nutrients Review Sarcopenia, Malnutrition, and Cachexia: Adapting Definitions and Terminology of Nutritional Disorders in Older People with Cancer Delky Meza-Valderrama 1,2,3,4 , Ester Marco 1,5,6,7 , Vanesa Dávalos-Yerovi 1,2,5 , Maria Dolors Muns 8 , Marta Tejero-Sánchez 1,5 , Esther Duarte 1,5,6 and Dolores Sánchez-Rodríguez 1,2,9,10,11, * 1 Rehabilitation Research Group, Hospital del Mar Medical Research Institute (IMIM), Dr. Aiguader, 88, 08003 Barcelona, Catalonia, Spain; dmezaconcepcion@psmar.cat (D.M.-V.); emarco@parcdesalutmar.cat (E.M.); ndavalos@parcdesalutmar.cat (V.D.-Y.); mtejero@parcdesalutmar.cat (M.T.-S.); eduarte@parcdesalutmar.cat (E.D.) 2 PhD Program in Biomedicine, Department of Experimental and Health Sciences, Universitat Pompeu Fabra—Doctoral School, Dr. Aiguader, 88, 08003 Barcelona, Catalonia, Spain 3 Physical Medicine and Rehabilitation Department, National Institute of Physical Medicine and Rehabilitation (INMFRE), Vía Centenario, Diagonal a la Universidad Tecnológica de Panamá, Panama City 0819, Panama 4 Physical Medicine and Rehabilitation Department, Policlínica Manuel Váldes, Caja de Seguro Social (C.S.S.), Calle de Circunvalacion, Panama City 0844, Panama 5 Physical Medicine and Rehabilitation Department, Hospital de la Esperança-Parc de Salut Mar,   Sant Josep de la Muntanya 12, 08024 Barcelona, Catalonia, Spain 6 School of Medicine, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Catalonia, Spain Citation: Meza-Valderrama, D.; 7 School of Medicine, Universitat International de Catalunya, c/Immaculada, 22, Marco, E.; Dávalos-Yerovi, V.; Muns, 08017 Barcelona, Catalonia, Spain M.D.; Tejero-Sánchez, M.; Duarte, E.; 8 Endocrinology and Nutrition Department, Hospital del Mar-Parc de Salut Mar, Sánchez-Rodríguez, D. Sarcopenia, Passeig Marítim de la Barceloneta, 25, 29, 08003 Barcelona, Catalonia, Spain; mmuns@psmar.cat 9 Clinical Research Unit, CHU Brugmann, Place Van Gehuchten 4, 1020 Brussels, Belgium Malnutrition, and Cachexia: 10 Geriatrics Department, Centro Forum-Parc de Salut Mar, Llull 410, 08029 Barcelona, Catalonia, Spain Adapting Definitions and 11 WHO Collaborating Centre for Public Health Aspects of Musculo-Skeletal Health and Ageing, Terminology of Nutritional Disorders Division of Public Health, Epidemiology and Health Economics, University of Liège, CHU, Sart Tilman, in Older People with Cancer. Quartier Hôpital, Avenue Hippocrate 13 (Bât. B23), 4000 Liège, Belgium Nutrients 2021, 13, 761. https:// * Correspondence: dolores.sanchez@uliege.be; Tel.: +32-43 66 25 19 doi.org/10.3390/nu13030761 Abstract: The recent publication of the revised Consensus on definition and diagnosis of sarcopenia Academic Editors: Paolo Pedrazzoli (EWGSOP2) and the Global Leadership Initiative on Malnutrition (GLIM) criteria changed the and Riccardo Caccialanza approach to research on sarcopenia and malnutrition. Whilst sarcopenia is a nutrition-related Received: 19 December 2020 disease, malnutrition and cachexia are nutritional disorders sharing the common feature of low Accepted: 15 February 2021 fat-free mass. However, they have differential characteristics and etiologies, as well as specific Published: 26 February 2021 therapeutic approaches. Applying the current definitions in clinical practice is still a challenge for health professionals and the potential for misdiagnosis is high. This is of special concern in the Publisher’s Note: MDPI stays neutral subgroup of older people with cancer, in which sarcopenia, malnutrition, and cancer cachexia are with regard to jurisdictional claims in highly prevalent and can overlap or occur separately. The purpose of this review is to provide an published maps and institutional affil- updated overview of the latest research and consensus definitions of sarcopenia, malnutrition, and iations. cachexia and to discuss their implications for clinical practice in older patients with cancer. The overall aim is to improve the quality of nutritional care in light of the latest findings. Keywords: sarcopenia; malnutrition; cachexia; cancer; muscle mass; older people. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and 1. Introduction conditions of the Creative Commons Sarcopenia, malnutrition, and cachexia may occur within a wide range of diseases, Attribution (CC BY) license (https:// and their presence is associated with poorer health outcomes in all populations; all three creativecommons.org/licenses/by/ 4.0/). are highly prevalent in older patients with cancer [1–3]. The potential for misdiagnosis Nutrients 2021, 13, 761. https://doi.org/10.3390/nu13030761 https://www.mdpi.com/journal/nutrients Nutrients 2021, 13, 761 2 of 10 is high because they share certain characteristics and overlap in some of their criteria; however, their physiopathology, etiology, and prognosis differ widely, as do diagnostic and therapeutic approaches. The harmonization of international terminologies, definitions, and diagnostic