Decreased immunity Increased risk of infection Decreased wound healing Increased muscle weakness Pressure ulcers Pneumonia Lack of healing Increased risk of death
Please cite this article as: G. Colloca, B. Di Capua, A. Bellieni, et al., Muscoloskeletal aging, sarcopenia and cancer, J Geriatr Oncol, https://doi.org/ 10.1016/j.jgo.2018.11.007
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by essential structural changes in muscle quality [31] which occurs in the older adult and shows up with functional impairment and/or strength reduction. Sarcopenia is a condition characterized by profound changes in muscle structure: muscle mass is infiltrated by fat and connective tissue, the number and size of type 1 and 2 fibers decrease together with a loss of motor units, disarrangement of myofilaments and Z-lines occurs, the lipofuscin accumulates inside the fibers [33]. This phenomenon is strictly connected to aging and provokes a reduction in muscle strength and function. Many studies show how sarcopenia is a condition related to functional decline and disability [32,34] and, consequently, with a higher risk of adverse outcomes such as immobility, disability, physical frailty, falls and fractures, and mortality [35,36]. Sarcopenia should be considered a geriatric syndrome since multiple contributing factors (the aging process, diet, bed rest, sedentary lifestyle, chronic diseases or drug treatments [37–39]) cause loss of muscle mass that leads to an impaired state of health [40,41]. Sarcopenia has a multifactorial origin [17]. Life habits including physical inactivity, bed rest, and malnutrition, can play an important role in most cases. In older adult, changes in the endocrine system, typical of aging, can cause an imbalance between anabolic and catabolic process [42]. There is a decrease in anabolic hormones (testosterone, estrogens, growth hormone, insulin-like growth factor-1) [43], alterations in renin-angiotensin system [44], and vitamin D deficiency [45]. Lowgrade systemic inflammation, typical of aging and chronic disease, also plays an important role, through the increase of inflammatory cytokines (IL-1, IL-6, TNFα). Recent studies show how mitochondrial dysfunction and oxidative stress could be central to the pathogenesis of sarcopenia [46]. The four most important definitions of sarcopenia it recognize sarcopenia as a bi-dimensional condition having a quantitative and qualitative component [17,47–49]. The most common definition is the European Working Group on Sarcopenia in Older People (EWGSOP) one. According to EWGSOP, sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength [50,51]. It is defined by the simultaneous presence of low appendicular lean mass, assessed by dual-energy X-ray absorptiometry [DEXA], plus muscle weakness, measured as poor handgrip strength, and/or impaired mobility (captured by slow gait speed). Recognizing stages of sarcopenia may help in selecting treatment and setting appropriate recovery goals “Fig. 3” [48]. There are three stages of sarcopenia, presarcopenia, sarcopenia and severe sarcopenia. In presarcopenia it can be observed: low muscle mass without having a decrease in muscle strength or physical performance. In sarcopenia, a loss of muscle mass is matched with either low muscle strength or low physical performance. Severe sarcopenia is a condition where all three criteria (low muscle mass, low muscle strength, and low physical performance) are present. Sometimes a shift in body composition may be observed, with an increase in fat mass and a decrease in lean body mass. This condition, which is called sarcopenic obesity, can be go unrecognized because of the stable body weight [52–54]. Finally, sarcopenia may be classified based on etiology, in primary or secondary form. Sarcopenia can be considered ‘primary’ when no underlying cause is found, while it's considered ‘secondary’ when one or more causes are evident. The most common causes of sarcopenia in the older adult are inactivity (sedentary lifestyle or deconditioning) and poor nutrition
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(inadequate dietary intake of energy/protein or when other conditions cause malabsorption). Other times, sarcopenia is related to advanced organ failure (heart, lung, liver, kidney, brain), malignancy or endocrine disease. However, most of the time, sarcopenia has a multifactorial etiology and it is difficult to identify a single specific underlying cause. The presence of sarcopenia in older adult with cancer has been associated with an increased risk of chemotherapy toxicity, more postoperative complications, and higher mortality rates [7], regardless of disease stage [4–6,55]. 