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Epidemiology of weight loss, malnutrition and sarcopenia: A transatlantic view
Nutrition 69 (2020) 110581
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Review
Epidemiology of weight loss, malnutrition and sarcopenia: a transatlantic view phane M. Schneider a,*, M. Isabel T.D. Correia b Ste a b
^te d’Azur, Nice, France Centre Hospitalier Universitaire de Nice, and Universite Co Medical School, Universidade Federal de Minas Gerais, and Eterna Nutrition Therapy Team, Rede Mater Dei, Belo Horizonte, MG, Brazil
A R T I C L E
I N F O
Keywords: Cancer Malnutrition Undernutrition Sarcopenia
A B S T R A C T
Malnutrition is a common comorbidity in patients with cancer, with determinants linked to the patients, the tumor, and the treatment. Cancer malnutrition, also called cachexia, represents the chronic form of diseaserelated malnutrition with chronic inflammation, and strongly impairs the prognosis. Reduced muscle mass, otherwise called sarcopenia in these patients, is a feature of malnutrition and thus of cancer cachexia that may appear before weight loss, and has a strong negative effect on prognosis, as well. The reported global prevalence of loss of muscle mass is 39%, whereas the prevalence of malnutrition in important cohorts varies from 25% to 70%. This is mostly due to the very different screening and diagnostic tools used throughout the world. The recent Global Leadership Initiative on Malnutrition has become a consensus alternative to standardize how malnutrition may be diagnosed based on etiologic and phenotypic criteria available everywhere, from rich to poor countries. This will lead to an easier diagnosis of cancer malnutrition that itself will help us speak the same language worldwide. © 2019 Elsevier Inc. All rights reserved.
Introduction The diagnostic criteria of malnutrition have received a lot of attention in recent years, especially among patients with cancer, the disease population most at risk for malnutrition [1]. Malnutrition in patients with cancer, as in most individuals, is a multifactorial comorbidity that is patient-, disease- and treatment-related, mostly involving a reduced food intake (Table 1 [2]), rarely an increased energy expenditure (considering reduced physical activity overcompensates the infrequent hypermetabolism) or increased digestive losses.
(because only based on muscle mass loss) called sarcopenia. A recent systematic review of the consequences of sarcopenia in 35 articles involving 6894 patients with cancer found that it was independently positively associated with complications of surgery and chemotherapy, but also negatively associated with overall survival during chemotherapy; relapse-free survival after surgery for extrahepatic biliary cancer, hematopoietic stem cell transplantation, and hepatectomy; and progression-free survival after chemotherapy for hepatocellular carcinoma and metastatic breast cancer [5]. Prevalence of malnutrition influenced my many factors
Malnutrition: a cancer comorbidity with severe consequences Malnutrition is not without consequences, and several studies have reported a direct relationship with increased morbidity, mortality, treatment toxicity (chemotherapy, radiation therapy, surgery), treatment failures, hospital length of stay and readmissions, costs, and reduced quality of life [3,4]. The consequences of malnutrition are mostly linked to the loss of fat-free mass and especially appendicular muscle mass, incorrectly MITDC is a grant recipient for Conselho Nacional de Desenvolvimento Científico e gico. Tecnolo *Corresponding author. Tel.: +33 492036168; Fax: +33 492036575. E-mail address: [email protected] (S.M. Schneider). https://doi.org/10.1016/j.nut.2019.110581 0899-9007/© 2019 Elsevier Inc. All rights reserved.
