Loss of skeletal muscle during systemic chemotherapy is prognostic of poor survival in patients with foregut cancer

Malnutrition, weight loss, and muscle wasting are common in patients with foregut cancers (oesophagus, stomach, pancreas, liver, and bile ducts) and are associated with adverse clinical outcomes. However, little is known about the changes in body composition that occur in these patients during chemotherapy and its impacts clinical outcomes.

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title: EUROCARE-4. Survival of cancer patients diagnosed in 1995-1999. Results and commentary.
abstract: EUROCARE-4 analysed about three million adult cancer cases from 82 cancer registries in 23 European countries, diagnosed in 1995-1999 and followed to December 2003. For each cancer site, the mean European area-weighted observed and relative survival at 1-, 3-, and 5-years by age and sex are presented. Country-specific 1- and 5-year relative survival is also shown, together with 5-year relative survival conditional to surviving 1-year. Within-country variation in survival is analysed for selected cancers. Survival for most solid cancers, whose prognosis depends largely on stage at diagnosis (breast, colorectum, stomach, skin melanoma), was highest in Finland, Sweden, Norway and Iceland, lower in the UK and Denmark, and lowest in the Czech Republic, Poland and Slovenia. France, Switzerland and Italy generally had high survival, slightly below that in the northern countries. There were between-region differences in the survival for haematologic malignancies, possibly due to differences in the availability of effective treatments. Survival of elderly patients was low probably due to advanced stage at diagnosis, comorbidities, difficult access or lack of availability of appropriate care. For all cancers, 5-year survival conditional to surviving 1-year was higher and varied less with region, than the overall relative survival.

title: Screening the nutritional status in oncology: a preliminary report on 1,000 outpatients
abstract: ObjectiveThis study presents the preliminary data of a prospective multi-centre investigation on the screening of the nutritional status of cancer outpatients with the purpose to define: (1) prevalence and rate of weight loss and nutritional risk in this patient population, and (2) to assess the association among some patient-dependent, tumour-dependent and therapy-dependent variables with the nutritional status and the nutritional risk.Materials and methodsSeventeen centres were involved to collect demographic data (age and sex), oncologic data (site of primary tumour, stage, Eastern Cooperative Oncology Group Performance State, oncologic therapy) and presence and severity of systemic and digestive/nutritional symptoms (fatigue, anorexia, nausea/vomiting, early satiety, dysgeusia/dysosmia, dysphagia/odynophagia, diarrhoea/constipation). Furthermore, the percentage of the weight loss on the usual body weight and the body mass index were computed. The nutritional risk was assessed according to the Nutrition Risk Screening 2002 questionnaire which scores the risk from 0 to 7.Main resultsOn the first 1,000 screened patients, a significant weight loss (≥10%) and a nutritional risk score ≥3 were observed in 39.7% and 33.8% of patients, respectively. Weight loss was higher in upper gastrointestinal tumours, in advanced stages of disease and in patients with a poor performance status. Similarly, the nutritional risk was higher in esophageal and pancreatic cancer and in those with a worse performance status. There was a good correlation between the severity of anorexia and the rate of the weight loss The majority of patients with no weight loss or a weight loss <10% were not anorectic; on the contrary, the majority of those with more severe weight loss had some degree of anorexia.ConclusionsWeight loss and nutritional risk are frequent in an unselected series of cancer outpatients. Site of primary tumour, stage and performance state appear to be associated, at a preliminary analysis, with significant weight loss and nutritional risk. Anorexia and weight loss are closely related, and this supports the concept that nutritional depletion can play a major role in the onset of malnutrition-cachexia.

title: Prevalence, risk factors and clinical implications of malnutrition in French Comprehensive Cancer Centres
abstract: This epidemiological observational study aimed at determining the prevalence of malnutrition in non-selected adults with cancer, to identify risk factors of malnutrition and correlate the results with length of stay and 2-month mortality.This prospective multicentre 1-day study conducted in 17 French Comprehensive Cancer Centres included 1545 patients. Body mass index (BMI), weight loss (WL) in the past 6 months and age were routinely recorded according to the French national recommendations for hospitalised patients; malnutrition was rated as absent, moderate or severe according to the level of WL and BMI. Age, sex, tumour site, type of hospitalisation and treatment, disease stage, World Health Organisation performance status (PS) and antibiotic therapy were the potential malnutrition risk factors tested. Follow-up at 2 months allowed to determine the correlation with length of stay and mortality.Malnutrition was reported in 30.9% of patients, and was rated as severe in 12.2%. In multivariate analysis, only pre-existing obesity (BMI⩾30), PS ⩾2 and head-and-neck or upper digestive cancers were associated with increased risk of malnutrition. Antibiotics use was significantly higher in malnourished patients (35.5 vs 22.8%; P<0.001). Severe malnutrition was independently associated with mortality. The median length of stay was 19.3±19.4 days for malnourished patients vs 13.3±19.4 days for others (In French Comprehensive Cancer Centres, one out of three cancer patients are malnourished and this was associated with a longer length of stay. Pre-existing obesity could be identified as a new risk factor for malnutrition in our cancer patient population perhaps because of a misidentification or a delay in nutrition support in this category of patients.

title: Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group.
abstract: The prognostic effect of weight loss prior to chemotherapy was analyzed using data from 3,047 patients enrolled in 12 chemotherapy protocols of the Eastern Cooperative Oncology Group. The frequency of weight loss ranged from 31 percent for favorable non-Hodgkin's lymphoma to 87 percent in gastric cancer. Median survival was significantly shorter in nine protocols for the patients with weight loss compared to the patients with no weight loss. Chemotherapy response rates were lower in the patients with weight loss, but only in patients with breast cancer was this difference significant. Decreasing weight was correlated with decreasing performance status except for patients with pancreatic and gastric cancer. Within performance status categories, weight loss was associated with decreased median survival. The frequency of weight loss increased with increasing number of anatomic sites involved with metastases, but within categories of anatomic involvement, weight loss was associated with decreased median survival. These observations emphasize the prognostic effect of weight loss, especially in patients with a favorable performance status or a limited anatomic involvement with tumor.

title: Definition and classification of cancer cachexia: an international consensus.
abstract: 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.

title: Marked changes in body composition following neoadjuvant chemotherapy for oesophagogastric cancer.
abstract: Patients with sarcopenia [reduced fat free mass (FFM)] have a higher incidence of chemotherapy-related toxicity and decreased survival. As there are no such data in patients with oesophagogastric cancer (OGC), this study investigated changes in body composition in OGC patients receiving neoadjuvant chemotherapy (NAC).



OGC patients who had CT scans before and after NAC were studied. CT images at the L3 vertebral level were analysed using SliceOmatic(®) software to derive estimates of FFM and fat mass (FM). Comparisons were made between pre- and post-NAC CT images. Data are reported as mean ± SD.



Forty-seven patients (34 male) aged 63 ± 12 years were studied and 79% completed their course of NAC. The interval between CT scans was 107 ± 27 days. The proportion of patients with sarcopenia increased from 57% pre-NAC to 79% post-NAC (p = 0.046). During NAC there were significant reductions in estimated FFM and FM (2.9 ± 4.7 kg, p < 0.0001 and 1.3 ± 3.2 kg, p = 0.007, respectively). No association was demonstrated between loss of FFM and non-completion of NAC, increased hospital stay or mortality.



In patients with OGC commencing NAC, sarcopenia was present in 57%. NAC was associated with further reductions in FFM and an increase in the proportion of patients becoming sarcopenic.

title: Sarcopenia is associated with toxicity in patients undergoing neo-adjuvant chemotherapy for oesophago-gastric cancer.
abstract: Patients with potentially curative oesophago-gastric cancer typically undergo neo-adjuvant chemotherapy prior to surgery. The majority of anti-cancer drugs have a narrow therapeutic index. The aim of this study was to determine if features of body composition, assessed using computed tomography (CT) scans, may be predictive of dose-limiting toxicity (DLT) in patients undergoing neo-adjuvant chemotherapy for oesophago-gastric cancer. The influence of sarcopenia and DLT on overall survival was also evaluated.