criteria of sarcopenia, malnutrition, and cachexia, as well as the early implementation of therapeutic approaches as part of the standard of care in clinical practice, will require a collaborative effort and must not be delayed. However, the overlapping criteria contained in the latest definitions makes it challenging to applying the definitions in clinical practice. An initial question is whether sarcopenia, malnutrition, and cachexia are to be defined as diseases, disorders, syndromes, or conditions—terms often used interchangeably, but having different meanings. A disease is any deviation from or interruption of the normal structure or function of an organ or system of the body as manifested by characteristic symptoms and signs [4]. A disorder is defined as a derangement or abnormality of function; a morbid physical or mental state [4]. A syndrome is a complex of signs and symptoms resulting from a common cause or appearing, in combination, to present a clinical picture of a disease or inherited abnormality [5]. Finally, condition indicates a state of physical and mental health or well-being. The illness defined as a condition might be further classified as a disease or a disorder. However, the term condition also might be used in place of disease or disorder when a value-neutral term is desired [5,6]. Sarcopenia was initially considered a geriatric syndrome by EWGSOP in 2010 [7], as well as a nutrition-related condition by the European Society of Clinical Nutrition and Metabolism (ESPEN) [8]. The inclusion of a disease in the International Classification of Diseases (ICD-10) has implications in terms of clinical practice and healthcare costs [9,10]. Particularly in the case of sarcopenia, this inclusion has led to the EWGSOP2 consid- eration of sarcopenia as a muscle disease related to age (primary sarcopenia), but also to other diseases (secondary sarcopenia). The ESPEN guidelines consider malnutrition and undernutrition as synonyms and define them as nutritional disorders [8]. Cachexia has been defined as a multifactorial syndrome associated with underlying illness [11,12]; more recently, cachexia has been conceptualized as a type of disease-related malnutrition associated with chronic inflammation that should not be perceived as an end-stage of malnutrition [8]. Regardless of the term used (disease, disorder, illness, syndrome, or condition), there may be multiple pathogenic backgrounds and differences in impact on specific popula- tions (e.g., older patients with cancer). Sarcopenia, malnutrition, and cachexia share the common feature of low fat-free mass, but they have differential characteristics, etiologies, and treatments. Other questions also arise: Should we approach age-related sarcopenia differently than sarcopenia related to diseases in older patients with cancer? Should we recommend physical activity to all patients with cancer, even those having a negative energy balance? A good understanding of these nutrition-related conditions, including definitions, screening tools, and diagnostic criteria, is the first step towards being able to answer these questions. The purpose of this review is to provide an updated overview of the latest research and consensus definitions of sarcopenia, malnutrition, and cachexia, and to discuss their implications for clinical practice in older patients with cancer. 2. Sarcopenia Sarcopenia in cancer patients has been associated with poorer quality of life, depres- sion [13], and adverse clinical outcomes [14]. Furthermore, sarcopenia is highly correlated with the incidence of severe chemotherapeutic toxicity and associated changes in body composition, including the loss of skeletal muscle mass secondary to oncospecific treat- ments [15–17]. Survival in older patients with cancer can be affected by a combination of factors: Increased vulnerability to adverse outcomes secondary to cancer treatment, reduced physical reserve, and in some cases, the impossibility of further cancer-directed treatment [18]. Early assessment could benefit all older patients at risk of developing Nutrients 2021, 13, 761 3 of 11 Nutrients 2021, 13, 761 3 of 10 treatment [18]. Early assessment could benefit all older patients at risk of developing sar- copenia. Validated screening tools have emerged for this purpose, being the SARC-F sarcopenia. Validated screening tools have emerged for this purpose, being the SARC- (Strength, Assistance in walking, Rise from chair, Climb stairs, and Falls) the most com- F (Strength, Assistance in walking, Rise from chair, Climb stairs, and Falls) the most monly recommended questionnaire to identify people at risk of developing sarcopenia- commonly recommended questionnaire to identify people at risk of developing sarcopenia- associated adverse outcomes [19–21]. associated adverse outcomes [19–21]. Since the term sarcopenia began to be used more than 20 years ago, researchers have Since the term sarcopenia began to be used more than 20 years ago, researchers have tried tried toto reach reach agreement agreement on onits itsdefinition: definition: Is Is itit an an age-related age-related loss loss of ofmuscle musclemass massand and function, aa disease, function, disease, oror aa process processof ofnormal normalaging? aging?