4. Cancer Cachexia and no Cancer Cachexia Cachexia is a complex metabolic syndrome associated with underlying illness which is characterized by loss of muscle muss with or without loss of fat mass that cannot be fully reversed by the conventional nutritional support and leads to progressive functional impairment. The most prominent clinical feature of cachexia is weight loss in adults or growth failure in children. Cachexia is distinct from starvation, agerelated loss of muscle mass, primary depression, malabsorption and hyperthyroidism and is associated with increased morbidity” [56,57]. Cancer is not the only disease known to be associated with cachexia. Chronic diseases, characterized by high levels of underlying inflammation, such as COPD, chronic heart failure, chronic renal failure, liver failure, chronic infection, and rheumatoid arthritis are also associated with cachexia [47]. Cachexia is linked to lower physical function [58] and reduced tolerance to anticancer therapy [59,60], and it increases patient morbidity and mortality [61]. Anorexia (defined as the reduced desire to eat), malnutrition [62] and metabolic disorders, as well as increased inflammation, insulin resistance, the breakdown of muscle proteins, impaired carbohydrate, protein and lipid metabolism all, contribute to the onset of cachexia [43,47,63–66]. The cornerstone in the pathogenesis of cachexia is inflammation: the imbalance between pro-inflammatory cytokines (tumor necrosis factor-a [TNF-a], interleukin-1 [IL-1], interleukin-6 [IL-6], interferon-g [IFN-g]) and anti-inflammatory cytokines (e.g., IL-4, IL-12, IL-15) [67] is currently believed to result in cachexia. Even if cancer-related cachexia affects the majority of patients with advanced disease, the variability of the prevalence of cachexia depends on both tumor and patient factors [68]. Evans et al. proposed specific criteria for diagnosing cachexia: weight loss of at least 5% in 12 months or BMI b20 kg/m2, associated with three or more of the following criteria: muscle weakness, fatigue, anorexia, low skeletal muscle index and/or abnormal biochemistry (increased inflammatory markers, anemia, low serum albumin) [56]. The international consensus on cancer cachexia describe cachexia as a continuum that can develop progressively through three different levels of severity: pre-cachexia, cachexia and refractory cachexia, although not all patients traverse the entire spectrum [57]. In pre-cachexia, initial changes in metabolism (such as anorexia and impaired glucose tolerance) are associated with the beginning of involuntary weight loss (≤ 5%). In cachexia, a patient has to meet one of the following criteria: - ≥ 5% Loss of Stable Body Weight over the Past 6 months - body- mass index (BMI) b20 kg/m2 and ongoing weight loss of N2% - Sarcopenia and Ongoing Weight Loss of N2%
Fig. 3. The Sarcopenia stages.
Please cite this article as: G. Colloca, B. Di Capua, A. Bellieni, et al., Muscoloskeletal aging, sarcopenia and cancer, J Geriatr Oncol, https://doi.org/ 10.1016/j.jgo.2018.11.007
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Refractory cachexia is associated with very advanced cancer or rapidly progressive cancer. Over this stage, associated with high hypercatabolism, the management of weight-loss is no longer possible and is characterized by a low physical performance status and b3 months of life expectancy [57]. 5. Musculoskeletal Aging, Sarcopenia and Cachexia as Overlapping Conditions in Older Adults with Cancer Aging is related to a decline in muscle mass and strength [15] but only when this decline becomes pathological (sarcopenia) does this process lead to adverse health outcomes [3]. In patients with cancer, many studies show how the loss of muscle mass is a prevalent condition independent of disease stage and body mass [69]. The prevalence of low muscle mass, defined using CT images, is highly variable, ranging from 5% to 89% in different groups of oncological patients [70]. Patients with cancer are at increased risk of muscle loss in two different ways: they can be affected by sarcopenia, defined as an accentuated decrease in muscle mass and muscle strength or physical performance, or they could develop cachexia, a more complex metabolic syndrome sustained by cytokine-mediated degradation of muscle mass [71]. The biological substrate of sarcopenia and cachexia largely overlaps, although some specific pathways are observed in sarcopenia but not in cachexia and vice versa. Some fundamental clinical differences make the two conditions diverge in diagnosis and management (Table 2). The decrease in muscle mass is, of course, a common feature, while weight loss and a decrease of fat mass are commonly seen in cachexia, but not typically found in sarcopenia. In cachexia, we can always find the specific disease that led to this condition, whereas sarcopenia is a multifactorial condition that often, can occur without a triggering disease. Inflammation is a cornerstone in the pathogenesis of cachexia but distinctively not in sarcopenia, although sometimes a low-grade of inflammation low grade, called ‘inflammaging’, has been associated with sarcopenia [72]. Many techniques are used to assess muscle mass changes. Each methodology has pros