89 Patients having potentially curative oesophago-gastric cancer surgery were studied. Patients studied had histologically confirmed oesophago-gastric cancer with no evidence of distant metastasis on pre-operative staging. CT scan was performed in all cases at diagnosis. DLT was defined as toxicity leading to postponement of treatment, a drug dose reduction or definitive interruption of drug administration.



DLT occurred in 37 out of 89 patients (41.6%) undergoing chemotherapy. Sarcopenia (odds ratio, 2.95; 95% confidence interval, 1.23-7.09; p = 0.015) was associated with DLT on multivariate analysis. Median overall survival for patients who were sarcopenic was 569 days (IQ range: 357-1230 days) vs. 1013 days (IQ range: 496-1318 days) for patients who were not sarcopenic (p = 0.04). There was no significant difference in overall survival in patients who experienced DLT compared with those that did not (p = 0.665).



Sarcopenia is a significant predictor of DLT in oesophago-gastric cancer patients undergoing neo-adjuvant chemotherapy. These results raise the potential for use of assessment of skeletal muscle mass using CT scans to predict toxicity and individualize chemotherapy dosing.

title: The impact of sarcopenia and myosteatosis on outcomes of unresectable pancreatic cancer or distal cholangiocarcinoma.
abstract: Patients with pancreatic cancer have a poor prognosis, are often cachectic, and frequently demonstrate features of systemic inflammation, which may contribute to the phenomenon of myosteatosis. Analysis of body composition from CT scans has been used to study sarcopenia and its association with prognosis in a number of types of cancer, particular in combination with obesity. It has also been suggested that myosteatosis, defined as attenuated mean skeletal muscle Hounsfield units (HU), is associated with reduced survival in cancer. This study aimed to assess the association between body composition (sarcopenia and myosteatosis) and outcome in patients with unresectable pancreatic cancer.



All patients diagnosed with unresectable pancreatic cancer at Nottingham University Hospitals NHS Trust between 2006 and 2013 were considered for the study. A total of 228 patients were included retrospectively. Body composition was assessed using cross-sectional CT analysis to calculate a skeletal muscle index (SMI) for sarcopenia and use mean skeletal muscle HU for myosteatosis.



The prevalence of sarcopenia in the whole patient group at baseline was 60.5% (138/228). Overall, patients who were sarcopenic had no significant difference in overall survival versus those who were not (p = 0.779). However, patients who were overweight/obese and sarcopenic had a significantly lower survival (p = 0.013). Of the 58 patients who were overweight or obese and sarcopenic, 32 were also myosteatotic. The prevalence of myosteatosis overall at baseline was 55.3% (126/228) and this was associated with significant reduction in overall survival (p = 0.049). Univariate Cox regression revealed myosteatosis but not sarcopenia to be predictive of reduced survival, however this relationship was lost on multivariate testing. Myosteatosis was associated with significantly greater levels of systemic inflammation (white cell count, neutrophil-lymphocyte ratio and C-reactive protein), anaemia and worsening of baseline blood urea. This relationship was not seen with sarcopenia.



This is the largest study on the association between body composition and survival in patients with unresectable pancreatic cancer and has shown that although sarcopenia alone did not have a bearing on survival, the presence of myosteatosis was associated significantly with the presence of systemic inflammation and reduced survival.

title: Relationships among body mass index, longitudinal body composition alterations, and survival in patients with locally advanced pancreatic cancer receiving chemoradiation: a pilot study.
abstract: In pancreatic cancer, the presence of obesity or weight loss is associated with higher mortality.



To explore the relationships among body mass index, longitudinal body composition alterations, and clinical outcomes in pancreatic cancer patients.



Records of 41 patients with inoperable locally advanced pancreatic cancer who participated in a prospective chemoradiation study were reviewed. Body composition was analyzed from two sets of computed tomography images obtained before and after radiation treatment (median interval 104 days).



Median age was 59 years and 56% of patients were female. Twenty-four (59%) patients were either overweight (22%) or obese (37%). Sarcopenia was present in 26 (63%) patients. At follow-up, weight loss was experienced by 33 (81%) patients. The median losses (%) before and after treatment were weight 5% (P<0.001), skeletal muscle (SKM) 4% (P=0.003), visceral adipose tissue (VAT) 13% (P<0.001), and subcutaneous adipose tissue 11% (P=0.002). SKM loss positively correlated with age (P=0.03), baseline body mass index (P<0.001), and VAT (P=0.04) index. Obese patients experienced higher losses in weight (P=0.009), SKM (P=0.02), and VAT (P=0.02). Median survival was 12 months. In univariate analysis, age, baseline obesity, sarcopenic obesity, and losses (%) in weight, SKM, and VAT were associated with worse survival. In multivariate analysis, only age (hazard ratio=1.033, P=0.04) and higher VAT loss (hazard ratio=2.6 and P=0.03) remained significant.



Our preliminary findings suggest that obese patients experience higher losses in weight, SKM, and VAT, which may contribute to poorer survival in these patients.

title: Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study.
abstract: 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] > or =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.

title: Sarcopenia is an independent predictor of complications following pancreatectomy for adenocarcinoma
abstract: Sarcopenia, which is subclinical loss of skeletal muscle mass, is commonly observed in patients with malignancy. The objective of this study is to determine the correlation between sarcopenia and operative complications following pancreatectomy for cancer.

title: Sarcopenia is associated with postoperative infection and delayed recovery from colorectal cancer resection surgery
abstract: Skeletal muscle depletion (sarcopenia) predicts morbidity and mortality in the elderly and cancer patients.We tested whether sarcopenia predicts primary colorectal cancer resection outcomes in stage II–IV patients (n=234). Sarcopenia was assessed using preoperative computed tomography images. Administrative hospitalisation data encompassing the index surgical admission, direct transfers for inpatient rehabilitation care and hospital re-admissions within 30 days was searched for International Classification of Disease (ICD)-10 codes for postoperative infections and inpatient rehabilitation care and used to calculate length of stay (Overall, 38.9% were sarcopenic; 16.7% had an infection and 9.0% had inpatient rehabilitation care. Length of stay was longer for sarcopenic patients overall (15.9±14.2 days vs 12.3±9.8 days, P=0.038) and especially in those ⩾65 years (20.2±16.9 days vs 13.1±8.3 days, P=0.008). Infection risk was greater for sarcopenic patients overall (23.7% vs 12.5%; P=0.025), and especially those ⩾65 years (29.6% vs 8.8%, P=0.005). Most (90%) inpatient rehabilitation care was in patients ⩾65 years. Inpatient rehabilitation was more common in sarcopenic patients overall (14.3% vs 5.6%; P=0.024) and those ⩾65 years (24.1% vs 10.7%, P=0.06). In a multivariate model in patients ⩾65 years, sarcopenia was an independent predictor of both infection (odds ratio (OR) 4.6, (95% confidence interval (CI) 1.5, 13.9) P<0.01) and rehabilitation care (OR 3.1 (95% CI 1.04, 9.4) P<0.04).Conclusion:Sarcopenia predicts postoperative infections, inpatient rehabilitation care and consequently a longer LOS.

title: Sarcopenia negatively impacts short-term outcomes in patients undergoing hepatic resection for colorectal liver metastasis.
abstract: As indications for liver resection expand, objective measures to assess the risk of peri-operative morbidity are needed. The impact of sarcopenia on patients undergoing liver resection for colorectal liver metastasis (CRLM) was investigated.



Sarcopenia was assessed in 259 patients undergoing liver resection for CRLM by measuring total psoas area (TPA) on computed tomography (CT). The impact of sarcopenia was assessed after controlling for clinicopathological factors using multivariate modelling.



Median patient age was 58 years and most patients (60%) were male. Forty-one (16%) patients had sarcopenia (TPA ≤ 500 mm(2) /m(2) ). Post-operatively, 60 patients had a complication for an overall morbidity of 23%; 26 patients (10%) had a major complication (Clavien grade ≥3). The presence of sarcopenia was strongly associated with an increased risk of major post-operative complications [odds ratio (OR) 3.33; P= 0.008]. Patients with sarcopenia had longer hospital stays (6.6 vs. 5.4 days; P= 0.03) and a higher chance of an extended intensive care unit (ICU) stay (>2 days; P= 0.004). On multivariate analysis, sarcopenia remained independently associated with an increased risk of post-operative complications (OR 3.12; P= 0.02). Sarcopenia was not significantly associated with recurrence-free [hazard ratio (HR) = 1.07] or overall (HR = 1.05) survival (both P > 0.05).



