Sarcopenic obesity and myosteatosis are associated with higher mortality in patients with cirrhosis.

BACKGROUND AND AIMS: Obesity is frequently associated with cirrhosis, and cirrhotic patients may develop simultaneous loss of skeletal muscle and gain of adipose tissue, culminating in the condition of sarcopenic obesity. Additionally, muscle depletion is characterized by both a reduction in muscle size and increased proportion of muscular fat, termed myosteatosis. In this study, we aimed to establish the frequency and clinical significance of sarcopenia, sarcopenic obesity and myosteatosis in cirrhotic patients. METHODS: We analysed 678 patients with cirrhosis. Sarcopenia, sarcopenic obesity and myosteatosis were analysed by CT scan using the third lumbar vertebrae skeletal muscle and attenuation indexes, using previously validated gender-and body mass index-specific cutoffs. RESULTS: Patients were predominately men (n = 457, 67%), and cirrhosis aetiology was hepatitis C virus in 269 patients (40%), alcohol in 153 (23%), non-alcoholic steatohepatitis/cryptogenic in 96 (14%), autoimmune liver disease in 55 (8%), hepatitis B virus in 43 (6%), and others in 5 patients (1%). Sarcopenia was present in 292 (43%), 135 had sarcopenic obesity (20%) and 353 had myosteatosis (52%). Patients with sarcopenia (22 ± 3 vs. 95 ± 22 months, P < 0.001), sarcopenic obesity (22 ± 3 vs. 95 ± 22 months, P < 0.001), and myosteatosis (28 ± 5 vs. 95 ± 22 months, P < 0.001) had worse median survival than patients without muscular abnormalities. By multivariate Cox regression analysis, both sarcopenia [hazard ratio (HR) 2.00, 95% confidence interval (CI) 1.44-2.77, P < 0.001], and myosteatosis (HR 1.42, 95% CI 1.02-1.07, P = 0.04) were associated with mortality. CONCLUSIONS: Sarcopenia, sarcopenic obesity and myosteatosis are often present in patients with cirrhosis, and sarcopenia and myosteatosis are independently associated with a higher long-term mortality in cirrhosis.

Study Design and Rationale for the Phase 3 Clinical Development Program of Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of Muscle Wasting in Cancer Patients (POWER Trials).

Muscle wasting in cancer is a common and often occult condition that can occur prior to overt signs of weight loss and before a clinical diagnosis of cachexia can be made. Muscle wasting in cancer is an important and independent predictor of progressive functional impairment, decreased quality of life, and increased mortality. Although several therapeutic agents are currently in development for the treatment of muscle wasting or cachexia in cancer, the majority of these agents do not directly inhibit muscle loss. Selective androgen receptor modulators (SARMs) have the potential to increase lean body mass (LBM) and hence muscle mass, without the untoward side effects seen with traditional anabolic agents. Enobosarm, a nonsteroidal SARM, is an agent in clinical development for prevention and treatment of muscle wasting in patients with cancer (POWER 1 and 2 trials). The POWER trials are two identically designed randomized, double-blind, placebo-controlled, multicenter, and multinational phase 3 trials to assess the efficacy of enobosarm for the prevention and treatment of muscle wasting in subjects initiating first-line chemotherapy for non-small-cell lung cancer (NSCLC). To assess enobosarm's effect on both prevention and treatment of muscle wasting, no minimum weight loss is required. These pivotal trials have pioneered the methodological and regulatory fields exploring a therapeutic agent for cancer-associated muscle wasting, a process hereby described. In each POWER trial, subjects will receive placebo (n = 150) or enobosarm 3 mg (n = 150) orally once daily for 147 days. Physical function, assessed as stair climb power (SCP), and LBM, assessed by dual-energy X-ray absorptiometry (DXA), are the co-primary efficacy endpoints in both trials assessed at day 84. Based on extensive feedback from the US Food and Drug Administration (FDA), the co-primary endpoints will be analyzed as a responder analysis. To be considered a physical function responder, a subject must have ≥10 % improvement in physical function compared to baseline. To meet the definition of response on LBM, a subject must have demonstrated no loss of LBM compared with baseline. Secondary endpoints include durability of response assessed at day 147 in those responding at day 84. A combined overall survival analysis for both studies is considered a key secondary safety endpoint. The POWER trials design was established with extensive clinical input and collaboration with regulatory agencies. The efficacy endpoints are a result of this feedback and discussion of the threshold for clinical benefit in patients at risk for muscle wasting. Full results from these studies will soon be published and will further guide the development of future anabolic trials. Clinical Trial ID: NCT01355484. https://clinicaltrials.gov/ct2/show/NCT01355484 , NCT01355497. https://clinicaltrials.gov/ct2/show/NCT01355497?term=g300505&rank=1 .

A Uridine Glucuronosyltransferase 2B7 Polymorphism Predicts Epirubicin Clearance and Outcomes in Early-Stage Breast Cancer.