and cons depending on the purposes and setting in which it is applied [35,73,74]. Costs, availability, and convenience may determine whether the technique is more suitable for clinical practice or for research [48]. MRI and CT scans are considered the gold standards for estimating muscle mass, since they more accurately can distinguish fat from other tissue. However, both are very expensive and are not always available. They are also time-consuming, involve exposure to radiation and a specialist is required for interpretation of results. Thus MRI and CT are not routinely used in geriatric clinical practice, but since sarcopenia is becoming increasingly relevant in elderly patients with cancer, CT scans are turning out to be the most frequently used technique in this field. Using CT scans, muscle mass can be determined by measuring either the total psoas cross-sectional area (TPA) at the L3 cervical spine level [75–79] or the total abdominal muscle area (TAMA) at the L3 level [69,80–82]. DEXA scan (Dual Energy X-Ray Absorptiometry) is a quite accurate technique to discriminate and quantify between fat, bone mineral and lean tissue, and it may be useful for research and clinical use. It exposes Table 2 Comparison between Sarcopenia and Cachexia.
Weight Lean tissue Fat tissue Appetite Cortisol Inflammatory disease Pathway
Sarcopenia
Cachexia
= ↓ = or ↑ = = No Does not lead to cachexia
↓↓ ↓↓ ↓ ↓ ↑ Yes May lead to sarcopenia
the patient to low dose radiation, it doesn't require dedicated training and is less expensive than MRI or CT scans. Bioimpedance analysis (BIA) is a commonly used method for estimating the volume of fat and lean body mass. The device is easy to use, portable, and the exam is inexpensive. These characteristics make it very convenient for both outpatients and hospitalized patients. BIA results correlate well with MRI predictions [83] and indipendent reference values have been established for men and women, including older adults [84–86]. Anthropometric measures have been used to assess muscle mass, but they have very limited accuracy and are not recommended [48]. To estimate muscle strength, handgrip is the most widely used method. The Strength is the magnitude of the force generated by a muscle. Although lower limbs are considered to be more important for evaluating disability and physical impairment, isometric handgrip strength was shown to be related to lower extremity muscle power, knee extension torque and calf cross-sectional muscle area [34]. It has been shown that a linear relationship exists between baseline handgrip strength and incident disability for activities of daily living (ADL) [87]. Other techniques used for this purpose are knee flexion/extension and peak expiratory flow. To evaluate physical performance the European Working Group on Sarcopenia in Older People suggested the following techniques: • Short physical performance battery (SPPB): SPPB is a composite measure that assesses balance, gait speed, lower extremity strength and endurance in a single evaluation [88]. • Usual gait speed: Several studies demonstrate the predictive value of usual gait speed for adverse events (severe mobility limitation, mortality) [89–91]. • Timed get-up-and-go test: this is a dynamic measurement where the patient has to stand up from a chair, walk a few meters, turn around, return and sit down again [92]. • Stair climb power test: has been proposed as an indicator of leg power [93] and is mostly used in a research setting. 6. Conclusion Muscular aging is a physiological phenomenon, but once the muscle mass decline becomes pathological, it must be taken into account in the cancer management as it has an impact on negative outcomes (longer hospitalization, overall survival or toxicity). Sarcopenia and muscle wasting related to physical inactivity are considered treatable and reversible conditions. The most effective strategy appears to be a combination of nutritional interventions (protein/ amino acid supplementation, multinutrient supplementation, vitamin D supplementation) and physical exercise (typically an exercise program which involved both resistance training and additional exercises such as aerobic exercises, flexibility, and balance). Cachexia is a complex metabolic syndrome associated with an underlying illness that cannot be fully reversed by the conventional nutritional support [94]. In the personalization of treatments, it becomes increasingly important especially for the older adults with cancer to be able to determine the reversible predictors of survival and toxicity. For this reason, it is extremely important in the management of the older adults with cancer to recognize the differences between these three conditions, and how to treat them. Disclosures and Conflict of Interest Statements The authors have declared no conflict of interest. Author Contributions Conception and design: G.Colloca, B.Di Capua, A. Bellieni, R. Calvani, E. Marzetti, V.Valentini, M.Cesari.