Sarcopenia impacts short-, but not long-term outcomes after resection of CRLM. While patients with sarcopenia are at an increased risk of post-operative morbidity and longer hospital stay, long-term survival is not impacted by the presence of sarcopenia.

title: Sarcopenic obesity: A probable risk factor for dose limiting toxicity during neo-adjuvant chemotherapy in oesophageal cancer patients.
abstract: Profound weight loss and malnutrition subsequent to severe dysphagia and cancer cachexia are cardinal symptoms in oesophageal cancer (OC). Low muscle mass/sarcopenia has been linked to toxicity during neo-adjuvant therapy in other cancers, with worser effects in sarcopenic obesity. In this study the association between sarcopenia and/or sarcopenic obesity and dose limiting toxicity (DLT) during cycle one chemotherapy in resectable OC patients was evaluated.



Body composition was assessed from computed tomography scans of 72 consecutively diagnosed OC patients. Lean body mass and body fat mass were estimated. Patients were grouped as sarcopenic or non-sarcopenic based on pre-defined gender-specific cut-offs for sarcopenia, and as underweight/normal (BMI < 25) or overweight/obese (BMI ≥ 25). Sarcopenic obesity was defined as sarcopenia combined with overweight and obesity. DLT was defined as temporary reduction/delay or permanent discontinuation of drugs due to adverse effects. Odds ratios for developing toxicity were ascertained using multiple logistic regression.



Of 72 patients, 85% (n = 61) were males. Sarcopenia and sarcopenic obesity were present in 31 (43%) and 10 (14%), respectively, prior to chemotherapy. Sarcopenic patients had significantly lower adipose tissue index (p = 0.02) compared to non-sarcopenic patients. Patients with DLT (n = 24) had lower skeletal muscle mass (p = 0.04) than those without DLT. Sarcopenic patients (OR = 2.47; 95% CI: 0.88-6.93) showed a trend towards increased DLT risk (p < 0.10). Logistic regression with BMI as an interaction term indicated higher DLT risk in sarcopenic patients with normal BMI (OR = 1.60; 95% CI 0.30-8.40), but was non-significant. In the sarcopenic obese, risk of DLT increased significantly (OR = 5.54; 95% CI 1.12-27.44).



Sarcopenic and sarcopenic obese OC patients may be at a higher risk for developing DLT during chemotherapy compared to non-sarcopenic OC patients.

title: Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index.
abstract: Emerging evidence suggests muscle depletion predicts survival of patients with cancer.



At a cancer center in Alberta, Canada, consecutive patients with cancer (lung or GI; N = 1,473) were assessed at presentation for weight loss history, lumbar skeletal muscle index, and mean muscle attenuation (Hounsfield units) by computed tomography (CT). Univariate and multivariate analyses were conducted. Concordance (c) statistics were used to test predictive accuracy of survival models.



Body mass index (BMI) distribution was 17% obese, 35% overweight, 36% normal weight, and 12% underweight. Patients in all BMI categories varied widely in weight loss, muscle index, and muscle attenuation. Thresholds defining associations between these three variables and survival were determined using optimal stratification. High weight loss, low muscle index, and low muscle attenuation were independently prognostic of survival. A survival model containing conventional covariates (cancer diagnosis, stage, age, performance status) gave a c statistic of 0.73 (95% CI, 0.67 to 0.79), whereas a model ignoring conventional variables and including only BMI, weight loss, muscle index, and muscle attenuation gave a c statistic of 0.92 (95% CI, 0.88 to 0.95; P < .001). Patients who possessed all three of these poor prognostic variables survived 8.4 months (95% CI, 6.5 to 10.3), regardless of whether they presented as obese, overweight, normal weight, or underweight, in contrast to patients who had none of these features, who survived 28.4 months (95% CI, 24.2 to 32.6; P < .001).



CT images reveal otherwise occult muscle depletion. Patients with cancer who are cachexic by the conventional criterion (involuntary weight loss) and by two additional criteria (muscle depletion and low muscle attenuation) share a poor prognosis, regardless of overall body weight.

title: Assessment of sarcopenia and changes in body composition after neoadjuvant chemotherapy and associations with clinical outcomes in oesophageal cancer
abstract: ObjectivesSarcopenia and changes in body composition following neoadjuvant chemotherapy (NAC) may affect clinical outcome. We assessed the associations between CT body composition changes following NAC and outcomes in oesophageal cancer. total of 35 patients who received NAC followed by oesophagectomy, and underwent CT assessment pre- and post-NAC were included. Fat mass (FM), fat-free mass (FFM), subcutaneous fat to muscle ratio (FMR) and visceral to subcutaneous adipose tissue ratio (VA/SA) were derived from CT. Changes in FM, FFM, FMR, VA/SA and sarcopenia were correlated to chemotherapy dose reductions, postoperative complications, length of hospital stay (LOS), circumferential resection margin (CRM), pathological chemotherapy response, disease-free survival (DFS) and overall survival (OS).ResultsNine (26 %) patients were sarcopenic before NAC and this increased to 15 (43 %) after NAC. Average weight loss was 3.7 % ± 6.4 (SD) in comparison to FM index (−1.2 ± 4.2), FFM index (−4.6 ± 6.8), FMR (−1.2 ± 24.3) and VA/SA (−62.3 ± 12.7). Changes in FM index (p = 0.022), FMR (p = 0.028), VA/SA (p = 0.024) and weight (p = 0.007) were significant univariable factors for CRM status. There was no significant association between changes in body composition and survival.ConclusionsLoss of FM, differential loss of VA/SA and skeletal muscle were associated with risk of CRM positivity.Key Points• Changes in CT body composition occur after neoadjuvant chemotherapy in oesophageal cancer.• Sarcopenia was more prevalent after neoadjuvant chemotherapy.• Fat mass, fat-free mass and weight decreased after neoadjuvant chemotherapy.• Changes in body composition were associated with CRM positivity.• Changes in body composition did not affect perioperative complications and survival.

title: Measurement of skeletal muscle radiation attenuation and basis of its biological variation
abstract: Skeletal muscle contains intramyocellular lipid droplets within the cytoplasm of myocytes as well as intermuscular adipocytes. These depots exhibit physiological and pathological variation which has been revealed with the advent of diagnostic imaging approaches: magnetic resonance (MR) imaging, MR spectroscopy and computed tomography (CT). CT uses computer‐processed X‐rays and is now being applied in muscle physiology research. The purpose of this review is to present CT methodologies and summarize factors that influence muscle radiation attenuation, a parameter which is inversely related to muscle fat content. Pre‐defined radiation attenuation ranges are used to demarcate intermuscular adipose tissue [from −190 to −30 Hounsfield units (HU)] and muscle (−29 HU to +150 HU). Within the latter range, the mean muscle radiation attenuation [muscle (radio) density] is reported. Inconsistent criteria for the upper and lower HU cut‐offs used to characterize muscle attenuation limit comparisons between investigations. This area of research would benefit from standardized criteria for reporting muscle attenuation. Available evidence suggests that muscle attenuation is plastic with physiological variation induced by the process of ageing, as well as by aerobic training, which probably reflects accumulation of lipids to fuel aerobic work. Pathological variation in muscle attenuation reflects excess fat deposition in the tissue and is observed in people with obesity, diabetes type II, myositis, osteoarthritis, spinal stenosis and cancer. A poor prognosis and different types of morbidity are predicted by the presence of reduced mean muscle attenuation values in patients with these conditions; however, the biological features of muscle with these characteristics require further investigation.

title: Skeletal muscle radiodensity is prognostic for survival in patients with advanced non-small cell lung cancer.
abstract: Recent research indicates that severe muscular depletion (sarcopenia) is frequent in cancer patients and linked to cachexia and poor survival. Our aim was to investigate if measures of skeletal muscle hold prognostic information in advanced non-small cell lung cancer (NSCLC).



We included NSCLC patients with disease stage IIIB/IV, performance status 0-2, enrolled in three randomised trials of first-line chemotherapy (n = 1305). Computed tomography (CT) images obtained before start of treatment were used for body composition analyses at the level of the third lumbar vertebra (L3). Skeletal muscle mass was assessed by measures of the cross sectional muscle area, from which the skeletal muscle index (SMI) was obtained. Skeletal muscle radiodensity (SMD) was measured as the mean Hounsfield unit (HU) of the measured muscle area. A high level of mean HU indicates a high SMD.