[22]. [22].The TheEuropean European Working Working Group Group on Sarcopenia in Older People 2 (EWGSOP2) defines sarcopenia on Sarcopenia in Older People 2 (EWGSOP2) defines sarcopenia as a muscle disease as a muscle disease (muscle failure) failure) (muscle rooted in adverse rooted musclemuscle in adverse changeschanges that accrue across across that accrue a lifetime, associated a lifetime, with a associated higher probability of adverse outcomes such as falls, fractures, physical with a higher probability of adverse outcomes such as falls, fractures, physical disability, disability, and mortality [20]. Other international initiatives led by the Asian Working and mortality [20]. Other international initiatives led by the Asian Working Group for Group for Sarco- penia (AWGS) Sarcopenia and the (AWGS) andSarcopenia Definition the Sarcopenia Definition and Outcomes and Outcomes Consortium Consortium (SDOC) have (SDOC) launched new diagnostic criteria based on the scientific evidence have launched new diagnostic criteria based on the scientific evidence obtained over the obtained over the years [20,23,24], years but a but [20,23,24], universal consensus a universal is stillislacking. consensus Since muscle still lacking. strength Since muscle has a greater strength has a capacity than muscle mass to predict poor outcome in patients greater capacity than muscle mass to predict poor outcome in patients with sarcopenia, the with sarcopenia, the EWGSOP2 guidelines point out the loss of muscle strength as the most EWGSOP2 guidelines point out the loss of muscle strength as the most relevant criterion for relevant criterion fordiagnosis. its its diagnosis. Hence, Hence, sarcopenia sarcopenia must bemust be suspected suspected in the presence in the presence of lowstrength of low muscle muscle strength and and confirmed confirmed by documentation by documentation of loss muscle of loss of skeletal of skeletal massmuscle (Figure mass (Figure 1). The 1). The EWGSOP2 EWGSOP2 distinguishes distinguishes between primarybetween primary(age-related) sarcopenia sarcopenia (age-related) and secondary andsarcopenia secondary(in sarco- the penia (inof presence the presence of underlying underlying systemic systemic disease disease or inflammatory or inflammatory processes) and processes) provides and pro- specific vides specific cut-off cut-off points for points (1) low for 1)strength muscle low muscleandstrength and 2) low (2) low muscle mass. muscle Gait mass. speed,Gait the speed, Short the ShortPerformance Physical Physical Performance Battery Battery (SPPB), (SPPB), or the Timed or Get-Up the Timed andGet-Up Go test,and Go test, used commonly com- monly to assessused to assess physical physical performance, performance, become indicators become indicators of the severityofofthe theseverity diseaseof theitdis- once is ease once it[20,23,25]. diagnosed is diagnosed [20,23,25]. Low muscle strength Low muscle mass Physical performance By handgrip ASM ASM/height2 One of the following criteria: EWGSOP2 criteria < 27 kg for men FOR Gait speed: ≤ 0.8 m/s < 20 kg or < 7.0 Kg/m2 SEVERITY < 16 kg for women for men SPPB: ≤ 8point score By chair stand test: < 15 kg or < 5.5 Kg/m2 TUG: ≥ 20s for women > 15s for five rises 400m walk test: ≥ 6min /NC Low Muscle strength Low usual gait speed SDOC criteria Muscle weakness: by handgrip Slowness: < 35.5 kg in men < 20 kg in women < 0.8 m/s Low muscle mass Reduced Muscle Physical performance ASM/height2 by DXA and BIA strength One of the following criteria: < 7.0 Kg/m2 for men By handgrip OR AWGS criteria 6-meter walk < 1.0 m/s < 5.4 Kg/m2 (by DXA) < 28 kg for men 5-time chair stand test ≥ 12s < 5.7 Kg/m2 (by BIA) for women < 18 kg for women SPPB ≤ 9 FOR SEVERITY The presence of all three criteria: severe sarcopenia Figure1.1.Update Figure Updateof ofthe thesarcopenia sarcopeniadiagnostic diagnosticcriteria. criteria.Abbreviations: Abbreviations: EWGSOP2: EWGSOP2: European European Work- Working ing Group on Sarcopenia in Older People 2; AWGS: Asian Working Group for Sarcopenia; SDOC: Group on Sarcopenia in Older People 2; AWGS: Asian Working Group for Sarcopenia; SDOC: Sarcopenia Definition and Outcomes Consortium; ASM: Appendicular Skeletal Muscle Mass; Sarcopenia Definition and Outcomes Consortium; ASM: Appendicular Skeletal Muscle Mass; SPPB: SPPB: Short Physical Performance Battery; TUG: Timed-Up and Go test; NC: Non-completion. Short DXA: Physical Performance Dual-energy Battery; TUG:BIA: X-ray Absorptiometry. Timed-Up and Go Bioelectrical test; NC:Analysis Impedance Non-completion. [20,23,25]. DXA: Dual-energy X-ray Absorptiometry. BIA: