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A number of therapeutics that target mediators of signalling in the hypothalamic and brainstem regions that control appetite, ingestive behaviour, satiety, nausea and vomiting are starting to move the needle on cancer cachexia. However, clarification of meaningful clinical benefits for patients and the primary end points that should support regulatory approval of cachexia treatments is needed.

To develop a framework for the definition and classification of cancer cachexia a panel of experts participated in a formal consensus process, including focus groups and two Delphi rounds. Cancer cachexia was defined as a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology is characterised by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. The agreed diagnostic criterion for cachexia was weight loss greater than 5%, or weight loss greater than 2% in individuals already showing depletion according to current bodyweight and height (body-mass index [BMI] <20 kg/m 2) or skeletal muscle mass (sarcopenia). An agreement was made that the cachexia syndrome can develop progressively through various stages—precachexia to cachexia to refractory cachexia. Severity can be classified according to degree of depletion of energy stores and body protein (BMI) in combination with degree of ongoing weight loss. Assessment for classification and clinical management should include the following domains: anorexia or reduced food intake, catabolic drive, muscle mass and strength, functional and psychosocial impairment. Consensus exists on a framework for the definition and classification of cancer cachexia. After validation, this should aid clinical trial design, development of practice guidelines, and, eventually, routine clinical management.

Background: Prognostic significance of adiposity, at the time of cancer diagnosis, on survival is not clear. Body mass index (kg m −2 ) does not provide an appropriate assessment of body composition; therefore, the concept of the ‘obesity paradox’ needs to be investigated based on the prognostic significance of fat and muscle. Independent prognostic significance of adipose tissue in predicting mortality, importance of visceral and subcutaneous adiposity in the presence and absence of sarcopenia on survival, was investigated. Methods: Adiposity markers including total adipose index (TATI), visceral adipose tissue index (VATI) and subcutaneous adipose tissue index (SATI) were estimated for 1473 gastrointestinal and respiratory cancer patients and 273 metastatic renal cell carcinoma patients using computed tomography. Univariate and multivariate analysis to determine mortality hazard ratios (HR) were conducted using cox proportional hazard models. Results: Low SATI (SATI <50.0 cm 2  m −2 in males and <42.0 cm 2  m −2 in females) independently associated with increased mortality (HR: 1.26; 95% CI: 1.11–1.43; P <0.001) and shorter survival (13.1 months; 95% CI, 11.4–14.7) compared to patients with high SATI (19.3 months; 95% CI, 17.6–21.0; P <0.001). In the presence of sarcopenia, the longest survival was observed in patients with high subcutaneous adiposity. Conclusions: Subcutaneous adipose tissues appear to associate with reduction in mortality risk demonstrating the prognostic importance of fat distribution. The effect of sarcopenia on survival was more pronounced in patients with low subcutaneous adiposity.

Background The KPC mouse model of pancreatic cancer is gaining use in research, but detailed understanding of ingestive behaviour changes in this and other cachexia models is limited. Methods Male C57BL/6 J mice (7 weeks) were maintained under standard feed (PicoLab5L0D) and housing conditions (12:12 h; Light:Dark). Spontaneous feeding was observed in a Comprehensive Lab Animal Monitoring System: meal size, frequency, intermeal intervals and satiety ratio (i.e., time between meals divided by kcal energy in the preceding meal). Feeding was observed at baseline and over time after intraperitoneal injection syngeneic KPC pancreatic adenocarcinoma cells. Separate cohorts of mice were used to study homeostatic feeding responses at baseline and on Day 14 after KPC injection (KPC₁4). These responses were fasting‐evoked refeeding, ghrelin injection (1 mg/kg) and lights‐out cue. Results Spontaneous food intake declined by 50% by 14 days after tumour injection. At baseline, food intake was observed during 23 of 24 h daily; at KPC₁4, hours without any food intake increased from 1 to 12 (p ≤ 0.0001). At KPC₁4, intermeal intervals increased (light cycle: 60.5 ± 11.2 vs. 146.4 ± 19.6 min; p < 0.0001; dark cycle: 26.0 ± 3.8 vs. 42.0 ± 5.5 min; p = 0.0045), and the satiety ratio tripled (light cycle: 23.1 ± 5.9 vs. 69.4 ± 10.5 min/0.1 kcal; p < 0.0001; dark cycle: 11.3 ± 3.4 vs. 27.1 ± 5.0 min/0.1 kcal; p = 0.0028). By contrast, meal size and ingestion rate were unchanged. At KPC₁4 mice showed reduced responses to homeostatic feeding cues. After 12‐h starvation, refeeding intake during 4 h was 0.81 ± 0.3 g vs. 0.39 ± 0.19 g at KPC₁4 (−52%, p = 0.02). Ghrelin response was also blunted 0.66 ± 0.19 g vs. 0.42 ± 0.27 g at KPC₁4 (−36%, p = 0.005). Mice responded to lights‐out with 4 h of vigorous feeding, ingesting a total of 0.94 ± 0.2 g at baseline; this amount was reduced to 0.55 ± 0.3 g (−41%, p < 0.01) at KPC₁4, predominantly due to a steep decline in feeding after the end of the first dark hour. Conclusions Mice with KPC show response to homeostatic feeding cues; however, these were of diminished amplitude and sustainability. Large increases in intermeal interval and satiety ratio were notable, with mice eating nothing at all for extended periods of time, consistent with enhanced satiety and/or a failure to generate signals sufficient to generate a new feeding event.