The prevalence of malnutrition in published surveys ranges between 25% and 70% [2,6 8]. It depends on several factors (Table 2), including the time of assessment during the course of the disease and most importantly the tool used for diagnosis. In an Italian survey of 1952 patients on their first medical oncology visit, 9% were considered overtly malnourished (based on the Mini Nutritional Assessment [MNA] tool) [9], whereas in a French survey of 2197 patients at any time point in their treatment history, 39% were considered malnourished (based on weight loss, body mass index [BMI], and albumin levels) [10]. An earlier, similarly designed French study found the same prevalence of malnutrition among 1903 patients, with an increased prevalence among those with tumors of the pancreas, upper digestive tract, head and neck,
2
S.M. Schneider and M.I.T.D. Correia / Nutrition 69 (2020) 110581
Table 1 Reasons for decreased food intake in 1074 patients with cancer [2] Reason
Patients, %
Anorexia Loss of taste Nausea Difficulty swallowing Poor or inadequate diet Constipation Oral pain Abdominal pain Vomiting Diarrhea Loss of smell
63 42 30 26 19 19 16 15 14 13 2
lung, colon, uterus, and ovaries [2]. A Brazilian survey of 4783 hospitalized patients with cancer found a high prevalence of malnutrition based on the patient-generated subjective global assessment (PG-SGA; 45% stage B and 12% stage C) [11]. The prevalence of malnutrition also was increased in upper digestive, head and neck, colon, lung, gynecologic, and hematologic cancers. An Australian survey of 3590 patients hospitalized (including ambulatory) for cancer treatment or management found a lower prevalence of malnutrition with PG-SGA (24% stage B and 4% stage C). Older age, 5% weight loss, hospital admission, and metastatic disease were factors significantly associated with malnutrition. Patients with upper gastrointestinal, head and neck, and lung cancers were more likely to be malnourished [12]. The prevalence of sarcopenia before treatment was assessed by a recent systematic review of 35 articles involving 6894 patients. Sarcopenia was found in 39% of patients (95% confidence interval, 37 40], with the highest prevalence in esophageal and small cell lung cancers [5]. Unintentional weight loss is an important component of the medical history of any individual, and, in particular, when carrying out the nutritional status assessment of any patient. In fact, among patients with cancer, it is the first visible sign of the disease, with 40% of the patients saying they had lost >10% of their usual weight when first diagnosed [13]. The severity of the weight loss varies according to type of tumor, with those of the gastrointestinal tract leading to increased losses due to nausea, vomiting, and obstructive symptoms. However, despite its objectivity and the rather easy information on the amount that has been lost, weight loss alone does not provide the diagnosis of the nutritional status. Weight loss is a risk factor variable that influences the diagnosis of the nutritional status, which should be provided on the basis of a full medical history and physical examination, completed when necessary and if available by more sophisticated tests, according to the preferences of the health care professionals. Nonetheless, Table 2 Factors influencing prevalence of malnutrition in a cohort Patient-related Age Sex Tumor-related Tumor type (inflammatory status) Tumor location (digestive tract) Regional extension Metastatic status Treatment-related Active vs palliative/abstention Setting-related Community vs hospital Method-related Time of assessment Screening or diagnostic tool used
weight is a universal measurement that is commonly available for most patients, and for those without this objective information, by using various clinical queries (e.g., the size of clothes or belts) one may infer if the patient has lost weight and approximately how much. Weight loss together with other information will help establish the nutritional diagnosis of an individual as well-nourished or malnourished. Different definitions of a common phenotype The definition of malnutrition has been widely discussed [14 22], and some authors have claimed it as an impossible mission [17]. If there is controversy over what malnutrition refers to, it is also very difficult to provide a consensus on methods to diagnose it. But, one thing is certain, the lack of adequate amount of food and weight loss, in previous healthy individuals, was long ago shown to affect body compartments, metabolic pathways, and adverse clinical events, which were only slowly recovered after months of refeeding [23 27]. More recently, two other nutritional terms have been added: cachexia and sarcopenia [28 30]. Both contemplate changes in body composition as criteria for diagnosis, with sarcopenia adding functionality disorders to its definition. The most recent consensus on sarcopenia defines it as “progressive and generalized skeletal muscle disorder that is associated with increased likelihood of adverse outcomes including falls, fractures, physical disability and mortality” [29]. There is a double penalty in older patients who are more affected than their younger counterparts by both age-related sarcopenia and cancer [31]. This leads to an increased prevalence of malnutrition (74% versus 68%, P = 0.009 in a survey of 2095 patients with cancer) [32]. Muscle loss and functionality are part of the malnutrition conundrum, and many authors have indistinctly used the three terms to describe cancerassociated nutrition diagnosis and outcomes [1,33 41]. Noteworthy, age-related sarcopenia does not usually fall under the malnutrition umbrella, whereas secondary sarcopenia, which is part of the cancer cachexia diagnosis, is