General Definitions and Concepts of Sarcopenia: History
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Subjects: Oncology
Contributor:
Federica Medici
,
Stefania Rizzo
,
Milly Buwenge
,
Alessandra Arcelli
,
Martina Ferioli
,
Gabriella Macchia
,
Francesco Deodato
,
Savino Cilla
,
Pierandrea De Iaco
,
Anna Myriam Perrone
,
Silvia Strolin
,
Lidia Strigari
,
Gloria Ravegnini
,
Alberto Bazzocchi
,
Alessio G. Morganti

Sarcopenia (SP) is a syndrome characterized by age-associated loss of skeletal muscle mass and function.

  • radiotherapy
  • sarcopenia
  • adult cancer
  • sarcopenic obesity
  • cachexia
  • myosteatosis

1. Introduction

Sarcopenia (SP) is a syndrome characterized by loss of skeletal muscle mass (quantitative impairment) and function (qualitative impairment) [1][2][3]. In recent years, interest in SP in oncology has been growing due to the high prevalence of SP (15–74%) in cancer patients [4].
In particular, attention to SP has grown in the field of radiotherapy (RT), given the evidence of the significant impact of SP on the prognosis of RT-treated patients, and the possibility of preventing and at least partially treating this syndrome [5]. In fact, only in 2020 and 2021, 114 papers were registered on PubMed including seven systematic reviews on RT and SP [6]. For this reason, it may be useful to provide a quick guide to radiation oncologists on this topic.