Complete data were available for 734 patients, mean age 65 years. Both skeletal muscle index (SMI) and muscle radiodensity (SMD) varied largely. Mean SMI and SMD were 47.7 cm2/m2 and 37.4 HU in men (n = 420), 39.6 cm2/m2 and 37.0 HU in women (n = 314). Multivariable Cox regression analyses, adjusted for established prognostic factors, showed that SMD was independently prognostic for survival (Hazard ratio (HR) 0.98, 95% CI 0.97-0.99, p = 0.001), whereas SMI was not (HR 0.99, 95% CI 0.98-1.01, p = 0.329).



Low SMD is associated with poorer survival in advanced NSCLC. Further research is warranted to establish whether muscle measures should be integrated into routine practice to improve prognostic accuracy.

title: Low skeletal muscle density is associated with poor survival in patients who receive chemotherapy for metastatic gastric cancer.
abstract: Low skeletal muscle density (SMD) and low skeletal muscle index (SMI) are associated with poor overall survival (OS) in patients with various types of cancer. We retrospectively studied SMD and SMI using computed tomographic (CT) scans in patients with gastric cancer receiving chemotherapy to evaluate its prognostic significance. SMD and SMI were obtained from CT-based analysis using Slice-O-Matic® medical imaging software in patients who received S-1 plus cisplatin chemotherapy for metastatic gastric cancer. The CT images taken within 1 month before starting chemotherapy were used. The cut-off values for determining low SMD [<33 Hounsfield units (HU) in obese and <41 HU in non-obese patients] and low SMI (<41 cm2/m2 in females, <43 cm2/m2 in non-obese males and <53 cm2/m2 in obese males) were referenced from a large population based study. The CT images of 53 patients were reviewed. The median SMD was 36.8 HU (range, 19.5-59.3 HU), and the median SMI was 39.8 cm2/m2 (range, 23.7-60.0 cm2/m2). Patients with low SMD had significantly shorter OS compared with patients having normal SMD (8.9 vs. 12.8 months, P=0.03). However, OS did not differ significantly between patients with low and normal SMI (11.1 and 14.3 months, P=0.18). Multivariate analyses confirmed that low SMD was an independent predictor of poor outcomes (P<0.01). SMD is an important prognosticator of survival in patients with metastatic gastric cancer receiving chemotherapy.

title: Skeletal muscle density predicts prognosis in patients with metastatic renal cell carcinoma treated with targeted therapies
abstract: Studies have shown that skeletal muscle and adipose tissue are linked to overall survival (OS) and progression‐free survival (PFS). Because targeted therapies have improved the outcome in patients with metastatic renal cell carcinoma (mRCC), new prognostic parameters are required. The objective of the current study was to analyze whether body composition parameters play a prognostic role in patients with mRCC.

title: Loss of Muscle Mass During Chemotherapy Is Predictive for Poor Survival of Patients With Metastatic Colorectal Cancer.
abstract: Low muscle mass is present in approximately 40% of patients with metastatic colorectal cancer (mCRC) and may be associated with poor outcome. We studied change in skeletal muscle during palliative chemotherapy in patients with mCRC and its association with treatment modifications and overall survival.



In 67 patients with mCRC (mean age ± standard deviation, 66.4 ± 10.6 years; 63% male), muscle area (square centimeters) was assessed using computed tomography scans of the third lumbar vertebra before and during palliative chemotherapy. Treatment modifications resulting from toxicity were evaluated, including delay, dose reduction, or termination of chemotherapy. Multiple regression analyses were performed for the association between change in muscle area and treatment modification and secondly overall survival.



Muscle area of patients with mCRC decreased significantly during 3 months of chemotherapy by 6.1% (95% CI, -8.4 to -3.8; P < .001). Change in muscle area was not associated with treatment modifications. However, patients with muscle loss during treatment of 9% or more (lowest tertile) had significantly lower survival rates than patients with muscle loss of less than 9% (at 6 months, 33% v 69% of patients alive; at 1 year, 17% v 49% of patients alive; log-rank P = .001). Muscle loss of 9% or more remained independently associated with survival when adjusted for sex, age, baseline lactate dehydrogenase concentration, comorbidity, mono-organ or multiorgan metastases, treatment line, and tumor progression at first evaluation by computed tomography scan (hazard ratio, 4.47; 95% CI, 2.21 to 9.05; P < .001).



Muscle area decreased significantly during chemotherapy and was independently associated with survival in patients with mCRC. Further clinical evaluation is required to determine whether nutritional interventions and exercise training may preserve muscle area and thereby improve outcome.

title: Accelerated muscle and adipose tissue loss may predict survival in pancreatic cancer patients: the relationship with diabetes and anaemia
abstract: Weight loss leading to cachexia is associated with poor treatment response and reduced survival in pancreatic cancer patients. We aim to identify indicators that allow for early detection that will advance our understanding of cachexia and will support targeted anti-cachexia therapies. A total of fifty pancreatic cancer patients were analysed for skeletal muscle and visceral adipose tissue (VAT) changes using computed tomography (CT) scans. These changes were related to physical characteristics, secondary disease states and treatment parameters. Overall, patients lost 1·72 (sd 3·29) kg of muscle and 1·04 (sd 1·08) kg of VAT during the disease trajectory (413 (sd 213) d). After sorting patients into tertiles by rate of VAT and muscle loss, patients losing VAT at > − 0·40 kg/100 d had poorer survival outcomes compared with patients with < − 0·10 kg/100 d of VAT loss (P= 0·020). Patients presenting with diabetes at diagnosis demonstrated significantly more and accelerated VAT loss compared with non-diabetic patients. In contrast, patients who were anaemic at the first CT scan lost significantly more muscle tissue and at accelerated rates compared with non-anaemic patients. Accelerated rates of VAT loss are associated with reduced survival. Identifying associated features of cachexia, such as diabetes and anaemia, is essential for the early detection of cachexia and may facilitate the attenuation of complications associated with cachexia.

title: Does IGFR1 inhibition result in increased muscle mass loss in patients undergoing treatment for pancreatic cancer?
abstract: BackgroundIGF-1 plays a role in the growth of multiple tumor types, including pancreatic cancer. IGF-1 also serves as a growth factor for muscle. The impact of therapeutic targeting of IGF-1 on muscle mass is unknown.MethodsWe evaluated muscle mass at L3 in patients enrolled in a randomized phase II study of MK-0646 (M), a monoclonal antibody directed against the IGF-1 protein, in patients with metastatic pancreatic cancer (MPC). Two different doses of M were tested, 5 and 10 mg/kg. We used the Slice-o-matic (ver 4.3) software to segregate CT images into muscle and fat components and measured muscle area (cm2) at baseline and after 2 and 4 months of treatment. Patients received either gemcitabine with erlotinib (G + E), G + E + M, or G + M. Differences between the groups were compared using t tests.ResultsFifty-three patients had both baseline and 2-month imaging available for analysis. Of these, 42 received M with their chemo, and 11 had G + E only. After 2 months of treatment, both groups demonstrated decrease in muscle mass. G + E patients lost 5.6 % of muscle mass; M patients lost 9.1 and 8.6 % after treatment with 5 and 10 mg/kg, respectively (p = 0.53). Patients demonstrating a response lost less muscle (median 4.6 %) than those with stable disease (9.6 %) and progressive disease (8.9 %, p = 0.14). Muscle retention from baseline to 2-month imaging, defined as loss of <6 cm2 of muscle, correlated with better survival than those patients demonstrating a muscle loss (HR 0.51, p = 0.03).ConclusionsMPC patients can be expected to lose muscle mass even while having clinical benefit (PR or SD) from chemotherapy. Muscle loss correlated with a risk of study drop-out and death. There was a non-significant trend toward greater muscle mass loss in patients on anti-IGF-1R therapy. However, it is unclear if this loss translates into functional differences between patients.