Bioelectrical Impedance Analysis [20,23,25]. The Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium published a series of for The Foundation manuscripts framed the National underof“The Institutes FNIH Health Sarcopenia (FNIH) Project” Biomarkers with spe- Consortium published a series of manuscripts framed under “The FNIH Sarcopenia Project”muscle cific recommendations on cut-off points for weakness and low appendicular lean with mass [26]; specific the EWGSOP2 later recommendations used very on cut-off similar points cut-off points for weakness and[20,26,27]. In 2016, tolean low appendicular ad- dress the need for a refined and updated operational definition of sarcopenia, the muscle mass [26]; the EWGSOP2 later used very similar cut-off points [20,26,27]. In 2016, toFNIH address the need for a refined and updated operational definition of sarcopenia, the FNIH Nutrients 2021, 13, 761 4 of 10 and the National Institute of Aging funded the SDOC. This consortium, in its 2020 position statements, considers that muscle weakness, defined by low grip strength (<35.5 kg in men or 20 kg in women), and slowness (usual gait speed <0.8 m/s) are sufficient criteria to diagnose sarcopenia [24,25]. The most controversial SDOC recommendation is to exclude lean mass measured by dual-energy x-ray absorptiometry (DXA) from the sarcopenia definition [25]. The SDOC states that both low grip strength and low usual gait speed are independent predictive factors of falls, self-reported mobility limitation, hip fractures, and mortality in community-dwelling older adults; therefore, they should be included in the definition of sarcopenia. However, lean mass measured by DXA was not associated with incident adverse health-related outcomes. Finally, the AWGS, in its 2019 consensus update, maintains the original definition of sarcopenia as an age-related loss of skeletal muscle mass accompanied by low muscle strength and/or physical performance [23]. The presence of all three criteria corresponds to severe sarcopenia (Figure 1). Advances in the diagnosis and treatment of sarcopenia and the evidence supporting its association with adverse outcomes in older people establish that sarcopenia is an age- related muscle disease [9,20,23,24] rather than simply a normal physiologic process of aging [28]. It is important to emphasize that approaching sarcopenia as a normal part of aging may result in a misinterpretation of the current definition. The adequate qualitative and quantitative measurement of muscle mass remains a challenge, particularly for older patients with cancer, and no consensus has been reached on the use and interpretation of these measurements [29]. 3. Malnutrition Malnutrition has been described as a state resulting from lack of intake or uptake of nutrients that leads to altered body composition and body cell mass, resulting in im- paired physical and mental function [8,30,31]. The ESPEN guidelines on definitions and terminology of clinical nutrition provides an etiology-based approach, distinguishing among disease-related malnutrition (DRM) with inflammation, DRM without inflamma- tion, and malnutrition without disease [8,32]. Societies such as the American Society for Parenteral and Enteral Nutrition (ASPEN) and the ESPEN developed clinical guidelines that recommend the use of screening tools for early detection and treatment of nutritional disorders [33,34]; the Mini Nutritional Assessment Short Form (MNA-SF) is considered one of the major malnutrition screening tools in older adults [35,36]. One of the main features of malnutrition is involuntary weight loss, which is associated with an increased likelihood of post-discharge institutionalization [37]. Regardless of the importance of weight loss, malnutrition should be addressed as a muscle-related disorder, including a proper skeletal muscle assessment in clinical practice [38]. The Academy of Nutrition and Dietetics (AND) and ASPEN emphasize that no single parameter is definitive for adult malnutrition diagnosis and recommend assessing energy intake, weight loss, muscle mass, subcutaneous fat, fluid accumulation, and muscle strength [32]. Subsequently, the ESPEN launched two diagnostic criteria based on three variables: Weight loss, reduced body mass index (BMI), and reduced fat-free mass index [31]. Even though diagnostic criteria were associated with a longer length of hospital stay, the prevalence of malnutrition in post-acute care was very different when compared using the AND/ASPEN and ESPEN proposals [39]. Given the lack of a worldwide consensus on diagnostic criteria, together with new evidence supporting the influence of disease and inflammation on malnutrition, the Global Leadership Initiative on Malnutrition (GLIM) engaged the majority of nutrition societies in an effort to standardize the diagnosis of malnutrition in clinical settings [36,40]. The GLIM proposes a three-step approach: First, patients must be identified by