The term sarcopenia was introduced in 1988. The original definition was a “muscle loss” of the appendicular muscle mass in the older people as measured by dual energy x‐ray absorptiometry (DXA). In 2010, the definition was altered to be low muscle mass together with low muscle function and this was agreed upon as reported in a number of consensus papers. The Society of Sarcopenia, Cachexia and Wasting Disorders supports the recommendations of more recent consensus conferences, i.e. that rapid screening, such as with the SARC‐F questionnaire, should be utilized with a formal diagnosis being made by measuring grip strength or chair stand together with DXA estimation of appendicular muscle mass (indexed for height2). Assessments of the utility of ultrasound and creatine dilution techniques are ongoing. Use of ultrasound may not be easily reproducible. Primary sarcopenia is aging associated (mediated) loss of muscle mass. Secondary sarcopenia (or disease‐related sarcopenia) has predominantly focused on loss of muscle mass without the emphasis on muscle function. Diseases that can cause muscle wasting (i.e. secondary sarcopenia) include malignant cancer, COPD, heart failure, and renal failure and others. Management of sarcopenia should consist of resistance exercise in combination with a protein intake of 1 to 1.5 g/kg/day. There is insufficient evidence that vitamin D and anabolic steroids are beneficial. These recommendations apply to both primary (age‐related) sarcopenia and secondary (disease related) sarcopenia. Secondary sarcopenia also needs appropriate treatment of the underlying disease. It is important that primary care health professionals become aware of and make the diagnosis of age‐related and disease‐related sarcopenia. It is important to address the risk factors for sarcopenia, particularly low physical activity and sedentary behavior in the general population, using a life‐long approach. There is a need for more clinical research into the appropriate measurement for muscle mass and the management of sarcopenia. Accordingly, this position statement provides recommendations on the management of sarcopenia and how to progress the knowledge and recognition of sarcopenia.

Background Widespread lack of awareness and limited real‐world prevalence evidence have impeded cachexia care and research. We hypothesized that healthcare professionals may identify the term cachexia, leading to International Classification of Diseases (ICD) coding for this term, with or without records of body weight loss for diagnosing cancer cachexia, and that frequently, ICD coding does not accurately reflect weight data. Methods We assessed cachexia prevalence in patients diagnosed with cancer, using the Clinical Data Warehouse of a French hospital containing two types of real‐world digitized data: (a) ‘structured’: coded diagnoses and electronic records; (b) ‘unstructured’: uncoded clinical narratives/reports: discharge summaries, procedure results, letters. Two sequential searches covering 2018–2023 (1) determined the prevalence of cachexia in all patients with a diagnosis of cancer using ICD‐10 code R64 (cachexia), electronic records of body weight and unstructured narrative data; and (2) examined data of cancers of high‐prevalence cachexia: colorectal, pancreatic and bronchial/lung cancers, determining (a) prevalence of cachexia by these criteria; (b) extent to which a diagnosis of cachexia was supported by weight loss data; and (c) extent to which the diagnosis of cachexia was not made despite objective weight data indicating its presence. Results A total of 76 547 of 737 906 patients had cancer of any primary type; 1856 (2.42%) of these had a cachexia diagnosis: 620 identified by ICD code, 1507 by unstructured data, including 271 by both. Of 6946 patients with colorectal, pancreatic or bronchial/lung cancer, 2033 patients (29.3%) were identified with cachexia by structured and/or unstructured data; both approaches were required to discover cachexia cases. From structured data an ICD‐R64 search found only 254 patients described by the term cachexia, of which 127 had weight data supporting the diagnosis in the electronic medical record. An additional 1340 patients with BMI < 20 kg/m2 or weight loss > 5% were not coded as cachectic. Unstructured data for the three cancers identified 439 additional cachexic patients. Conclusions (1) Standard ICD code‐searching underestimated cachexia prevalence in all patients and those with high‐prevalence‐cachexia cancers; (2) Many cachexia cases were not diagnosed, although data indicated its presence; (3) Many cachexia cases diagnosed by judgement were not supported by data; (4) Increasing provider awareness of cancer cachexia definitions would likely improve cachexia care and research.