title: Changes in skeletal muscle mass during palliative chemotherapy in patients with advanced lung cancer
abstract: Sarcopenia is a defining feature of cancer cachexia associated with physical decline, poor quality of life and poor prognosis. Thus, maintaining muscle mass is an important aim of cachexia treatment. Many patients at risk for developing cachexia or with cachexia experience side effects of chemotherapy that might aggravate the development of cachexia. However, achieving tumor control might reverse the catabolic processes causing cachexia. There is limited knowledge about muscle mass changes during chemotherapy or whether changes in muscle mass are associated with response to chemotherapy.  In this pilot study, patients with advanced non-small cell lung cancer (NSCLC) receiving three courses of palliative chemotherapy were analyzed. Muscle mass was measured as skeletal muscle cross sectional area (SMCA) at the level of the third lumbar vertebrae using CT images taken before and after chemotherapy.  In total 35 patients, 48% women, mean age 67 years (range 56–86), participated; 83% had stage IV disease and 71% were sarcopenic at baseline. Mean reduction in SMCA from pre- to post-chemotherapy was 4.6 cm2 (CI 95% −7.3–−1.9; p < 0.002), corresponding to a 1.4 kg loss of whole body muscle mass. Sixteen patients remained stable or gained SMCA. Of these, 14 (56%) responded to chemotherapy, while two progressed (p = 0.071). Maintaining or gaining SMCA resulted in longer median overall survival (loss: 5.8 months, stable/gain: 10.7 months; p = 0.073). Stage of disease (p = 0.003), treatment regimen (p = 0.023), response to chemotherapy (p = 0.007) and SMCA change (p = 0.040), but not sarcopenia at baseline, were significant prognostic factors in the multivariate survival analyses.  Almost half of the patients had stable or increased muscle mass during chemotherapy without receiving any cachexia treatment. Nearly all of these patients responded to the chemotherapy. Increase in muscle mass, but not sarcopenia at baseline, was a significant prognostic factor.

title: Sarcopenia in an Overweight or Obese Patient Is an Adverse Prognostic Factor in Pancreatic Cancer
abstract: The average weight-losing pancreatic cancer patient undergoing palliative therapy is frequently overweight rather than underweight, and this can confound conventional measures used for risk stratification. The aim of this study was to evaluate if weight and body composition, specifically sarcopenia, assessed from diagnostic computed tomography (CT) scans, is of prognostic value in patients with pancreatic cancer. The nature and extent of tissue loss over subsequent months was also evaluated.  A total of 111 patients entering a palliative therapy program, who had CT images and had undergone nutritional screening, were studied. In patients for whom follow-up scans were available (n = 44), longitudinal changes in body composition were studied at a mean of 230 62 and 95 60 days prior to demise.  Sixty-two patients (55.9) were sarcopenic, 44 (39.6) were overweight/obese, and 18 (16.2) were both. Age 59 years (hazard ratio, 1.71; 95 confidence interval, 1.10-2.66; P = 0.018), and overweight/obese sarcopenia (hazard ratio, 2.07; 95 confidence interval, 1.23-3.50; P = 0.006) were identified as independent predictors of survival on multivariate analysis. Longitudinal analysis revealed that total fat-free mass index decreased from 15.5 2.5 kg/m2 to 14.5 2.0 kg/m2 (P = 0.002), and total fat mass index decreased from 7.5 2.0kg/m2 to 6.0 1.5kg/m2 (P < 0.0001) over 135 days.  Sarcopenia in overweight/obese patients with advanced pancreatic cancer is an occult condition but can be identified using CT scans. This condition is an independent adverse prognostic indicator that should be considered for stratification of patients' entering clinical trials, systemic therapy, or support care programs.

title: Negative Impact of Skeletal Muscle Loss after Systemic Chemotherapy in Patients with Unresectable Colorectal Cancer
abstract: Skeletal muscle depletion (sarcopenia) is closely associated with limited physical ability and high mortality. This study evaluated the prognostic significance of skeletal muscle status before and after chemotherapy in patients with unresectable colorectal cancer (CRC).  We conducted a retrospective analysis of 215 consecutive patients with unresectable CRC who underwent systemic chemotherapy. Skeletal muscle cross-sectional area was measured by computed tomography. We evaluated the prognostic value of skeletal muscle mass before chemotherapy and the rate of skeletal muscle change in cross-sectional area after chemotherapy.  One-hundred-eighty-two patients met our inclusion criteria. There were no significant differences in progression-free survival (PFS) or overall survival (OS) associated with skeletal muscle mass before chemotherapy. However, 22 patients with skeletal muscle loss (>5%) after chemotherapy showed significantly shorter PFS and OS compared with those without skeletal muscle loss (PFS, log-rank p = 0.029; OS, log-rank p = 0.009). Multivariate Cox regression analysis revealed that skeletal muscle loss after chemotherapy (hazard ratio, 2.079; 95% confidence interval, 1.194–3.619; p = 0.010) was independently associated with OS.  Skeletal muscle loss after chemotherapy was an independent, negative prognostic factor in unresectable CRC.

title: Central tenet of cancer cachexia therapy: do patients with advanced cancer have exploitable anabolic potential?
abstract: Skeletal muscle wasting is considered the central feature of cachexia, but the potential for skeletal muscle anabolism in patients with advanced cancer is unproven.



We investigated the clinical course of skeletal muscle wasting in advanced cancer and the window of possible muscle anabolism.



We conducted a quantitative analysis of computed tomography (CT) images for the loss and gain of muscle in population-based cohorts of advanced cancer patients (lung, colorectal, and pancreas cancer and cholangiocarcinoma) in a longitudinal observational study.



Advanced-cancer patients (n = 368; median survival: 196 d) had a total of 1279 CT images over the course of their disease. With consideration of all time points, muscle loss occurred in 39% of intervals between any 2 scans. However, the overall frequency of muscle gain was 15.4%, and muscle was stable in 45.6% of intervals between any 2 scans, which made the maintenance or gain of muscle the predominant behavior. Multinomial logistic regression revealed that being within 90 d (compared with >90 d) from death was the principal risk factor for muscle loss (OR: 2.67; 95% CI: 1.45, 4.94; P = 0.002), and muscle gain was correspondingly less likely (OR: 0.37; 95% CI: 0.20, 0.69; P = 0.002) at this time. Sex, age, BMI, and tumor group were not significant predictors of muscle loss or gain.



A window of anabolic potential exists at defined early phases of the disease trajectory (>90 d survival), creating an opportunity for nutritional intervention to stop or reverse cachexia. Cancer patients within 90 d of death have a low likelihood of anabolic potential.

title: Loss of skeletal muscle during neoadjuvant chemotherapy is related to decreased survival in ovarian cancer patients
abstract: Malnutrition, weight loss, and muscle wasting (sarcopenia) are common among women with advanced ovarian cancer and have been associated with adverse clinical outcomes and survival. Our objective is to investigate overall survival (OS) related to changes in skeletal muscle (SM) for patients with advanced ovarian cancer treated with neoadjuvant chemotherapy and interval debulking.

title: Human body composition: advances in models and methods.
abstract: The field of human body composition research is reaching a mature stage in its development: The three interconnected areas that define body composition research--models and their rules, methodology, and biological effects--are well-defined and are actively investigated by scientists in diverse disciplines from many different nations; and methods are available for measuring all major atomic, molecular, cellular, and tissue-system level body composition components in research, clinical, and epidemiological settings. This review summarizes main body composition research concepts, examines new component-measurement methodologies, and identifies potential areas of future research.

title: Cadaver validation of skeletal muscle measurement by magnetic resonance imaging and computerized tomography.
abstract: Magnetic resonance imaging (MRI) and computerized tomography (CT) are promising reference methods for quantifying whole body and regional skeletal muscle mass. Earlier MRI and CT validation studies used data-acquisition techniques and data-analysis procedures now outdated, evaluated anatomic rather than adipose tissue-free skeletal muscle (ATFSM), studied only the relatively large thigh, or found unduly large estimation errors. The aim of the present study was to compare arm and leg ATFSM cross-sectional area estimates (cm2) by using standard MRI and CT acquisition and image-analysis methods with corresponding cadaver estimates. A second objective was to validate MRI and CT measurements of adipose tissue embedded within muscle (interstitial adipose tissue) and surrounding muscle (subcutaneous adipose tissue). ATFSM area (n = 119) by MRI [38.9 +/- 22.3 (SD) cm2], CT (39.7 +/- 22.8 cm2), and cadaver (39.5 +/- 23.0 cm2) were not different (P > 0.001), and both MRI and CT estimates of ATFSM were highly correlated with corresponding cadaver values [MRI: r = 0.99, SE of estimate (SEE) 3.9 cm2, P < 0.001; and CT: r = 0.99, SEE = 3.8 cm2, P < 0.001]. Similarly good results were observed between MRI- and CT-measured vs. cadaver-measured interstitial and subcutaneous adipose tissue. For MRI-ATFSM the intraobserver correlation for duplicate measurements in vivo was 0. 99 [SEE = 8.7 cm2 (2.9%), P < 0.001]. These findings strongly support the use of MRI and CT as reference methods for appendicular skeletal muscle, interstitial and subcutaneous adipose tissue measurement in vivo.