Please cite this article as: G. Colloca, B. Di Capua, A. Bellieni, et al., Muscoloskeletal aging, sarcopenia and cancer, J Geriatr Oncol, https://doi.org/ 10.1016/j.jgo.2018.11.007
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Please cite this article as: G. Colloca, B. Di Capua, A. Bellieni, et al., Muscoloskeletal aging, sarcopenia and cancer, J Geriatr Oncol, https://doi.org/ 10.1016/j.jgo.2018.11.007
Contents lists available at ScienceDirect
Journal of Geriatric Oncology
Muscoloskeletal aging, sarcopenia and cancer Colloca Giuseppe a,⁎, Di Capua Beatrice b, Bellieni Andrea b, Cesari Matteocenzo c, Valentini Vincenzo a, Marzetti Emanuele b, Calvani Riccardo b a Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Istituto di Radiologia, Fondazione Policlinico A. Gemelli IRCCS - Università Cattolica Sacro Cuore, Largo A. Gemelli, 8, 00168, Rome, Italy b Università Cattolica del Sacro Cuore, Rome 00168, Italy c Unit of Epidemiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
a r t i c l e
i n f o
Article history: Received 3 February 2018 Received in revised form 26 August 2018 Accepted 20 November 2018 Available online xxxx
a b s t r a c t In the context of the management of the elderly patient with cancer, currently, a key topic may be expressed by sarcopenia. Sarcopenia in its various definitions and ambiguities in the older adult is always related to negative outcomes. A close correlation between sarcopenia and adverse outcomes such as treatment response or toxicity has also been shown in the patient with cancer. For these reasons, it becomes increasingly important to try to understand and therefore differentiate conditions such as the loss of muscle mass linked to normal aging, an independent pathological condition such as sarcopenia and finally a sometimes confusing pathologic condition called cachexia. © 2018 Elsevier Ltd. All rights reserved.
1. Introduction In the scenario of the general population, aging and the increasing number of diagnosed and treated cancer in the older adult, it has become more and more important to identify, understand and assess the so-called geriatric syndromes in the elderly patient with cancer. Among these more attention is being placed on sarcopenia. For this reason, it has become important to know the differences between sarcopenia and the loss of muscle mass related to the normal process of muscle aging, but also how to differentiate them from an overlapping pathological condition called cachexia (both cancer and no-cancer related cachexia). Cachexia has similar clinical features to sarcopenia but is deeply different in terms of pathophysiological and etiological characteristics. 2. Muscle Aging Muscle is a major component of lean body mass (LBM) and plays a vital role in maintaining health “Fig.1”. It has been shown that there is a direct or indirect relationship between muscle and strength, energy, mobility, skeletal support, balance, wound healing, immune function, digestive function, and skin health. Furthermore, decreasing muscle strength and age-related muscle loss, are currently considered the most common changes that accompany aging [1,2]. The decrease in muscle mass and strength represent the most relevant descriptor of physiological aging, considered by some as the basis ⁎ Corresponding author. E-mail address: [email protected] (G. Colloca).
for understanding the aging process “Fig. 2”. Moreover an accentuated muscle loss can lead to adverse health outcomes (e.g., mobility disability, physical frailty, falls and fractures, mortality) and worse survival in older adults [3]. Muscle wasting can affect the risk of developing cancer, as muscle tissue is a major regulator of metabolic and inflammatory pathways [4–6], and in adults with cancer it has been associated with increased chemotherapy toxicity, postoperative complications, and higher mortality rates [7], independent of disease stage. (Table 1). The muscle tissue is a complex organ system, an organ, with an enormous plasticity able to regulate its functional, structural and metabolic properties in order to adapt to varying physiological demands. The muscle decline has a multifactorial origin, involving lifestyle habits, disease triggers, and age-dependent biological changes. This phenomenon is part of the geriatric literature and is starting to disseminate into other specialties dealing with the complexity of frail older persons. Muscle tissue changes with aging and specific alterations include: a reduction in cell number, decreased sarcoplasmic reticulum volume and calcium pumping capacity, unorganized sarcomere spacing, reduced excitability of the muscle plasma membrane, increases in fat storage within and around the muscle cells, decreased muscle twitch time and twitch force, a lower number of motor neurons, and a reduced regenerative abilities of the nervous tissue. Testosterone concentrations gradually decrease which may cause lower muscle protein synthesis and muscle mass [8]. The Growth hormone and insulin-like growth factor exhibit a gradual and progressive decline during normal aging, this is related to a decrease in muscle mass but not on muscle strength [9,10]. A mitochondrial DNA deletion mutation subsequent to oxidative
https://doi.org/10.1016/j.jgo.2018.11.007 1879-4068/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: G. Colloca, B. Di Capua, A. Bellieni, et al., Muscoloskeletal aging, sarcopenia and cancer, J Geriatr Oncol, https://doi.org/ 10.1016/j.jgo.2018.11.007
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Fig. 1. Percentage of body composition by weight.