a validated screening tool; second, malnutrition requires the presence of at least one phenotypical criterion and one etiological criterion; and finally, severity is based on threshold levels of the phenotypic criteria (Figure 2). ommendations for action against cancer-related malnutrition to facilitate nutriti port in clinical practice for the care of patients with cancer. Three key points wer 1) Screen all patients with cancer, 2) expand nutrition-related assessment practice use multimodal nutritional interventions with individualized plans [1]. All thes Nutrients 2021, 13, 761 tives seek to raise awareness among health professionals about the importanc 5 of 10 sessing malnutrition in patients with cancer, as well as providing timely measure tritional support that help improve outcomes in cancer patients. Phenotypic criteria Etiologic criteria Non-volitional weight loss Reduced food intake or assimilation Assessment criteria Low body mass index (BMI) Disease burden / Reduced muscle mass inflammatory condition Phenotypic criterion Etiologic criterion Diagnosis MALNUTRITION Moderate / Stage 1 Severe / Stage 2 5-10 % weight loss within the > 10 % weight loss within the past 6month or past 6month or Severity grading 10-20 % beyond 6 month > 20 % beyond 6 month BMI < 20 kg/m2 if < 70 year or BMI < 18.5 kg/m2 if < 70 year < 22 kg/m2 if ≥ 70 year or Based on the presence of 1 phenotypic < 20 kg/m2 if ≥ 70 year criterion with these features Mild to moderate deficit of muscle mass Severe deficit of muscle mass Figure Figure 2. The Global 2. The Global Leadership Leadership Initiative Initiative on Malnutrition on Malnutrition (GLIM) (GLIM) criteria criteria of malnutrition of malnutrition diagnosis sis and severity grading [36]. and severity grading [36]. 4. Cancer In patients with cancer,Cachexia the assessment of malnutrition should be a fundamental and mandatory part of the clinical is Cachexia evaluation, a commonsince nutritional manifestation and metabolic of several disorderssuch serious illnesses, are as chron associated with failure, a negative effectimmune acquired on clinical outcomes deficiency [1,41] such syndrome, andascancer a longer [48].length of and, m Cachexia hospital stay [42], increased cifically, infection cancer andishospital cachexia a type of readmissions disease-related[43],malnutrition postoperative com- associated with plications [42,44], and mortalitywhich inflammation, [43,45–47]. should ThenotESPEN guidelines be perceived on nutrition as end-stage in cancer [8]. Rea malnutrition patients launched in 2016 single aimed to definition provide with precise specific recommendations diagnostic fora the criteria is still multimodal challenge for the scienti nutritional management [41]. Shortly thereafter, munity [11,12,49,50]. One of thethe ESPEN first expertattempts successful group launched recom- in the C was achieved mendations for action Consensusagainst cancer-related Conference held inmalnutrition WashingtontoDC facilitate nutrition in December 2006support [11]. Cachexia in clinical practice fined as “a complex metabolic syndrome associated with underlying (1) for the care of patients with cancer. Three key points were given: illness and Screen all patients with by terized cancer, (2)muscle loss of expandwith nutrition-related or without loss assessment of fat mass”, practices, and (3)loss was where weight use multimodal nutritional out as theinterventions most important with feature individualized plans in of cachexia [1].adults. All these initiativescriteria i Diagnostic seek to raise awareness weight lossamong health professionals as a primary criterion, plusabout threethe importance of five of assessing other criteria (Figure 3). In the malnutrition in patients with cancer, as well as providing timely measures of of data on weight history, this consensus recommends the use of BMI < 20 kg/m nutritional support that helpmary improve outcomes criterion in cancer [11]. These patients. criteria required specific equipment to assess muscle 4. Cancer Cachexia Cachexia is a common manifestation of several serious illnesses, such as chronic heart failure, acquired immune deficiency syndrome, and cancer [48]. Cachexia and, more specifically, cancer cachexia is a type of disease-related malnutrition associated with chronic inflammation, which should not be perceived as end-stage malnutrition [8]. Reaching a single definition with specific diagnostic criteria is still a challenge for the scientific community [11,12,49,50]. One of the first successful attempts was achieved in the Cachexia Consensus Conference held in Washington DC in December 2006 [11]. Cachexia was defined as “a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass”, where weight loss was pointed out as the most important feature of cachexia in adults. Diagnostic criteria included weight loss as a primary criterion, plus three of five other criteria (Figure 3). In the absence of data on weight history, this consensus recommends the use of BMI < 20 kg/m2 as primary criterion [11]. These criteria required specific equipment to assess muscle strength Nutrients 2021, 13, 761 6 of 11 and body composition, as well as blood testing, which might have limited the use of this Nutrients 2021, 13, 761 definition in clinical practice. 