BackgroundSarcopenia, visceral obesity (VO), and reduced muscle radiodensity (myosteatosis) are suggested risk factors for postoperative morbidity in colorectal cancer (CRC), but usually are not concurrently assessed. Published thresholds used to define these features are not CRC-specific and are defined in relation to mortality, not postoperative outcomes. This study aimed to evaluate body composition in relation to length of hospital stay (LOS) and postoperative outcomes.MethodsPre-surgical computed tomography (CT) images were assessed for total area and radiodensity of skeletal muscle and visceral adipose tissue in a pooled Canadian and UK cohort (n = 2100). Sex- and age-specific values for these features were calculated. For 1139 of 2100 patients, LOS data were available, and sex- and age-specific thresholds for sarcopenia, myosteatosis, and VO were defined on the basis of LOS. Association of CT-defined features with LOS and readmissions was explored using negative binomial and logistic regression models, respectively.ResultsIn the multivariable analysis, the predictors of LOS (P < 0.001) were age, surgical approach, major complications (incidence rate ratio [IRR] 2.42; 95% confidence interval [CI] 2.18–2.68), study cohort, and three body composition profiles characterized by myosteatosis combined with either sarcopenia (IRR, 1.27; 95% CI 1.12–1.43) or VO (IRR, 1.25; 95% CI 1.10–1.42), and myosteatosis combined with both sarcopenia and VO (IRR, 1.58; 95% CI 1.29–1.93). In the multivariable analysis, risk of readmission was associated with VO alone (odds ratio [OR] 2.66; 95% CI 1.18–6.00); P = 0.018), VO combined with myosteatosis (OR, 2.72; 95% CI 1.36–5.46; P = 0.005), or VO combined with myosteatosis and sarcopenia (OR, 2.98; 95% CI 1.06–5.46; P = 0.038). Importantly, the effect of body composition profiles on LOS and readmission was independent of major complications.ConclusionThe findings showed that CT-defined multidimensional body habitus is independently associated with LOS and hospital readmission.

Pancreatic and periampullary adenocarcinomas are associated with abnormal body composition visible on CT scans, including low muscle mass (sarcopenia) and low muscle radiodensity due to fat infiltration in muscle (myosteatosis). The biological and clinical correlates to these features are poorly understood. Clinical characteristics and outcomes were studied in 123 patients who underwent pancreaticoduodenectomy for pancreatic or non-pancreatic periampullary adenocarcinoma and who had available preoperative CT scans. In a subgroup of patients with pancreatic cancer (n = 29), rectus abdominus muscle mRNA expression was determined by cDNA microarray and in another subgroup (n = 29) 1H-NMR spectroscopy and gas chromatography-mass spectrometry were used to characterize the serum metabolome. Muscle mass and radiodensity were not significantly correlated. Distinct groups were identified: sarcopenia (40.7%), myosteatosis (25.2%), both (11.4%). Fat distribution differed in these groups; sarcopenia associated with lower subcutaneous adipose tissue (P<0.0001) and myosteatosis associated with greater visceral adipose tissue (P<0.0001). Sarcopenia, myosteatosis and their combined presence associated with shorter survival, Log Rank P = 0.005, P = 0.06, and P = 0.002, respectively. In muscle, transcriptomic analysis suggested increased inflammation and decreased growth in sarcopenia and disrupted oxidative phosphorylation and lipid accumulation in myosteatosis. In the circulating metabolome, metabolites consistent with muscle catabolism associated with sarcopenia. Metabolites consistent with disordered carbohydrate metabolism were identified in both sarcopenia and myosteatosis. Muscle phenotypes differ clinically and biologically. Because these muscle phenotypes are linked to poor survival, it will be imperative to delineate their pathophysiologic mechanisms, including whether they are driven by variable tumor biology or host response.

Emerging evidence on body composition suggests that sarcopenic obesity (obesity with depleted muscle mass) might be predictive of morbidity and mortality in non-malignant disease and also of toxicity to chemotherapy. We aimed to assess the prevalence and clinical implications of sarcopenic obesity in patients with cancer. Between Jan 13, 2004, and Jan 19, 2007, 2115 patients with solid tumours of the respiratory or gastrointestinal tract from a cancer treatment centre serving northern Alberta, Canada, were identified. Available lumbar CT images of the obese patients were analysed for total skeletal muscle cross-sectional area; these values were also used to estimate total body fat-free mass (FFM). Of the 2115 patients initially identified, 325 (15%) were classified as obese (body-mass index [BMI] ≥30). Of these obese patients, 250 had CT images that met the criteria for analysis. The remaining 75 patients were recorded as without assessable scans. Obese patients had a wide range of muscle mass. Sex-specific cut-offs that defined a significant association between low muscle mass with mortality were ascertained by optimum stratification analysis: 38 (15%) of 250 patients who had assessable CT images that met the criteria for analysis were below these cut-offs and were classified as having sarcopenia. Sarcopenic obesity was associated with poorer functional status compared with obese patients who did not have sarcopenia (p=0·009), and was an independent predictor of survival (hazard ratio [HR] 4·2 [95% CI 2·4–7·2], p<0·0001). Estimated FFM showed a poor association with body-surface area ( r 2=0·37). Assuming that FFM represents the volume of distribution of many cytotoxic chemotherapy drugs, we estimated that individual variation in FFM could account for up to three-times variation in effective volume of distribution for chemotherapy administered per unit body-surface area, in this population. This study provides evidence of the great variability of body composition in patients with cancer and links body composition, especially sarcopenic obesity, to clinical implications such as functional status, survival, and potentially, chemotherapy toxicity. Canadian Institutes of Health Research (Ottawa, ON, Canada), Alberta Cancer Board (Edmonton, AB, Canada), and Translational Research Training in Cancer (Edmonton, AB, Canada).