damage and a slight reduction in overall metabolic rate has been reported [11,12]. Moreover, the most striking aspect is a reduction in protein synthesis, with a closely related progressive decrease in muscle mass [13,14]. The basal metabolic rate falls during the normal aging process, after the age of 30 years decrease at the rate of 3–8% per decade, and it is entirely due to involuntary loss of muscle (the metabolic rate corrected for muscle mass does not decline). After the age of 50, approximately 1–2% per year of muscle mass is lost, which accelerates to 3% per year past the age of 60, in conjunction with decline in strength of 1.5% annual [15,16]. A completely different topic but closely related to muscle aging is muscle inactivity [17]. A controversial study showed that prolonged inactivity can cause a significant decrease in muscle protein synthesis, whole body lean mass, lower extremity lean mass, and strength, even if an equicaloric diet is consumed and the recommended amount of protein is consumed (0.8 g/kg of protein per day), in this study the researchers held in bed twelve men and woman continuously for ten days, except for toileting [18].
Physical exercise is currently considered to be equivalent to medications and special attention is devoted to the design and standardization of recommendations for its prescription [19]. Thus physical inactivity it could be considered as one of the strongest predictors of disability in older adults [20]. Evidence shows an inverse relation between mortality/morbidity and physical activity [21]. Longitudinal studies have demonstrated that regular physical activity extends longevity and reduces the risk of physical disability, improves muscle twitch time and twitch force [22], reduces osteoporosis, induces a release of neuro-hormonal mediators as endorphins and serotonin, reduces the risk of sudden death related to cardiovascular diseases [23], reduces the development metabolic disorders, and delays cognitive function decline [24]. The research of the Leveille group [25] of The National Institute of Aging is an excellent example of what exercise can do for physical disability; they found that those who perform regular physical activity are twice as likely to be disability-free at death [26,27]. Consistent findings have also been reported from similar studies conducted in smaller groups of patients with cancer showing the beneficial effects of exercise [28,29].
3. Sarcopenia Etiological Factors and Mechanisms The term sarcopenia was coined by Rosenberg in 1989 to describe the age-related reduction of muscle mass that occurs with advancing age [30]. However, the important changes in muscle quality [31] and structure not just mass, necessitate a functional measurement to establish the true power of muscles mass [32]. Thus currently, sarcopenia can be defined as: a pathological loss of skeletal muscle mass characterized Table 1 Associated complications to loss of lean body mass. % Loss of LBM
Associated complications
10%
• • • • • • • •
20% 30% Fig. 2. Loss of muscle mass and strength: After the age of 40, healthy adults can lose 8% of muscle mass every 10 years, between the age of 40 to 70 years old, healthy adults lose an average of 24% of muscle mass.