always synonymous with malnutrition [29]. Thus, it is very difficult to provide transatlantic data on the prevalence of nutritional status derangements and outcomes in cancer patients, and in particular considering the various available tools that may assess them. Another confounding factor is the worldwide prevalence of obesity that has also affected patients with cancer. In this regard, the improved survival of obese patients has been named the obesity paradox [42] and it has been considered an emergent issue in oncology. However, Flegal and Ioannidis recently challenged the term, and have suggested that the survival benefit of overweight and obese individuals against the worst outcomes of normal weight individuals is perhaps due to selection bias, undetected weight loss or cachexia [43]. According to the authors, instead of studying the obesity paradox, the normal weight paradox should be addressed to find why normal weight is not associated with better survival. The high prevalence of obesity makes BMI a non-trustworthy diagnostic tool for malnutrition and highlights the importance of weight loss in this diagnosis: A Malaysian study of surgical patients with digestive cancers found that the mean BMI of malnourished patients was 26 § 6 kg/m2 [44]. The wide variation of malnutrition prevalence rates worldwide is a consequence of the many different used tools. To make things even more complicated, there has been a misunderstanding between what screening and assessment tools are [45], and the reported rates of malnutrition may sometimes reflect risk factors (screening) [46,47], whereas other authors used assessment instruments [2,48]. Sealy et al. [49] carried out a systematic review of studies in patients with cancer that considered malnutrition as a variable. The authors used 11 key concepts based within the three domains (nutrient balance; changes in body shape, body area, and
S.M. Schneider and M.I.T.D. Correia / Nutrition 69 (2020) 110581
body composition; and function), all acknowledged by the two nutritional expert societies—the American Society of Parenteral and Enteral Nutrition and the European Society for Clinical Nutrition and Metabolism (ESPEN). Content validity indices, regarded as “the degree to which a sample of items, taken together, constitute an adequate operational definition of a construct” [50], were calculated per assessment tool. An acceptable content validity was considered when it was 0.80. Of the 160 included articles, three methods scored higher: the MNA (0.72); the Scored PG-SGA (0.61), and the SGA (0.53), but none had by definition acceptable content validity. Among these three tools, the only one that was specifically developed for the cancer population was the Scored- PG-SGA, but its original development and validity were only published as an abstract [51], and only later was validated against SGA [52]. It is also important to pinpoint that many of the available instruments used to carry out nutritional screening and assessment were not validated according to the scientific method basic percepts that require adequate sample sizes and statistical analysis. An international consensus on definitions Taking these aspects together, and considering there is no single instrument at the moment that is the gold standard for the nutritional diagnosis and its related morbidity/mortality for sick individuals, a recent global consensus (Global Leadership Initiative on Malnutrition [GLIM]) proposed a scheme based on three phenotypic criteria (non-intentional weight loss, low BMI, and reduced muscle mass) and two etiologic criteria (reduced food intake or assimilation and inflammation or disease burden). It is recommended that one phenotypic criterion and one etiologic criterion provide the diagnosis of malnutrition, and the severity is supported by variations in any of the phenotypic criteria [53,54]. The GLIM consensus scheme demands validation studies in regard to its sensitivity, sensibility, positive, and negative predictive prognostic values in terms of nutrition-related outcomes. ESPEN guidelines recommend the detection of nutritional disturbances at an early stage, to regularly evaluate nutritional intake, weight change, and BMI, beginning with cancer diagnosis and repeated depending on the stability of the clinical situation. In patients with abnormal screening, ESPEN recommends objective and quantitative assessment of nutritional intake, nutrition impact symptoms, muscle mass, physical performance, and the degree of systemic inflammation [55]. The heterogeneity of cohorts makes it difficult to make comparisons, but the real transatlantic (and transpacific also) view is that of speaking the same language from now on. Huge progress has been made by defining cachexia as the chronic form of diseaserelated malnutrition with inflammation and secondary sarcopenia as part of the cachexia syndrome [14]. Low muscle mass that today is called sarcopenia by oncologists will tomorrow be the phenotypic part of the diagnosis of malnutrition. Speaking the same language will allow us to conduct studies with similar criteria and some day to make world comparisons. References [1] Ryan AM, Power DG, Daly L, Cushen SJ, Ni Bhuachalla E, Prado CM. Cancerassociated malnutrition, cachexia and sarcopenia: the skeleton in the hospital closet 40 years later. Proc Nutr Soc 2016;75:199–211. [2] Hebuterne X, Lemarie E, Michallet M, de Montreuil CB, Schneider SM, Goldwasser F. Prevalence of malnutrition and current use of nutrition support in patients with cancer. JPEN J Parenter Enteral Nutr 2014;38:196–204. [3] Arends J, Baracos V, Bertz H, Bozzetti F, Calder PC, Deutz NEP, et al. ESPEN expert group recommendations for action against cancer-related malnutrition. Clin Nutr 2017;36:1187–96.