title: A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care.
abstract: Human body composition is important in numerous cancer research domains. Our objective was to evaluate clinically accessible methods to achieve practical and precise measures of body composition in cancer patients. Dual-energy X-ray absorptiometry (DXA)-based analysis of fat and fat-free mass was performed in 50 cancer patients and compared with bioelectrical impedance analysis (BIA) and with regional computed tomography (CT) images available in the patients' medical records. BIA overestimated or underestimated fat-free mass substantially compared with DXA as the method of reference (up to 9.3 kg difference). Significant changes in fat-free mass over time detected with DXA in a subset of 21 patients (+2.2 +/- 3.2%/100 days, p = 0.003), was beyond the limits of detection of BIA. Regional analysis of fat and fat-free tissue at the 3rd lumbar vertebra with either DXA or CT strongly predicted whole-body fat and fat-free mass (r = 0.86-0.94; p < 0.001). CT images provided detail on specific muscles, adipose tissues and organs, not provided by DXA or BIA. CT presents great practical significance due to the prevalence of these images in patient diagnosis and follow-up, thus marrying clinical accessibility with high precision to quantify specific tissues and to predict whole-body composition.

title: Strength conditioning in older men: skeletal muscle hypertrophy and improved function.
abstract: The effects of strength conditioning on skeletal muscle function and mass were determined in older men. Twelve healthy untrained volunteers (age range 60-72 yr) participated in a 12-wk strength training program (8 repetitions/set; 3 sets/day; 3 days/wk) at 80% of the one repetition maximum (1 RM) for extensors and flexors of both knee joints. They were evaluated before the program and after 6 and 12 wk of training. Weekly measurements of 1 RM showed a progressive increase in strength in extensors and flexors. By 12 wk extensor and flexor strength had increased 107.4 (P less than 0.0001) and 226.7% (P less than 0.0001), respectively. Isokinetic peak torque of extensors and flexors measured on a Cybex II dynamometer increased 10.0 and 18.5% (P less than 0.05) at 60 degrees/s and 16.7 and 14.7% (P less than 0.05) at 240 degrees/s. The torque-velocity relationship showed an upward displacement of the curve at the end of training, mainly in the slow-velocity high-torque region. Midthigh composition from computerized tomographic scans showed an increase (P less than 0.01) in total thigh area (4.8%), total muscle area (11.4%), and quadriceps area (9.3%). Biopsies of the vastus lateralis muscle revealed similar increases (P less than 0.001) in type I fiber area (33.5%) and type II fiber area (27.6%). Daily excretion of urinary 3-methyl-L-histidine increased with training (P less than 0.05) by an average 40.8%. Strength gains in older men were associated with significant muscle hypertrophy and an increase in myofibrillar protein turnover.

title: Aging of skeletal muscle: a 12-yr longitudinal study.
abstract: The present study examines age-related changes in skeletal muscle size and function after 12 yr. Twelve healthy sedentary men were studied in 1985-86 (T1) and nine (initial mean age 65.4 +/- 4.2 yr) were reevaluated in 1997-98 (T2). Isokinetic muscle strength of the knee and elbow extensors and flexors showed losses (P < 0.05) ranging from 20 to 30% at slow and fast angular velocities. Computerized tomography (n = 7) showed reductions (P < 0.05) in the cross-sectional area (CSA) of the thigh (12.5%), all thigh muscles (14.7%), quadriceps femoris muscle (16.1%), and flexor muscles (14. 9%). Analysis of covariance showed that strength at T1 and changes in CSA were independent predictors of strength at T2. Muscle biopsies taken from vastus lateralis muscles (n = 6) showed a reduction in percentage of type I fibers (T1 = 60% vs. T2 = 42%) with no change in mean area in either fiber type. The capillary-to-fiber ratio was significantly lower at T2 (1.39 vs. 1. 08; P = 0.043). Our observations suggest that a quantitative loss in muscle CSA is a major contributor to the decrease in muscle strength seen with advancing age and, together with muscle strength at T1, accounts for 90% of the variability in strength at T2.

title: The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study.
abstract: The loss of muscle mass is considered to be a major determinant of strength loss in aging. However, large-scale longitudinal studies examining the association between the loss of mass and strength in older adults are lacking.



Three-year changes in muscle mass and strength were determined in 1880 older adults in the Health, Aging and Body Composition Study. Knee extensor strength was measured by isokinetic dynamometry. Whole body and appendicular lean and fat mass were assessed by dual-energy x-ray absorptiometry and computed tomography.



Both men and women lost strength, with men losing almost twice as much strength as women. Blacks lost about 28% more strength than did whites. Annualized rates of leg strength decline (3.4% in white men, 4.1% in black men, 2.6% in white women, and 3.0% in black women) were about three times greater than the rates of loss of leg lean mass ( approximately 1% per year). The loss of lean mass, as well as higher baseline strength, lower baseline leg lean mass, and older age, was independently associated with strength decline in both men and women. However, gain of lean mass was not accompanied by strength maintenance or gain (ss coefficients; men, -0.48 +/- 4.61, p =.92, women, -1.68 +/- 3.57, p =.64).



Although the loss of muscle mass is associated with the decline in strength in older adults, this strength decline is much more rapid than the concomitant loss of muscle mass, suggesting a decline in muscle quality. Moreover, maintaining or gaining muscle mass does not prevent aging-associated declines in muscle strength.

title: Sarcopenia is a Negative Prognostic Factor After Curative Resection of Colorectal Cancer
abstract: BackgroundSkeletal muscle depletion (sarcopenia) is closely associated with limited physical ability and high mortality. This study was performed to evaluate the prognostic significance of skeletal muscle depletion in patients with resectable stage I–III colorectal cancer (CRC).MethodsWe conducted a retrospective analysis of 220 consecutive patients with stage I–III CRC who underwent curative resection. The skeletal muscle cross-sectional area was measured by preoperative computed tomography. The lowest sex-specific quartile of skeletal muscle mass was classified as sarcopenia. Factors contributing to recurrence-free survival (RFS) were analyzed by univariate and multivariate Cox proportional hazard models.ResultsOf 220 patients who met our inclusion criteria, 55 (25 %) had sarcopenia. The median follow-up duration was 41.4 months. Patients with sarcopenia were younger and had higher carcinoembryonic antigen levels than patients without sarcopenia. RFS and overall survival (OS) were significantly shorter in patients with sarcopenia than those without (5-year RFS, 56 vs. 79 %, log-rank p = 0.006; 5-year OS, 68 vs. 85 %, log-rank p = 0.015). Multivariate Cox regression analysis revealed that sarcopenia was independently associated with shorter RFS (hazard ratio [HR] 2.176; 95 % confidence interval [CI] 1.200–3.943; p = 0.010) and OS (HR 2.270; 95 % CI 1.147–4.494; p = 0.019). The influence of sarcopenia on patient outcome was modified by age at surgery (p value for interaction = 0.026); sarcopenia was associated with a poor prognosis, especially in young patients (log-rank p < 0.001).ConclusionsSarcopenia negatively impacts survival in patients undergoing curative resection for stage I–III CRC.

title: Prognostic value of sarcopenia in adults with solid tumours: A meta-analysis and systematic review.
abstract: Body composition plays an important role in predicting treatment outcomes in adults with cancer. Using existing computed tomographic (CT) cross-sectional imaging and readily available software, the assessment of skeletal muscle mass to evaluate sarcopenia has become simplified. We performed a systematic review and meta-analysis to quantify the prognostic value of skeletal muscle index (SMI) obtained from cross-sectional CT imaging on clinical outcomes in non-haematologic solid tumours.