40%
Decreased immunity Increased risk of infection Decreased wound healing Increased muscle weakness Pressure ulcers Pneumonia Lack of healing Increased risk of death
Please cite this article as: G. Colloca, B. Di Capua, A. Bellieni, et al., Muscoloskeletal aging, sarcopenia and cancer, J Geriatr Oncol, https://doi.org/ 10.1016/j.jgo.2018.11.007
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by essential structural changes in muscle quality [31] which occurs in the older adult and shows up with functional impairment and/or strength reduction. Sarcopenia is a condition characterized by profound changes in muscle structure: muscle mass is infiltrated by fat and connective tissue, the number and size of type 1 and 2 fibers decrease together with a loss of motor units, disarrangement of myofilaments and Z-lines occurs, the lipofuscin accumulates inside the fibers [33]. This phenomenon is strictly connected to aging and provokes a reduction in muscle strength and function. Many studies show how sarcopenia is a condition related to functional decline and disability [32,34] and, consequently, with a higher risk of adverse outcomes such as immobility, disability, physical frailty, falls and fractures, and mortality [35,36]. Sarcopenia should be considered a geriatric syndrome since multiple contributing factors (the aging process, diet, bed rest, sedentary lifestyle, chronic diseases or drug treatments [37–39]) cause loss of muscle mass that leads to an impaired state of health [40,41]. Sarcopenia has a multifactorial origin [17]. Life habits including physical inactivity, bed rest, and malnutrition, can play an important role in most cases. In older adult, changes in the endocrine system, typical of aging, can cause an imbalance between anabolic and catabolic process [42]. There is a decrease in anabolic hormones (testosterone, estrogens, growth hormone, insulin-like growth factor-1) [43], alterations in renin-angiotensin system [44], and vitamin D deficiency [45]. Lowgrade systemic inflammation, typical of aging and chronic disease, also plays an important role, through the increase of inflammatory cytokines (IL-1, IL-6, TNFα). Recent studies show how mitochondrial dysfunction and oxidative stress could be central to the pathogenesis of sarcopenia [46]. The four most important definitions of sarcopenia it recognize sarcopenia as a bi-dimensional condition having a quantitative and qualitative component [17,47–49]. The most common definition is the European Working Group on Sarcopenia in Older People (EWGSOP) one. According to EWGSOP, sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength [50,51]. It is defined by the simultaneous presence of low appendicular lean mass, assessed by dual-energy X-ray absorptiometry [DEXA], plus muscle weakness, measured as poor handgrip strength, and/or impaired mobility (captured by slow gait speed). Recognizing stages of sarcopenia may help in selecting treatment and setting appropriate recovery goals “Fig. 3” [48]. There are three stages of sarcopenia, presarcopenia, sarcopenia and severe sarcopenia. In presarcopenia it can be observed: low muscle mass without having a decrease in muscle strength or physical performance. In sarcopenia, a loss of muscle mass is matched with either low muscle strength or low physical performance. Severe sarcopenia is a condition where all three criteria (low muscle mass, low muscle strength, and low physical performance) are present. Sometimes a shift in body composition may be observed, with an increase in fat mass and a decrease in lean body mass. This condition, which is called sarcopenic obesity, can be go unrecognized because of the stable body weight [52–54]. Finally, sarcopenia may be classified based on etiology, in primary or secondary form. Sarcopenia can be considered ‘primary’ when no underlying cause is found, while it's considered ‘secondary’ when one or more causes are evident. The most common causes of sarcopenia in the older adult are inactivity (sedentary lifestyle or deconditioning) and poor nutrition
3
(inadequate dietary intake of energy/protein or when other conditions cause malabsorption). Other times, sarcopenia is related to advanced organ failure (heart, lung, liver, kidney, brain), malignancy or endocrine disease. However, most of the time, sarcopenia has a multifactorial etiology and it is difficult to identify a single specific underlying cause. The presence of sarcopenia in older adult with cancer has been associated with an increased risk of chemotherapy toxicity, more postoperative complications, and higher mortality rates [7], regardless of disease stage [4–6,55]. 4. Cancer Cachexia and no Cancer Cachexia Cachexia is a complex metabolic syndrome associated with underlying illness which is characterized by loss of muscle muss with or without loss of fat mass that cannot be fully reversed by the conventional nutritional support and leads to progressive functional impairment. The most prominent clinical feature of cachexia is weight loss in adults or growth failure in children. Cachexia is distinct from starvation, agerelated loss of muscle mass, primary depression, malabsorption and hyperthyroidism and is associated with increased morbidity” [56,57]. Cancer is not the only disease known to be associated with cachexia. Chronic diseases, characterized by high levels of underlying inflammation, such as COPD, chronic heart failure, chronic renal failure, liver failure, chronic infection, and rheumatoid arthritis are also associated with cachexia [47]. Cachexia is linked to lower physical