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[4] Zhang X, Tang T, Pang L, Sharma SV, Li R, Nyitray AG, et al. Malnutrition and overall survival in older adults with cancer: a systematic review and metaanalysis. J Geriatr Oncol 2019. [5] Pamoukdjian F, Bouillet T, Levy V, Soussan M, Zelek L, Paillaud E. Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: a systematic review. Clin Nutr 2018;37:1101–13. [6] Planas M, Alvarez-Hernandez J, Leon-Sanz M, Celaya-Perez S, Araujo K, Garcia de Lorenzo A, et al. Prevalence of hospital malnutrition in cancer patients: a sub-analysis of the PREDyCESÒ study. Support Care Cancer 2016;24:429–35. [7] Pressoir M, Desne S, Berchery D, Rossignol G, Poiree B, Meslier M, et al. Prevalence, risk factors and clinical implications of malnutrition in French Comprehensive Cancer Centres. Br J Cancer 2010;102:966–71. [8] Silva FR, de Oliveira MG, Souza AS, Figueroa JN, Santos CS. Factors associated with malnutrition in hospitalized cancer patients: a cross-sectional study. Nutr J 2015;14:123. [9] Muscaritoli M, Lucia S, Farcomeni A, Lorusso V, Saracino V, Barone C, et al. Prevalence of malnutrition in patients at first medical oncology visit: the PreMiO study. Oncotarget 2017;8:79884–96. [10] Gyan E, Raynard B, Durand JP, Lacau Saint Guily J, Gouy S, Movschin ML, et al. Malnutrition in patients with cancer: comparison of perceptions by patients, relatives, and physicians—results of the NutriCancer2012 Study. JPEN J Parenter Enteral Nutr 2018;42:255–60. [11] de Pinho NB, Martucci RB, Rodrigues VD, D'Almeida CA, Thuler LCS, Saunders C, et al. Malnutrition associated with nutrition impact symptoms and localization of the disease: results of a multicentric research on oncological nutrition. Clin Nutr 2019;38:1274–9. [12] Marshall KM, Loeliger J, Nolte L, Kelaart A, Kiss NK. Prevalence of malnutrition and impact on clinical outcomes in cancer services: a comparison of two time points. Clin Nutr 2019;38:644–51. [13] Brousse N, Verkarre V, Patey-Mariaud de Serre N, Cellier C, Cerf-Bensussan N, Delabesse E, et al. Is complicated celiac disease or refractory sprue an intestinal intra-epithelia cryptic T-cell lymphoma? Blood 1999;93:3154–5. [14] Cederholm T, Barazzoni R, Austin P, Ballmer P, Biolo G, Bischoff SC, et al. ESPEN guidelines on definitions and terminology of clinical nutrition. Clin Nutr 2016;36:335–40. [15] Soeters P, Bozzetti F, Cynober L, Forbes A, Shenkin A, Sobotka L. Defining malnutrition: a plea to rethink. Clin Nutr 2017;36:896–901. s J, Aversa Z, Bauer JM, Biolo G, et al. Consensus [16] Muscaritoli M, Anker SD, Argile definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) "cachexia-anorexia in chronic wasting diseases" and "nutrition in geriatrics". Clin Nutr 2010;29:154–9. [17] Meijers JM, van Bokhorst-de van der Schueren MA, Schols JM, Soeters PB, Halfens RJ. Defining malnutrition: mission or mission impossible? Nutrition 2010;26:432–40. [18] Jensen GL, Mirtallo J, Compher C, Dhaliwal R, Forbes A, Grijalba RF, et al. Adult starvation and disease-related malnutrition: a proposal for etiology-based diagnosis in the clinical practice setting from the International Consensus Guideline Committee. JPEN J Parenter Enteral Nutr 2010;34:156–9. [19] Hoffer LJ. The need for consistent criteria for identifying malnutrition. Nestle Nutr Workshop Ser Clin Perform Programme 2009;12:41–52. [20] Soeters PB, Schols AM. Advances in understanding and assessing malnutrition. Curr Opin Clin Nutr Metab Care 2009;12:487–94. [21] Jensen GL, Bistrian B, Roubenoff R, Heimburger DC. Malnutrition syndromes: a conundrum vs continuum. JPEN J Parenter Enteral Nutr 2009;33:710–6. [22] Cederholm T, Bosaeus I, Barazzoni R, Bauer J, Van Gossum A, Klek S, et al. Diagnostic criteria for malnutrition—an ESPEN consensus statement. Clin Nutr 2015;34:335–40. [23] Keys A. Experimental human starvation; general and metabolic results of a loss of one fourth the body weight in six months. Fed Proc 1946;5:55. [24] Keys A. Experimental studies of starvation on men. Bull Chic Med Soc 1946;49:42–6. [25] Keys A. Human starvation and its consequences. J Am Diet Assoc 1946;22:582–7. [26] Keys A. Nutritional problems of starvation and rehabilitation. Certif Milk 1946;21:5–16. [27] Keys A, Taylor HL. Famine edema and the mechanism of its formation. Science 1946;103:669. [28] Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011;12:489–95. [29] Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyere O, Cederholm T, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 2019;48:16–31. [30] Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, et al. Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010;39:412–23. [31] Mislang AR, Di Donato S, Hubbard J, Krishna L, Mottino G, Bozzetti F, et al. Nutritional management of older adults with gastrointestinal cancers: an International Society of Geriatric Oncology (SIOG) review paper. J Geriatr Oncol 2018;9:382–92. [32] Lacau St Guily J, Bouvard E, Raynard B, Goldwasser F, Maget B, Prevost A, et al. NutriCancer: a French observational multicentre cross-sectional study of malnutrition in elderly patients with cancer. J Geriatr Oncol 2018;9:74–80. [33] van der Kroft G, Bours D, Janssen-Heijnen DM, van Berlo D, Konsten D. Value of sarcopenia assessed by computed tomography for the prediction of