We searched PubMed and the American Society Clinical Oncology online database of meeting abstracts up to October 2015 for relevant studies. We included studies assessing the prognostic impact of pre-treatment SMI on clinical outcomes in patients with non-haematologic solid tumours. The primary outcome was overall survival (OS) and the secondary outcomes included cancer-specific survival (CSS), disease-free survival (DFS), and progression-free survival (PFS). The summary hazard ratio (HR) and 95% confidence interval (CI) were calculated.



A total of 7843 patients from 38 studies were included. SMI lower than the cut-off was associated with poor OS (HR = 1.44, 95% CI = 1.32-1.56, p < 0.001). The effect of SMI on OS was observed among various tumour types and across disease stages. Worse CSS was also associated with low SMI (HR = 1.93, 95% CI = 1.38-2.70, p < 0.001) as well as DFS (HR = 1.16, 95% CI = 1.00-1.30, p = 0.014), but not PFS (HR = 1.54, 95% CI = 0.90-2.64, p = 0.117).



This meta-analysis demonstrates that low SMI at cancer diagnosis is associated with worse survival in patients with solid tumours. Further research into understanding and mitigating the negative effects of sarcopenia in adults with cancer is needed.

title: Sarcopenia as a predictor of overall survival after cytoreductive nephrectomy for metastatic renal cell carcinoma.
abstract: Cytoreductive nephrectomy (CN) is a therapeutic consideration in patients with metastatic renal cell carcinoma (mRCC). We hypothesized that sarcopenia, a novel marker of nutritional status, is a predictor of survival after CN.



Of 105 patients who underwent CN at our institution for mRCC, 93 had preoperative imaging available for analysis. Skeletal muscle index was calculated on axial images at the third lumbar vertebrae, and a threshold skeletal muscle index of<43 cm(2)/m(2) in men with a body mass index (BMI)<25 kg/m(2),<53 cm(2)/m(2) in men with a BMI>25 kg/m(2), and<41 cm(2)/m(2) in women was used to classify patients as sarcopenic vs. nonsarcopenic. This classification was then retrospectively correlated with overall survival (OS).



Overall, 27 patients (29.0%) had sarcopenia before surgery. Sarcopenic patients received neoadjuvant systemic therapy more often (P = 0.022), had lower BMI (P = 0.001), had a higher incidence of hypoalbuminemia before surgery (P = 0.035), received more blood transfusions perioperatively (P = 0.006) owing to lower preoperative hemoglobin levels (P = 0.001), and had longer length of stay after surgery (P = 0.02). Median OS in sarcopenic patients was 7 months (95% CI: 0.8-13.2) vs. 23 months (95% CI: 12.4-33.6) in nonsarcopenic patients. On multivariate analysis, sarcopenia was an independent predictor of OS (hazard ratio = 2.13, 95% CI: 1.15-3.92; P = 0.016) in addition to number of metastatic sites>2 (hazard ratio = 2.09, 95% CI: 1.24-3.53; P = 0.006).



Sarcopenia can be an important prognostic factor associated with worse OS after CN for mRCC.

title: Sarcopenia as a Prognostic Biomarker of Advanced Urothelial Carcinoma
abstract: Sarcopenia, a novel concept reflecting the degenerative loss of skeletal muscle mass, is an objective indicator of cancer cachexia. We investigated its role as a prognostic biomarker in advanced urothelial carcinoma (UC) patients.  This retrospective study consisted of 88 UC patients with cT4 and/or metastases to lymph nodes/distant organs. Skeletal muscle index (SMI), an indicator of whole-body muscle mass, was measured from computed tomography (CT) images at the diagnosis. Sarcopenia was defined as SMIs of <43 cm2/m2 for males with body mass index (BMI) <25 cm2/m2, <53 cm2/m2 for males with BMI ≥25 cm2/m2, and <41 cm2/m2 for females. Predictors of overall survival (OS) were examined using Cox proportional hazard models.  Sixty-seven patients (76%) died during the median follow-up of 13 months. The median OS rate was 13 months. Multivariate analysis revealed that SMI was a significant and independent predictor of shorter OS (hazard ratio (HR) 0.90, P <0.001). In the present cohort, 53 (60%) were diagnosed with sarcopenia. The median OS rates were 11 and 31 months for sarcopenic and non-sarcopenic patients, respectively (P <0.001). On multivariate analysis, sarcopenia was a significant and independent predictor of shorter OS (HR 3.36, P <0.001), along with higher C-reactive protein (CRP) (P = 0.001), upper urinary tract cancer (P = 0.007), higher lactate dehydrogenase (LDH) (P = 0.047), and higher alkaline phosphatase (ALP) (P = 0.048).  Sarcopenia, which is readily evaluated on routine CT scans, is a useful prognostic biomarker of advanced UC. Non-sarcopenic patients can expect long-term survival. Evaluating sarcopenia can be helpful for decision-making processes in the management of advanced UC patients.

title: Cancer Cachexia: Mechanisms and Clinical Implications
abstract: Cachexia is a multifactorial process of skeletal muscle and adipose tissue atrophy resulting in progressive weight loss. It is associated with poor quality of life, poor physical function, and poor prognosis in cancer patients. It involves multiple pathways: procachectic and proinflammatory signals from tumour cells, systemic inflammation in the host, and widespread metabolic changes (increased resting energy expenditure and alterations in metabolism of protein, fat, and carbohydrate). Whether it is primarily driven by the tumour or as a result of the host response to the tumour has yet to be fully elucidated. Cachexia is compounded by anorexia and the relationship between these two entities has not been clarified fully. Inconsistencies in the definition of cachexia have limited the epidemiological characterisation of the condition and there has been slow progress in identifying therapeutic agents and trialling them in the clinical setting. Understanding the complex interplay of tumour and host factors will uncover new therapeutic targets.

title: Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with n-3 fatty acids
abstract: The aim of the study was to assess the total energy expenditure (TEE), resting energy expenditure (REE) and physical activity level (PAL) in home-living cachectic patients with advanced pancreatic cancer. The influence of an energy and protein dense oral supplement either enriched with or without the n-3 fatty acid eicosapentaenoic acid (EPA) and administered over an 8-week period was also determined. In total, 24 patients were studied at baseline. The total energy expenditure was measured using doubly labelled water and REE determined by indirect calorimetry. Patients were studied at baseline and then randomised to either oral nutritional supplement. Measurements were repeated at 8 weeks. At baseline, REE was increased compared with predicted values for healthy individuals (1387(42) vs 1268(32) kcal day−1, P=0.001), but TEE (1732(82) vs 1903(48) kcal day−1, P=0.023) and PAL (1.24(0.04) vs 1.50) were reduced. After 8 weeks, the REE, TEE and PAL of patients who received the control supplement did not change significantly. In contrast, although REE did not change, TEE and PAL increased significantly in those who received the n-3 (EPA) enriched supplement. In summary, patients with advanced pancreatic cancer were hypermetabolic. However, TEE was reduced and this was secondary to a reduction in physical activity. The control energy and protein dense oral supplement did not influence the physical activity component of TEE. In contrast, administration of the supplement enriched with EPA was associated with an increase in physical activity, which may reflect improved quality of life.

title: Association of skeletal muscle wasting with treatment with sorafenib in patients with advanced renal cell carcinoma: results from a placebo-controlled study.
abstract: Effects of specific antineoplastic therapies on progression of cancer-associated wasting remain uncharacterized. We selected a targeted therapy, sorafenib, because of its reported association with weight loss.  Patients with metastatic renal cell cancer (RCC) who were resistant to standard therapy (N = 80) received sorafenib 400 mg twice daily or placebo in a randomized, double-blinded clinical trial. Computed tomography image analysis, which has high precision and specificity for evaluation of specific muscles and adipose tissues, was used to define change in total skeletal muscle and adipose tissue.  At inclusion, 51% of patients were overweight or obese (ie, body mass index [BMI] > 25 kg/m(2)). Only 5% were underweight. Advanced muscle wasting (ie, sarcopenia) was present in 72% of patients with BMI less than 25 and in 34% of those with a BMI greater than 25. Patients received placebo for an average of 6 months and received sorafenib for 1 year. Patients in the placebo group had stable body weight during 6 months (0.8 kg +/- 0.7 kg), with no significant alteration of muscle or fat. Patients who received sorafenib lost 2.1 kg +/- 0.6 kg (P < .01) in 6 months and lost 4.2 kg +/- 0.7 kg (P < .01) by 1 year. Sorafenib-treated patients lost skeletal muscle progressively at 6 months (decrease of 4.9%; P < .01) and 12 months (decrease of 8.0%; P < .01).  Sarcopenia is prevalent in patients with metastatic RCC and is an occult condition in patients with normal or high BMI. Muscle loss is specifically exacerbated by sorafenib, consistent with the evidence for a role of kinases in regulating muscle mass. Muscle loss is a sorafenib adverse effect that may relate to asthenia, fatigue, and physical disability.

title: Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials.
abstract: Patients with advanced cancer frequently experience anorexia and cachexia, which are associated with reduced food intake, altered body composition, and decreased functionality. We assessed anamorelin, a novel ghrelin-receptor agonist, on cachexia in patients with advanced non-small-cell lung cancer and cachexia.