function [58] and reduced tolerance to anticancer therapy [59,60], and it increases patient morbidity and mortality [61]. Anorexia (defined as the reduced desire to eat), malnutrition [62] and metabolic disorders, as well as increased inflammation, insulin resistance, the breakdown of muscle proteins, impaired carbohydrate, protein and lipid metabolism all, contribute to the onset of cachexia [43,47,63–66]. The cornerstone in the pathogenesis of cachexia is inflammation: the imbalance between pro-inflammatory cytokines (tumor necrosis factor-a [TNF-a], interleukin-1 [IL-1], interleukin-6 [IL-6], interferon-g [IFN-g]) and anti-inflammatory cytokines (e.g., IL-4, IL-12, IL-15) [67] is currently believed to result in cachexia. Even if cancer-related cachexia affects the majority of patients with advanced disease, the variability of the prevalence of cachexia depends on both tumor and patient factors [68]. Evans et al. proposed specific criteria for diagnosing cachexia: weight loss of at least 5% in 12 months or BMI b20 kg/m2, associated with three or more of the following criteria: muscle weakness, fatigue, anorexia, low skeletal muscle index and/or abnormal biochemistry (increased inflammatory markers, anemia, low serum albumin) [56]. The international consensus on cancer cachexia describe cachexia as a continuum that can develop progressively through three different levels of severity: pre-cachexia, cachexia and refractory cachexia, although not all patients traverse the entire spectrum [57]. In pre-cachexia, initial changes in metabolism (such as anorexia and impaired glucose tolerance) are associated with the beginning of involuntary weight loss (≤ 5%). In cachexia, a patient has to meet one of the following criteria: - ≥ 5% Loss of Stable Body Weight over the Past 6 months - body- mass index (BMI) b20 kg/m2 and ongoing weight loss of N2% - Sarcopenia and Ongoing Weight Loss of N2%
Fig. 3. The Sarcopenia stages.
Please cite this article as: G. Colloca, B. Di Capua, A. Bellieni, et al., Muscoloskeletal aging, sarcopenia and cancer, J Geriatr Oncol, https://doi.org/ 10.1016/j.jgo.2018.11.007
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Refractory cachexia is associated with very advanced cancer or rapidly progressive cancer. Over this stage, associated with high hypercatabolism, the management of weight-loss is no longer possible and is characterized by a low physical performance status and b3 months of life expectancy [57]. 5. Musculoskeletal Aging, Sarcopenia and Cachexia as Overlapping Conditions in Older Adults with Cancer Aging is related to a decline in muscle mass and strength [15] but only when this decline becomes pathological (sarcopenia) does this process lead to adverse health outcomes [3]. In patients with cancer, many studies show how the loss of muscle mass is a prevalent condition independent of disease stage and body mass [69]. The prevalence of low muscle mass, defined using CT images, is highly variable, ranging from 5% to 89% in different groups of oncological patients [70]. Patients with cancer are at increased risk of muscle loss in two different ways: they can be affected by sarcopenia, defined as an accentuated decrease in muscle mass and muscle strength or physical performance, or they could develop cachexia, a more complex metabolic syndrome sustained by cytokine-mediated degradation of muscle mass [71]. The biological substrate of sarcopenia and cachexia largely overlaps, although some specific pathways are observed in sarcopenia but not in cachexia and vice versa. Some fundamental clinical differences make the two conditions diverge in diagnosis and management (Table 2). The decrease in muscle mass is, of course, a common feature, while weight loss and a decrease of fat mass are commonly seen in cachexia, but not typically found in sarcopenia. In cachexia, we can always find the specific disease that led to this condition, whereas sarcopenia is a multifactorial condition that often, can occur without a triggering disease. Inflammation is a cornerstone in the pathogenesis of cachexia but distinctively not in sarcopenia, although sometimes a low-grade of inflammation low grade, called ‘inflammaging’, has been associated with sarcopenia [72]. Many techniques are used to assess muscle mass changes. Each methodology has pros and cons depending on the purposes and setting in which it is applied [35,73,74]. Costs, availability, and convenience may determine whether the technique is more suitable for clinical practice or for research [48]. MRI and CT scans are considered the gold standards for estimating muscle mass, since they more accurately can distinguish fat from other tissue. However, both are very expensive and are not always available. They are also time-consuming, involve exposure to radiation and a specialist is required for interpretation of results. Thus MRI and CT are not routinely used in geriatric clinical practice, but since sarcopenia is becoming increasingly relevant in elderly patients with cancer, CT scans are turning out to be the most frequently used technique in this field. Using CT scans, muscle mass can be determined by measuring either the total psoas cross-sectional area (TPA) at the L3 cervical spine level [75–79] or the total abdominal muscle area (TAMA) at the L3 level [69,80–82]. DEXA scan (Dual Energy X-Ray Absorptiometry) is a quite accurate technique to discriminate and quantify between fat, bone mineral and lean tissue, and it may be useful for research and clinical use. It exposes Table 2 Comparison between Sarcopenia and Cachexia.