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S.M. Schneider and M.I.T.D. Correia / Nutrition 69 (2020) 110581 postoperative morbidity following oncological colorectal resection: a comparison with the malnutrition screening tool. Clin Nutr ESPEN 2018;24:114–9. Chen FF, Zhang FY, Zhou XY, Shen X, Yu Z, Zhuang CL. Role of frailty and nutritional status in predicting complications following total gastrectomy with D2 lymphadenectomy in patients with gastric cancer: a prospective study. Langenbecks Arch Surg 2016;401:813–22. Wagner D, DeMarco MM, Amini N, Buttner S, Segev D, Gani F, et al. Role of frailty and sarcopenia in predicting outcomes among patients undergoing gastrointestinal surgery. World J Gastrointest Surg 2016;8:27–40. Fukuda Y, Yamamoto K, Hirao M, Nishikawa K, Nagatsuma Y, Nakayama T, et al. Sarcopenia is associated with severe postoperative complications in elderly gastric cancer patients undergoing gastrectomy. Gastric Cancer 2016;19:986–93. Kovarik M, Hronek M, Zadak Z. Clinically relevant determinants of body composition, function and nutritional status as mortality predictors in lung cancer patients. Lung Cancer 2014;84:1–6. Prado CM, Maia YL, Ormsbee M, Sawyer MB, Baracos VE. Assessment of nutritional status in cancer—the relationship between body composition and pharmacokinetics. Anticancer Agents Med Chem 2013;13:1197–203. Antoun S, Borget I, Lanoy E. Impact of sarcopenia on the prognosis and treatment toxicities in patients diagnosed with cancer. Curr Opin Support Palliat Care 2013;7:383–9. Prado CM, Baracos VE, McCargar LJ, Reiman T, Mourtzakis M, Tonkin K, et al. Sarcopenia as a determinant of chemotherapy toxicity and time to tumor progression in metastatic breast cancer patients receiving capecitabine treatment. Clin Cancer Res 2009;15:2920–6. Prado CM, Lieffers JR, McCargar LJ, Reiman T, Sawyer MB, Martin L, et al. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol 2008;9:629–35. Pamoukdjian F, Aparicio T, Canoui-Poitrine F, Duchemann B, Levy V, Wind P, et al. Obesity survival paradox in cancer patients: results from the Physical Frailty in older adult cancer patients (PF-EC) study. Clin Nutr 2018. Flegal KM, Ioannidis JPA. The obesity paradox: a misleading term that should be abandoned. Obesity 2018;26:629–30.
[44] Loh KW, Vriens MR, Gerritsen A, Borel Rinkes IH, van Hillegersberg R, Schippers C, et al. Unintentional weight loss is the most important indicator of malnutrition among surgical cancer patients. Neth J Med 2012;70:365–9. [45] Correia MITD. Nutrition screening vs nutrition assessment: what’s the difference? Nutr Clin Pract 2018;33:62–72. [46] Boleo-Tome C, Monteiro-Grillo I, Camilo M, Ravasco P. Validation of the Malnutrition Universal Screening Tool (MUST) in cancer. Br J Nutr 2012;108:343–8. [47] Chao PC, Chuang HJ, Tsao LY, Chen PY, Hsu CF, Lin HC, et al. The Malnutrition Universal Screening Tool (MUST) and a nutrition education program for high risk cancer patients: strategies to improve dietary intake in cancer patients. Biomedicine 2015;5:17. [48] da Silva JB, Maurício SF, Bering T, Correia MI. The relationship between nutritional status and the Glasgow prognostic score in patients with cancer of the esophagus and stomach. Nutr Cancer 2013;65:25–33. [49] Sealy MJ, Nijholt W, Stuiver MM, van der Berg MM, Roodenburg JL, van der Schans CP, et al. Content validity across methods of malnutrition assessment in patients with cancer is limited. J Clin Epidemiol 2016. [50] Beck CT, Gable RK. Ensuring content validity: an illustration of the process. J Nurs Meas 2001;9:201–15. [51] Ottery FD. Definition of standardized nutritional assessment and interventional pathways in oncology. Nutrition 1996;12:S15–9. [52] Bauer J, Capra S, Ferguson M. Use of the scored Patient-Generated Subjective Global Assessment (PG-SGA) as a nutrition assessment tool in patients with cancer. Eur J Clin Nutr 2002;56:779–85. [53] Cederholm T, Jensen GL, Correia M, Gonzalez MC, Fukushima R, Higashiguchi T, et al. GLIM criteria for the diagnosis of malnutrition—a consensus report from the global clinical nutrition community. Clin Nutr 2019;38:1–9. [54] Jensen GL, Cederholm T, Correia M, Gonzalez MC, Fukushima R, Higashiguchi T, et al. GLIM criteria for the diagnosis of malnutrition: a consensus report from the global clinical nutrition community. JPEN J Parenter Enteral Nutr 2019;43:32–40. [55] Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, Bozzetti F, et al. ESPEN guidelines on nutrition in cancer patients. Clin Nutr 2017;36: 11–48.