6 of 10 The SCRINIO Working Group proposed simpler criteria based on the loss of at least 10% of body weight and the presence of one of the associated symptoms (fatigue, ano- rexia, or early satiation) [51]. These criteria allow ready identification of patients with can- and body composition, cer cachexia as well as and classification as precachexia blood testing,orwhich might cachexia [51];have this limited practicalthe use of this approach has definition in clinical practice. improved applicability [52]. Primary criterion Other criteria 1. Low muscle strength Assessment criteria Weight loss of at least 5 % in 3-6 2. Fatigue months for cancer or in 12 months for 3. Anorexia other chronic illness 4. Low fat-free mass index OR Low body mass index < 20 kg/m 2 5. Abnormal biochemistry (anemia, low serum albumin, and increased (in absence of data on weight history) inflammatory markers) Primary criterion 3 of other criteria Diagnosis CACHEXIA Figure3.3.Cachexia Figure Cachexiadiagnostic diagnosticcriteria criteriaby byEvans Evansetetal. al.[11]. [11]. In 2012, The SCRINIOan international Working Group consensus process proposed was initiated simpler to reach criteria based onathe more lossspecific def- of at least inition 10% of cancer of body weight cachexia, and theinvolving presence of anone expert of thepanel of the European associated symptomsPalliative Care Re- (fatigue, anorexia, search or earlyCollaborative, satiation) [51].the Society These on Cachexia criteria and Wasting allow ready Disorders, identification the National of patients Cancer with cancer Researchand cachexia Institute PalliativeasCare classification Clinical or precachexia Studies cachexia Group, [51];and thisthe European practical Societyhas approach for Clinical Nutrition improved applicability and [52]. Metabolism Special Interest Group on Cachexia. Cancer cachexia was In defined 2012, an as international a multifactorial syndrome consensus characterized process by antoongoing was initiated reach a lossmore ofspecific skeletal muscle mass definition (with or of cancer withoutinvolving cachexia, loss of fatanmass) expert that cannot panel be European of the fully reversed by conven- Palliative Care tional nutritional Research supportthe Collaborative, and leads to Society onprogressive Cachexia and functional Wasting impairment Disorders,[12].the One of the National Cancer criticalResearch Institute Palliative aspects introduced by this Care Clinical consensus wasStudies Group, of the concept andprogressivity the EuropeanofSociety cancer for Clinicalwhich cachexia, Nutrition and Metabolism prioritizes Specialfor the early search Interest signs Group that mayon indicate Cachexia.a Cancer negative cachexia protein was and defined as a multifactorial energy balance. syndrome The classification into characterized three stages became by an ongoing especiallyloss of skeletal important due muscle to theirmass (with or respective without loss therapeutic of fat mass)(Figure implications that cannot be fully reversed 4): Pre-cachexia by conventional represents the greatest nutritional opportunity support and leadsinterventions; for preventive to progressivecachexia functional impairment involves [12]. One multimodal of the critical management, fo- aspects introduced by this consensus was the concept of progressivity cused on reversible contributory factors; and refractory cachexia is understood as the of cancer cachexia, which prioritizes stage where therethe early is no searchtofor response signs that anticancer may indicate treatments, withaactive negative proteinand catabolism anda energy balance. The classification into three stages became especially life expectancy of fewer than three months. Refractory cachexia is part of palliative care important due to their aimed respective to relievetherapeutic symptoms implications and provide (Figure 4): Pre-cachexia the necessary support for represents patients theandgreatest families opportunity [12]. Not all for preventive patients interventions; go through cachexia all three stages: involves multimodal Progression depends on factorsmanagement, such as focused on reversible contributory factors; and refractory cachexia the severity of the oncological process, the level of systemic inflammation, reduced is understood asfood the stage where there is no response to anticancer intake, and lack of response to anticancer therapy [12] treatments, with active catabolism and a life expectancy of fewer than three months. Refractory cachexia is part All these criteria should be appropriate to detect cancer cachexia in older people, asof