ROMANA 1 and ROMANA 2 were randomised, double-blind, placebo-controlled phase 3 trials done at 93 sites in 19 countries. Patients with inoperable stage III or IV non-small-cell lung cancer and cachexia (defined as ≥5% weight loss within 6 months or body-mass index <20 kg/m(2)) were randomly assigned 2:1 to anamorelin 100 mg orally once daily or placebo, with a computer-generated randomisation algorithm stratified by geographical region, cancer treatment status, and weight loss over the previous 6 months. Co-primary efficacy endpoints were the median change in lean body mass and handgrip strength over 12 weeks and were measured in all study participants (intention-to-treat population). Both trials are now completed and are registered with ClinicalTrials.gov, numbers NCT01387269 and NCT01387282.



From July 8, 2011,  2014, 484 patients were enrolled in ROMANA 1 (323 to anamorelin, 161 to placebo), and from July 14, 2011, to Oct 31, 2013, 495 patients were enrolled in ROMANA 2 (330 to anamorelin, 165 to placebo). Over 12 weeks, lean body mass increased in patients assigned to anamorelin compared with those assigned to placebo in ROMANA 1 (median increase 0·99 kg [95% CI 0·61 to 1·36] vs -0·47 kg [-1·00 to 0·21], p<0·0001) and ROMANA 2 (0·65 kg [0·38 to 0·91] vs -0·98 kg [-1·49 to -0·41], p<0·0001). We noted no difference in handgrip strength in ROMANA 1 (-1·10 kg [-1·69 to -0·40] vs -1·58 kg [-2·99 to -1·14], p=0·15) or ROMANA 2 (-1·49 kg [-2·06 to -0·58] vs -0·95 kg [-1·56 to 0·04], p=0·65). There were no differences in grade 3-4 treatment-related adverse events between study groups; the most common grade 3-4 adverse event was hyperglycaemia, occurring in one (<1%) of 320 patients given anamorelin in ROMANA 1 and in four (1%) of 330 patients given anamorelin in ROMANA 2.



Anamorelin significantly increased lean body mass, but not handgrip, strength in patients with advanced non-small-cell lung cancer. Considering the unmet medical need for safe and effective treatments for cachexia, anamorelin might be a treatment option for patients with cancer anorexia and cachexia.

title: Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial.
abstract: Cancer-induced muscle wasting begins early in the course of a patient's malignant disease, resulting in declining physical function and other detrimental clinical consequences. This randomised, double-blind, placebo-controlled phase 2 trial assessed the efficacy and safety of enobosarm, a selective androgen receptor modulator, in patients with cancer.



We enrolled male (>45 years) and female (postmenopausal) patients with cancer who were not obese and who had at least 2% weight loss in the previous 6 months. Participants were randomly assigned (1:1:1 ratio, by computer generated list, block size three, stratified by cancer type) to receive once-daily oral enobosarm 1 mg, 3 mg, or placebo for up to 113 days at US and Argentinian oncology clinics. The sponsor, study personnel, and participants were masked to assignment. The primary endpoint was change in total lean body mass from baseline, assessed by dual-energy x-ray absorptiometry. Efficacy analyses were done only in patients who had a baseline and an on-treatment assessment in the protocol-specified window of within 10 days before baseline or first study drug, and within 10 days of day 113 or end of study (evaluable efficacy population). Adverse events and other safety measurements were assessed in the intention-to-treat (safety) population. 
Enrolment started on July 3, 2007, and the last patient completed the trial on Aug 1, 2008. 159 patients were analysed for safety (placebo, n=52; enobosarm 1 mg, n=53; enobosarm 3 mg, n=54). The evaluable efficacy population included 100 participants (placebo, n=34; enobosarm 1 mg, n=32; enobosarm 3 mg, n=34). Compared with baseline, significant increases in total lean body mass by day 113 or end of study were noted in both enobosarm groups (enobosarm 1 mg median 1·5 kg, range -2·1 to 12·6, p=0·0012; enodosarm 3 mg 1·0 kg, -4·8 to 11·5, p=0·046). Change in total lean body mass within the placebo group (median 0·02 kg, range -5·8 to 6·7) was not significant (p=0·88). The most common serious adverse events were malignant neoplasm progression (eight of 52 [15%] with placebo vs five of 53 [9%] with enobosarm 1 mg vs seven of 54 [13%] with enobosarm 3 mg), pneumonia (two [4%] vs two [4%] vs three [6%]), and febrile neutropenia (three [6%vs one [2%] vs none). None of these events were deemed related to study drug.



Cancer cachexia is an unmet medical need and our data suggest that use of enobosarm might lead to improvements in lean body mass, without the toxic effects associated with androgens and progestational agents.



GTx.

title: Cancer cachexia: developing multimodal therapy for a multidimensional problem.
abstract: Cancer cachexia is a multi-factorial syndrome that encompasses a spectrum from early weight loss (pre-cachexia) to a state of severe incapacity incompatible with life. The molecular basis of the syndrome in animal models (based on host-tumour cell interaction, the neuro-hormonal control of appetite and the hypertrophy/atrophy pathways that govern muscle-wasting) has provided a new raft of biomarkers and therapeutic targets. Key defining features of cachexia in humans (weight loss, reduced food intake and systemic inflammation) now provide not only a framework for classification but also a rationale for targets for therapeutic intervention. The role of age and immobility in muscle-wasting also provides a rationale for the nature of nutritional support in cachexia. There is now a substantive evidence that multimodal approaches that address these key issues can stabilise and even improve the nutritional status, function and quality of life of at least a proportion of advanced cancer patients. Novel biomarkers for patient stratification and more specific techniques for the estimation of muscle mass and physical activity level herald a new era in trial design. The current evidence-base justifies new enthusiasm for the design of complex intervention studies in the management of cancer cachexia.

title: Evidence base for multimodal therapy in cachexia
abstract: Purpose of reviewThe lack of success of unimodal treatment studies in cachexia and the growing awareness that multiple components are responsible for the development of cachexia have led to the view that cachexia intervention should include multimodal treatment. The aim of this article is to examine the evidence for multimodal treatment in the management of cancer cachexia. Recent findingsThere are some studies involving multimodal treatment that indicate significant effects on cachexia outcomes. There are, however, no randomized controlled trials to date that incorporate fully a structured exercise program, nutrition, good symptom treatment as well as drug treatment, to counteract the effects of altered metabolism. SummaryThe effectiveness of any drug intervention for cancer cachexia probably will only be maximized if incorporated into multimodal treatment. Further, cachexia treatment trials should also aim to include patients at an early phase in their cachexia trajectory and use validated outcome measures.

title: A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer
abstract: Cancer cachexia is a syndrome of weight loss (including muscle and fat), anorexia, and decreased physical function. It has been suggested that the optimal treatment for cachexia should be a multimodal intervention. The primary aim of this study was to examine the feasibility and safety of a multimodal intervention (n‐3 polyunsaturated fatty acid nutritional supplements, exercise, and anti‐inflammatory medication: celecoxib) for cancer cachexia in patients with incurable lung or pancreatic cancer, undergoing chemotherapy.