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Review
Epidemiology of weight loss, malnutrition and sarcopenia: a transatlantic view phane M. Schneider a,*, M. Isabel T.D. Correia b Ste a b
^te d’Azur, Nice, France Centre Hospitalier Universitaire de Nice, and Universite Co Medical School, Universidade Federal de Minas Gerais, and Eterna Nutrition Therapy Team, Rede Mater Dei, Belo Horizonte, MG, Brazil
A R T I C L E
I N F O
Keywords: Cancer Malnutrition Undernutrition Sarcopenia
A B S T R A C T
Malnutrition is a common comorbidity in patients with cancer, with determinants linked to the patients, the tumor, and the treatment. Cancer malnutrition, also called cachexia, represents the chronic form of diseaserelated malnutrition with chronic inflammation, and strongly impairs the prognosis. Reduced muscle mass, otherwise called sarcopenia in these patients, is a feature of malnutrition and thus of cancer cachexia that may appear before weight loss, and has a strong negative effect on prognosis, as well. The reported global prevalence of loss of muscle mass is 39%, whereas the prevalence of malnutrition in important cohorts varies from 25% to 70%. This is mostly due to the very different screening and diagnostic tools used throughout the world. The recent Global Leadership Initiative on Malnutrition has become a consensus alternative to standardize how malnutrition may be diagnosed based on etiologic and phenotypic criteria available everywhere, from rich to poor countries. This will lead to an easier diagnosis of cancer malnutrition that itself will help us speak the same language worldwide. © 2019 Elsevier Inc. All rights reserved.
Introduction The diagnostic criteria of malnutrition have received a lot of attention in recent years, especially among patients with cancer, the disease population most at risk for malnutrition [1]. Malnutrition in patients with cancer, as in most individuals, is a multifactorial comorbidity that is patient-, disease- and treatment-related, mostly involving a reduced food intake (Table 1 [2]), rarely an increased energy expenditure (considering reduced physical activity overcompensates the infrequent hypermetabolism) or increased digestive losses.
(because only based on muscle mass loss) called sarcopenia. A recent systematic review of the consequences of sarcopenia in 35 articles involving 6894 patients with cancer found that it was independently positively associated with complications of surgery and chemotherapy, but also negatively associated with overall survival during chemotherapy; relapse-free survival after surgery for extrahepatic biliary cancer, hematopoietic stem cell transplantation, and hepatectomy; and progression-free survival after chemotherapy for hepatocellular carcinoma and metastatic breast cancer [5]. Prevalence of malnutrition influenced my many factors
Malnutrition: a cancer comorbidity with severe consequences Malnutrition is not without consequences, and several studies have reported a direct relationship with increased morbidity, mortality, treatment toxicity (chemotherapy, radiation therapy, surgery), treatment failures, hospital length of stay and readmissions, costs, and reduced quality of life [3,4]. The consequences of malnutrition are mostly linked to the loss of fat-free mass and especially appendicular muscle mass, incorrectly MITDC is a grant recipient for Conselho Nacional de Desenvolvimento Científico e gico. Tecnolo *Corresponding author. Tel.: +33 492036168; Fax: +33 492036575. E-mail address: [email protected] (S.M. Schneider). https://doi.org/10.1016/j.nut.2019.110581 0899-9007/© 2019 Elsevier Inc. All rights reserved.