palliative care aimed to relieve they can symptoms identify patientsand provide with athe necessary higher support mortality risk for [2].patients However, andtheir families pros[12]. and Not cons all patients go through all three stages: Progression depends on deserve some consideration. While the criteria of Evans have shown a stronger predictive factors such as the severity of the oncological capacity on the overallprocess, the level survival of systemic of patients with inflammation, cancer [53], other reduced food criteria diagnostic intake, and such lack of response to anticancer therapy [12]. as those of Fearon and the SCRINIO Working Group seem to be more feasible for the All these systematic criteria bedside should beofappropriate assessment cachexia in to detect daily cancer clinical cachexia practice in older [2]. The common people, pa- as they can identify patients with a higher mortality risk [2]. However, their pros and rameters in the different and most accepted criteria proposed today are weight loss and cons deserve some consideration. While the criteria of Evans have shown a stronger predictive capacity on the overall survival of patients with cancer [53], other diagnostic criteria such as those of Fearon and the SCRINIO Working Group seem to be more fea- sible for the systematic bedside assessment of cachexia in daily clinical practice [2]. The common parameters in the different and most accepted criteria proposed today are weight loss and anorexia [2,11,12,51–53]. Therefore, screening for these parameters should be a Nutrients 2021, 13, 761 7 of 11 Nutrients 2021, 13, 761 7 of 10 anorexia [2,11,12,51–53]. Therefore, screening for these parameters should be a fundamen- fundamental tal part of thepart of assessment initial the initial assessment and of and follow-up follow-up all older of all older patients patients with with and and without can- without cer. cancer. Weight loss Measure of muscularity (WL) Appendicular skeletal muscle index (men < 7.26 kg/m2, women < 5.45 kg/m2 ) by DXA Screening Lumbar skeletal muscle index determined (men < 55 cm²/m² ; women < 39 cm²/m² ) by CT Body mass index (BMI) Body fat-free mass index (men < 14.6 kg/m² ; women < 11.4 kg/m² ), by BIA Mid upper-arm muscle area by anthropometry (men < 32 cm² , women < 18 cm² ) WL > 5 % or WL ≤ 5 % + Anorexia + Active catabolism, unresponsive BMI < 20 kg/m2 + WL > 2% or metabolic change to anticancer therapy Muscle mass loss and weight loss > 2% Diagnosis Precachexia Cachexia Refractory Cachexia Monitor Prioritization of reversible Palliative care, Management Preventive intervention contributory factors life expectancy < 3 months Figure4.4.Cancer Figure Cancercachexia cachexiaapproach approach by by Fearon Fearon et et al. al. [12]. [12]. Abbreviations: Abbreviations: DXA: DXA:Dual-energy Dual-energyX-ray X-ray Absorptiometry. CT: Computed Tomography. BIA: Bioelectrical Impedance Analysis. Absorptiometry. CT: Computed Tomography. BIA: Bioelectrical Impedance Analysis. 5.5.Overlap Overlapand andDifferential DifferentialDiagnosis: Diagnosis:Upcoming UpcomingLandmarks Landmarksand andPoints Pointsforfor Further Further DiscussionDiscussion Sarcopenia Sarcopenia and and cachexia can canoccur occurconcurrently concurrentlyinin thethe same same patient patient [54];[54]; this this is is asso- associated with poor outcomes, especially in older patients with cancer ciated with poor outcomes, especially in older patients with cancer [2,55]. The etiology of [2,55]. The etiology of muscle-wastingthat muscle-wasting thatseems seemstotobe bepresent present in in both sarcopenia and and cachexia cachexiahas hasdistinct distinct mechanisms mechanisms [56]; [56]; however, however, differential diagnosis might differential diagnosis mightbebedifficult difficultininclinical clinicalpractice, practice, as as thereisisno there noclear cleardemarcation demarcationline linebetween between thesethese two two entities entities [57] [57] or or screening screeningtools toolstoto distinguish distinguishbetween betweenthem them[58,59]. [58,59].Therefore, Therefore,overlap overlapisispossible possible[28,57]. [28,57]. The The loss of muscle mass is the common feature sharedby loss of muscle mass is the common feature shared bysarcopenia sarcopeniaand andcachexia. cachexia. Whilst Whilst the EWGSOP and the AWGS require both low muscle mass and decreasedstrength the EWGSOP and the AWGS require both low muscle mass and decreased strength for forthe thediagnosis diagnosisofofsarcopenia, sarcopenia,Evans Evansetetal. al.propose proposethe thepresence presenceofofdecreased decreasedmusclemuscle strength and/or low fat-free mass for the cachexia diagnosis [11], and strength and/or low fat-free mass for the cachexia diagnosis [11], and Fearon et al. suggest Fearon et al. suggest sarcopenia sarcopeniaas as aa diagnostic diagnostic criterion criterionfor forcancer cancercachexia cachexia[12]. [12]. While While involuntary