Weight Lean tissue Fat tissue Appetite Cortisol Inflammatory disease Pathway
Sarcopenia
Cachexia
= ↓ = or ↑ = = No Does not lead to cachexia
↓↓ ↓↓ ↓ ↓ ↑ Yes May lead to sarcopenia
the patient to low dose radiation, it doesn't require dedicated training and is less expensive than MRI or CT scans. Bioimpedance analysis (BIA) is a commonly used method for estimating the volume of fat and lean body mass. The device is easy to use, portable, and the exam is inexpensive. These characteristics make it very convenient for both outpatients and hospitalized patients. BIA results correlate well with MRI predictions [83] and indipendent reference values have been established for men and women, including older adults [84–86]. Anthropometric measures have been used to assess muscle mass, but they have very limited accuracy and are not recommended [48]. To estimate muscle strength, handgrip is the most widely used method. The Strength is the magnitude of the force generated by a muscle. Although lower limbs are considered to be more important for evaluating disability and physical impairment, isometric handgrip strength was shown to be related to lower extremity muscle power, knee extension torque and calf cross-sectional muscle area [34]. It has been shown that a linear relationship exists between baseline handgrip strength and incident disability for activities of daily living (ADL) [87]. Other techniques used for this purpose are knee flexion/extension and peak expiratory flow. To evaluate physical performance the European Working Group on Sarcopenia in Older People suggested the following techniques: • Short physical performance battery (SPPB): SPPB is a composite measure that assesses balance, gait speed, lower extremity strength and endurance in a single evaluation [88]. • Usual gait speed: Several studies demonstrate the predictive value of usual gait speed for adverse events (severe mobility limitation, mortality) [89–91]. • Timed get-up-and-go test: this is a dynamic measurement where the patient has to stand up from a chair, walk a few meters, turn around, return and sit down again [92]. • Stair climb power test: has been proposed as an indicator of leg power [93] and is mostly used in a research setting. 6. Conclusion Muscular aging is a physiological phenomenon, but once the muscle mass decline becomes pathological, it must be taken into account in the cancer management as it has an impact on negative outcomes (longer hospitalization, overall survival or toxicity). Sarcopenia and muscle wasting related to physical inactivity are considered treatable and reversible conditions. The most effective strategy appears to be a combination of nutritional interventions (protein/ amino acid supplementation, multinutrient supplementation, vitamin D supplementation) and physical exercise (typically an exercise program which involved both resistance training and additional exercises such as aerobic exercises, flexibility, and balance). Cachexia is a complex metabolic syndrome associated with an underlying illness that cannot be fully reversed by the conventional nutritional support [94]. In the personalization of treatments, it becomes increasingly important especially for the older adults with cancer to be able to determine the reversible predictors of survival and toxicity. For this reason, it is extremely important in the management of the older adults with cancer to recognize the differences between these three conditions, and how to treat them. Disclosures and Conflict of Interest Statements The authors have declared no conflict of interest. Author Contributions Conception and design: G.Colloca, B.Di Capua, A. Bellieni, R. Calvani, E. Marzetti, V.Valentini, M.Cesari.
Please cite this article as: G. Colloca, B. Di Capua, A. Bellieni, et al., Muscoloskeletal aging, sarcopenia and cancer, J Geriatr Oncol, https://doi.org/ 10.1016/j.jgo.2018.11.007
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Please cite this article as: G. Colloca, B. Di Capua, A. Bellieni, et al., Muscoloskeletal aging, sarcopenia and cancer, J Geriatr Oncol, https://doi.org/ 10.1016/j.jgo.2018.11.007