The prevalence of malnutrition in published surveys ranges between 25% and 70% [2,6 8]. It depends on several factors (Table 2), including the time of assessment during the course of the disease and most importantly the tool used for diagnosis. In an Italian survey of 1952 patients on their first medical oncology visit, 9% were considered overtly malnourished (based on the Mini Nutritional Assessment [MNA] tool) [9], whereas in a French survey of 2197 patients at any time point in their treatment history, 39% were considered malnourished (based on weight loss, body mass index [BMI], and albumin levels) [10]. An earlier, similarly designed French study found the same prevalence of malnutrition among 1903 patients, with an increased prevalence among those with tumors of the pancreas, upper digestive tract, head and neck,
2
S.M. Schneider and M.I.T.D. Correia / Nutrition 69 (2020) 110581
Table 1 Reasons for decreased food intake in 1074 patients with cancer [2] Reason
Patients, %
Anorexia Loss of taste Nausea Difficulty swallowing Poor or inadequate diet Constipation Oral pain Abdominal pain Vomiting Diarrhea Loss of smell
63 42 30 26 19 19 16 15 14 13 2
lung, colon, uterus, and ovaries [2]. A Brazilian survey of 4783 hospitalized patients with cancer found a high prevalence of malnutrition based on the patient-generated subjective global assessment (PG-SGA; 45% stage B and 12% stage C) [11]. The prevalence of malnutrition also was increased in upper digestive, head and neck, colon, lung, gynecologic, and hematologic cancers. An Australian survey of 3590 patients hospitalized (including ambulatory) for cancer treatment or management found a lower prevalence of malnutrition with PG-SGA (24% stage B and 4% stage C). Older age, 5% weight loss, hospital admission, and metastatic disease were factors significantly associated with malnutrition. Patients with upper gastrointestinal, head and neck, and lung cancers were more likely to be malnourished [12]. The prevalence of sarcopenia before treatment was assessed by a recent systematic review of 35 articles involving 6894 patients. Sarcopenia was found in 39% of patients (95% confidence interval, 37 40], with the highest prevalence in esophageal and small cell lung cancers [5]. Unintentional weight loss is an important component of the medical history of any individual, and, in particular, when carrying out the nutritional status assessment of any patient. In fact, among patients with cancer, it is the first visible sign of the disease, with 40% of the patients saying they had lost >10% of their usual weight when first diagnosed [13]. The severity of the weight loss varies according to type of tumor, with those of the gastrointestinal tract leading to increased losses due to nausea, vomiting, and obstructive symptoms. However, despite its objectivity and the rather easy information on the amount that has been lost, weight loss alone does not provide the diagnosis of the nutritional status. Weight loss is a risk factor variable that influences the diagnosis of the nutritional status, which should be provided on the basis of a full medical history and physical examination, completed when necessary and if available by more sophisticated tests, according to the preferences of the health care professionals. Nonetheless, Table 2 Factors influencing prevalence of malnutrition in a cohort Patient-related Age Sex Tumor-related Tumor type (inflammatory status) Tumor location (digestive tract) Regional extension Metastatic status Treatment-related Active vs palliative/abstention Setting-related Community vs hospital Method-related Time of assessment Screening or diagnostic tool used
weight is a universal measurement that is commonly available for most patients, and for those without this objective information, by using various clinical queries (e.g., the size of clothes or belts) one may infer if the patient has lost weight and approximately how much. Weight loss together with other information will help establish the nutritional diagnosis of an individual as well-nourished or malnourished. Different definitions of a common phenotype The definition of malnutrition has been widely discussed [14 22], and some authors have claimed it as an impossible mission [17]. If there is controversy over what malnutrition refers to, it is also very difficult to provide a consensus on methods to diagnose it. But, one thing is certain, the lack of adequate amount of food and weight loss, in previous healthy individuals, was long ago shown to affect body compartments, metabolic pathways, and adverse clinical events, which were only slowly recovered after months of refeeding [23 27]. More recently, two other nutritional terms have been added: cachexia and sarcopenia [28 30]. Both contemplate changes in body composition as criteria for diagnosis, with sarcopenia adding functionality disorders to its definition. The most recent consensus on sarcopenia defines it as “progressive and generalized skeletal muscle disorder that is associated with increased likelihood of adverse outcomes including falls, fractures, physical disability and mortality” [29]. There is a double penalty in older patients who are more affected than their younger counterparts by both age-related sarcopenia and cancer [31]. This leads to an increased prevalence of malnutrition (74% versus 68%, P = 0.009 in a survey of 2095 patients with cancer) [32]. Muscle loss and functionality are part of the malnutrition conundrum, and many authors have indistinctly used the three terms to describe cancerassociated nutrition diagnosis and outcomes [1,33 41]. Noteworthy, age-related sarcopenia does not usually fall under the malnutrition umbrella, whereas secondary sarcopenia, which is part of the cancer cachexia diagnosis, is always synonymous