involuntary weight weight loss loss and reduced food intake (anorexia) in the context of chronic and reduced food intake (anorexia) in the context of chronic systemic inflammation and systemic inflammation and metabolic metabolic alterations alterations are important are important features features of cachexia of cachexia [11,12,49], [11,12,49], sarcopenia sarcopenia is anisage- an age-related disease where weight loss is not a diagnostic related disease where weight loss is not a diagnostic criterion [20]. criterion [20]. The Thecontinuous continuoussearch search forfor clear concepts clear concepts thatthat leadlead to a to correct evaluation a correct of nutritional evaluation of nutri- status in older people is increasingly important in clinical practice. Nutrition-related con- tional status in older people is increasingly important in clinical practice. Nutrition-re- ditions such as sarcopenia and nutrition disorders such as malnutrition and cachexia are lated conditions such as sarcopenia and nutrition disorders such as malnutrition and ca- common in patients with cancer and even more so in the oldest patients [1–3]. However, chexia are common in patients with cancer and even more so in the oldest patients [1–3]. while malnutrition underlies an imbalance between energy intake, energy expenditure, However, while malnutrition underlies an imbalance between energy intake, energy ex- and the quality of the nutrient intake [8,36] and, as in cachexia, it may be associated with penditure, and the quality of the nutrient intake [8,36] and, as in cachexia, it may be asso- a disease with inflammatory activity [36], sarcopenia is a progressive and generalized ciated with a disease with inflammatory activity [36], sarcopenia is a progressive and gen- skeletal muscle disorder, which may or may not be associated with another disease or an eralized skeletal muscle disorder, which may or may not be associated with another dis- inflammatory process [20]. Nonetheless, decreased muscle mass is one of the foremost ease or an inflammatory process [20]. Nonetheless, decreased muscle mass is one of the features of sarcopenia, as in malnutrition and cachexia. In addition, malnutrition is a strong foremost features of sarcopenia, as in malnutrition and cachexia. In addition, malnutrition predictor of sarcopenia and severe sarcopenia [60]. Therefore, achieving adequate preven- is a strong predictor of sarcopenia and severe sarcopenia [60]. Therefore, achieving ade- tion and treatment measures is only possible if all these clinical concepts are sufficiently quateatprevention clear the time ofand treatment assessment, measuresif is especially anonly possibleprocess oncological if all these clinical concepts are is involved. sufficiently clear at the time of assessment, especially if an oncological process is involved. Nutrients 2021, 13, 761 8 of 10 This review provides information on similarities, differences, and possible overlap of sarcopenia, malnutrition, and cancer cachexia in older patients with cancer. Changes in body composition and their impact on nutritional status require further study. 6. Summary Adequate management of the patient with cancer requires assessment of muscle func- tion and nutritional status. In older patients with cancer, the use of validated screening tools, the follow-up of patients at risk, and accurate early diagnosis of malnutrition, cachexia, and/or sarcopenia are the pillars for timely treatment to improve clinical outcomes. There is still a lack of agreement, mainly in the criteria and diagnostic cut-off points for these three entities. However, current research has provided tools to help health professionals make an early diagnosis and prescribe treatment. Just as the research community is called to achieve consensus on definitions and diagnostic criteria applicable in clinical practice, physicians and other health professionals are called to put into practice the updated guidelines on sarcopenia, malnutrition, and cachexia. Author Contributions: D.M.-V. and E.M. equally contributed to the conception and design of the research; D.M.-V., V.D.-Y., M.D.M., M.T.-S., and E.D. drafted the manuscript. E.M. and D.S.-R. substantively revised the manuscript. D.M.-V. made substantial contributions to this research. This manuscript is part of Delky Meza-Valderrama’s PhD project “Sarcopenia: New strategies in the diagnostic and therapeutic approach” in the PhD program in Biomedicine, Department of Experimental and Health Sciences, Universitat Pompeu Fabra–Doctoral School, Barcelona, Catalonia, Spain. All authors have read and agreed to the published version of the manuscript. Funding: English language edition and publication fees of this manuscript have been supported by grants from the Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya. Acknowledgments: The authors thank Elaine Lilly, for English revision. 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