2. General Definitions and Concepts

What is sarcopenia? How is it defined?
Three consensus statements [1][2][3] agreed to define SP as a syndrome characterized by age-associated loss of skeletal muscle mass (quantitative impairment) and function (qualitative impairment) combined or not with increased fat mass (sarcopenic obesity—SO). Moreover, the European consensus separated primary (no etiology found) and secondary SP (associated with physical inactivity or some chronic conditions: malnutrition, endocrinopathies, chronic diseases, inflammatory disease, or cancer) [1]. Furthermore, pre-SP is considered an isolated loss of skeletal muscle without impaired muscle function [1]. Finally, in cancer patients, SP is considered the first step toward cachexia, a condition that is not fully reversible with nutritional intervention and leads to disability and reduced treatment efficacy.
What are the causes and mechanisms leading to sarcopenia?
The origin of SP is considered to be multifactorial. In particular, the following are considered causes of SP:
1
Aging is associated with a state of anorexia leading to weight loss [7][8]. The latter is due to both a reduction in fat (75%) and muscle and bone tissue (25%). In the case of weight recovery, this mainly affects the fat tissue leading to SO.
2
Furthermore, aging is also associated with motor neuron alterations [9] leading to muscle atrophy and decreased muscle function.
3
In the elderly anabolic hormones (growth hormone, insulin growth factor 1, DHEA, and testosterone) are reduced [10][11][12].
4
Aging and obesity favor a condition of insulin resistance, leading to reduced availability of glucose and proteins needed for muscle anabolism [13].
5
Finally, obesity and various diseases increase proinflammatory cytokines and thus activate NFkB and ultimately protein catabolism [14].
What are the clinical, biochemical, and molecular mechanisms underlying reduced therapeutic response?
Some mechanisms explaining the negative prognostic impact of SP in oncology can be summarized as follows:
1
SP is closely related to performance status, which in turn has an important and well-known prognostic impact on cancer patients [15][16].
2
SP is associated with a higher incidence of peri- and post-operative complications and therefore can delay or hinder adjuvant therapies with consequently worse prognosis [17][18].
3
The loss of muscle mass reduces the secretion of some circulating cytokines, which are produced by muscle cells (myokines: IL-6, IL-8, IL-15) and which hinder tumor progression.
4
SP is more common in patients with more advanced cancer [17][19][20].
5
SP worsens the frequency and severity of radiation-induced acute toxicity [21][22] and thus hinders the completion of RT on schedule [23].
6
SP is associated with increased radiation-induced late toxicity, with possible worsening of prognosis and quality of life [24].
Overall, SP is closely related to the patient’s general condition and can affect both tumor progression and treatment tolerability [4].
Why is sarcopenia different from cachexia and myosteatosis?
Based on an international consensus, cachexia was defined as the progressive and not completely reversible loss of skeletal muscle tissue associated with impaired muscle function. In particular, cachexia is considered to be a syndrome including successive stages, from pre-cachexia to cachexia, to refractory cachexia. Cachectic patients are subjects who have shown a weight reduction > 5% in six months or patients who have shown a weight reduction of at least 2% and concurrently have a BMI < 20 kg/m2 or an SP status [25]. Cachexia is caused by the combination of reduced dietary intake and alterations in metabolism and in particular, as SP, to the activation of factors regulating the degradation of proteins, even if the type of mediators is different from those involved in SP [26]. More specifically, SP appears to be related to changes in signals for muscle tissue growth, whereas cachexia would depend on cytokine-mediated degradation of muscle and adipose tissue [27]. Furthermore, cachexia, as well as the state of systemic inflammation, seem to be associated with the activation of specific genes that are more expressed in some tumors (lung, pancreas) in which the cachectic state is more frequent [28]. A more accurate understanding of the biomolecular pathways involved in SP and cachexia could lead to the development of drug therapies targeting these processes.
Myosteatosis (MS) is a pathological infiltration of muscle tissue by adipose tissue. In fact, in physiological conditions, skeletal muscles contain only minimal fat deposits which, during aerobic activity, are used as a source of energy. MS increases in old age and negatively affects metabolism as it is associated with insulin resistance and diabetes. The deposition of adipose tissue in the muscles can occur in different ways/sites:
1
Between different muscles (intermuscular),
2
In the extracellular site but within a single muscle (intramuscular),
3
Within the cells (intramiocellular). Furthermore, MS is characterized not only by the accumulation but also by the different chemical compositions of fats normally present in the muscles [29].
Therefore, MS is not synonymous with SP but the two conditions can coexist and produce synergistic effects, particularly at the metabolic level [30]. Indeed, MS is associated with diabetes and obesity [31][32][33], impaired muscle function [34], and cancer [35]. Its correlation with the prognosis in cancer patients has also been demonstrated [36].
What is sarcopenic obesity? Is it worse than Sarcopenia? Why?
SO is considered a “hidden form” of SP (due to large fat mass) [37]. Due to the lack of a shared definition, the prevalence varies between the different studies [37]. SO is independently related to higher mortality and worse complications after surgery and systemic treatments, with a worse impact compared to SP alone. The reasons for this effect are not fully understood but the simplest explanation is that patients with SO have both the risks of obesity and SP [38]. Furthermore, patients with SO are typically unfit and unable to tolerate stressful situations [37].
Moreover, it has been speculated that the greater chemotherapy toxicity in patients with SO is due to a high absolute drug dose which is distributed in a small volume. In fact, the Body Surface Area is traditionally used to calculate the dose of cytotoxic chemotherapy. Nevertheless, in patients with SO, the large Body Surface area determines a high dose of chemotherapy but is distributed in a reduced lean body mass with consequently hindered metabolism and elimination of drugs, and thus with a higher incidence of toxicity [37].
The clinical management of SO requires further study, starting with the formulation of a consensus definition. In fact, the following appear to be particularly necessary: (I) pharmacology studies to investigate the effect of SO on the distribution, metabolism, and elimination of chemotherapeutics, (II) analyses confirming the synergistic effect of PD and obesity, (III) studies aimed at defining SO treatment protocols and methods of dose-modulation of systemic therapies in subjects with SO. Indeed, at present, the only treatment strategy in this setting is empirically based on the combination of weight loss, adequate protein intake, and exercise [37][39].

This entry is adapted from the peer-reviewed paper 10.3390/curroncol29110671

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