with malnutrition [29]. Thus, it is very difficult to provide transatlantic data on the prevalence of nutritional status derangements and outcomes in cancer patients, and in particular considering the various available tools that may assess them. Another confounding factor is the worldwide prevalence of obesity that has also affected patients with cancer. In this regard, the improved survival of obese patients has been named the obesity paradox [42] and it has been considered an emergent issue in oncology. However, Flegal and Ioannidis recently challenged the term, and have suggested that the survival benefit of overweight and obese individuals against the worst outcomes of normal weight individuals is perhaps due to selection bias, undetected weight loss or cachexia [43]. According to the authors, instead of studying the obesity paradox, the normal weight paradox should be addressed to find why normal weight is not associated with better survival. The high prevalence of obesity makes BMI a non-trustworthy diagnostic tool for malnutrition and highlights the importance of weight loss in this diagnosis: A Malaysian study of surgical patients with digestive cancers found that the mean BMI of malnourished patients was 26 § 6 kg/m2 [44]. The wide variation of malnutrition prevalence rates worldwide is a consequence of the many different used tools. To make things even more complicated, there has been a misunderstanding between what screening and assessment tools are [45], and the reported rates of malnutrition may sometimes reflect risk factors (screening) [46,47], whereas other authors used assessment instruments [2,48]. Sealy et al. [49] carried out a systematic review of studies in patients with cancer that considered malnutrition as a variable. The authors used 11 key concepts based within the three domains (nutrient balance; changes in body shape, body area, and
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body composition; and function), all acknowledged by the two nutritional expert societies—the American Society of Parenteral and Enteral Nutrition and the European Society for Clinical Nutrition and Metabolism (ESPEN). Content validity indices, regarded as “the degree to which a sample of items, taken together, constitute an adequate operational definition of a construct” [50], were calculated per assessment tool. An acceptable content validity was considered when it was 0.80. Of the 160 included articles, three methods scored higher: the MNA (0.72); the Scored PG-SGA (0.61), and the SGA (0.53), but none had by definition acceptable content validity. Among these three tools, the only one that was specifically developed for the cancer population was the Scored- PG-SGA, but its original development and validity were only published as an abstract [51], and only later was validated against SGA [52]. It is also important to pinpoint that many of the available instruments used to carry out nutritional screening and assessment were not validated according to the scientific method basic percepts that require adequate sample sizes and statistical analysis. An international consensus on definitions Taking these aspects together, and considering there is no single instrument at the moment that is the gold standard for the nutritional diagnosis and its related morbidity/mortality for sick individuals, a recent global consensus (Global Leadership Initiative on Malnutrition [GLIM]) proposed a scheme based on three phenotypic criteria (non-intentional weight loss, low BMI, and reduced muscle mass) and two etiologic criteria (reduced food intake or assimilation and inflammation or disease burden). It is recommended that one phenotypic criterion and one etiologic criterion provide the diagnosis of malnutrition, and the severity is supported by variations in any of the phenotypic criteria [53,54]. The GLIM consensus scheme demands validation studies in regard to its sensitivity, sensibility, positive, and negative predictive prognostic values in terms of nutrition-related outcomes. ESPEN guidelines recommend the detection of nutritional disturbances at an early stage, to regularly evaluate nutritional intake, weight change, and BMI, beginning with cancer diagnosis and repeated depending on the stability of the clinical situation. In patients with abnormal screening, ESPEN recommends objective and quantitative assessment of nutritional intake, nutrition impact symptoms, muscle mass, physical performance, and the degree of systemic inflammation [55]. The heterogeneity of cohorts makes it difficult to make comparisons, but the real transatlantic (and transpacific also) view is that of speaking the same language from now on. Huge progress has been made by defining cachexia as the chronic form of diseaserelated malnutrition with inflammation and secondary sarcopenia as part of the cachexia syndrome [14]. Low muscle mass that today is called sarcopenia by oncologists will tomorrow be the phenotypic part of the diagnosis of malnutrition. Speaking the same language will allow us to conduct studies with similar criteria and some day to make world comparisons. References [1] Ryan AM, Power DG, Daly L, Cushen SJ, Ni Bhuachalla E, Prado CM. Cancerassociated malnutrition, cachexia and sarcopenia: the skeleton in the hospital closet 40 years later. Proc Nutr Soc 2016;75:199–211. [2] Hebuterne X, Lemarie E, Michallet M, de Montreuil CB, Schneider SM, Goldwasser F. Prevalence of malnutrition and current use of nutrition support in patients with cancer. JPEN J Parenter Enteral Nutr 2014;38:196–204. [3] Arends J, Baracos V, Bertz H, Bozzetti F, Calder PC, Deutz NEP, et al. ESPEN expert group recommendations for action against cancer-related malnutrition. Clin Nutr 2017;36:1187–96.
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