BACKGROUND: Epirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7), an enzyme rich in single nucleotide polymorphisms (SNPs). We studied whether the -161 C > T germline SNP in UGT2B7 was related to epirubicin metabolism and whether differences exist in the toxicity and efficacy of epirubicin-based chemotherapy among patients who were TT homozygotes, CT heterozygotes, and CC homozygotes. PATIENTS AND METHODS: A total of 132 women with non-metastatic breast cancer receiving FEC (5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), cyclophosphamide 500 mg/m(2)) were prospectively enrolled. Toxicity was assessed in cycle 1 using the National Cancer Institute Common Toxicity Criteria, version 2.0. RESULTS: The sequence at -161 was studied in 132 subjects; 37 were TT homozygotes, 63 were CT heterozygotes, 26 were CC homozygotes, and 6 could not be genotyped. The CC genotype patients had decreased epirubicin clearance (median, 103.3 L/hr) compared with the CT/TT genotype patients (median, 134.0 L/hr; P = .002). The CC homozygous patients had an increased risk of grade 3 to 4 leukopenia compared with the TT homozygotes or heterozygotes (P = .038 and P = .032, respectively). TT homozygotes or heterozygotes had an increased risk of early recurrence (P = .039; χ(2) test). CONCLUSION: The results of the present prospective pharmacogenetic study suggest that the UGT2B7 -161 C > T SNP correlate with drug metabolism, toxicity, and efficacy in patients receiving epirubicin chemotherapy. Further studies of this UGT2B7 SNP as a predictor of epirubicin toxicity and efficacy are warranted.

Lean tissue imaging: a new era for nutritional assessment and intervention.

Body composition refers to the amount of fat and lean tissues in our body; it is a science that looks beyond a unit of body weight, accounting for the proportion of different tissues and its relationship to health. Although body weight and body mass index are well-known indexes of health status, most researchers agree that they are rather inaccurate measures, especially for elderly individuals and those patients with specific clinical conditions. The emerging use of imaging techniques such as dual energy x-ray absorptiometry, computerized tomography, magnetic resonance imaging, and ultrasound imaging in the clinical setting have highlighted the importance of lean soft tissue (LST) as an independent predictor of morbidity and mortality. It is clear from emerging studies that body composition health will be vital in treatment decisions, prognostic outcomes, and quality of life in several nonclinical and clinical states. This review explores the methodologies and the emerging value of imaging techniques in the assessment of body composition, focusing on the value of LST to predict nutrition status.

The association between body composition and toxicities from the combination of Doxil and trabectedin in patients with advanced relapsed ovarian cancer.

Emerging research suggests that body composition can predict toxicity of certain chemotherapeutic agents. We used data from a clinical study to investigate associations between body composition and combined DOXIL (pegylated liposomal doxorubicin; PLD) and trabectedin (Yondelis) treatment, an effective treatment for ovarian cancer that shows high interpatient variation in toxicity profile. Patients (n = 74) participating in a phase III randomized trial of relapsed advanced ovarian cancer receiving PLD (30 mg/m(2)) and trabectedin (1.1 mg/m(2)) were included. Muscle tissue was measured by analysis of computerized tomography images, and an extrapolation of muscle and adipose tissue to lean body mass (LBM) and fat mass (FM) were employed. Toxicity profile after cycle 1 was used and graded according to the National Cancer Institute Common Toxicity Criteria (version 3). Patients presented with a wide range of body composition. In overweight and obese patients (body mass index (BMI) ≥ 25 kg/m(2), n = 48) toxicity was more prevalent in those with lower BMI (p = 0.028) and a lower FM (n = 43, p = 0.034). Although LBM alone was not predictive of toxicity, a lower FM/LBM ratio was the most powerful variable associated with toxicity (p = 0.006). A different pattern emerged among normal weight patients (n = 26) where toxicity was rare among patients with smaller BMI (<21 kg/m(2)). A clear association between both FM and LBM (primarily driven by FM) in explaining PLD plus trabectedin toxicity emerged, but only in individuals with excess body weight, with a lower ratio predicting higher exposure and risk for toxicity.

A population-based approach to define body-composition phenotypes.

BACKGROUND: Abnormal body compositions such as high adiposity (HA), low muscle mass (LM), or a combination of the 2 [high adiposity with low muscle mass (HA-LM)] are relevant phenotypes, but data on their prevalence and impact on health are still limited. This is largely because of a lack of a consensus definition for these conditions. Of particular interest is the HA-LM phenotype, also termed "sarcopenic obesity," which may confer greater health risk. OBJECTIVE: We propose a new approach for operationalizing abnormal body-composition phenotypes in a representative adult population. DESIGN: Whole-body dual-energy X-ray absorptiometry data obtained from the 1999-2004 NHANES were analyzed for 13,236 subjects aged ≥18 y (maximum weight and height of 136 kg and 1.96 m, respectively). Sex- and body mass index (BMI)-specific decile groups of appendicular skeletal muscle index (ASMI; kg/m²) and fat mass index (FMI; kg/m²) were developed. Cutoffs for HA and LM were incorporated into a diagnostic framework to characterize 4 specific body-composition phenotypes-low adiposity with high muscle mass, high adiposity with high muscle mass, low adiposity with low muscle mass, and HA-LM-and a subclassification of the phenotypes into classes I, II, and III. RESULTS: Abnormal phenotypes were prevalent across the age spectrum and BMI categories. The association between ASMI or FMI and age was modified by sex and BMI. The prevalence of HA-LM in the whole sample was 10.3% in women and 15.2% in men. The prevalence of all subclasses of HA-LM in obese women and men was 14.7% and 22.9%, respectively. HA-LM class III was more prevalent in obese men (2.3%) than in obese women (0.3%). CONCLUSIONS: We developed sex- and BMI-specific reference curves to harmonize the classification of body-composition phenotypes. The application of this classification will be particularly useful in the identification of cases of sarcopenic obesity. The association of these phenotypes with metabolic deregulation and increased disease risk awaits verification.

Severe muscle depletion predicts postoperative length of stay but is not associated with survival after liver transplantation.

Muscle depletion or sarcopenia is associated with increased mortality in patients with cirrhosis; how it affects mortality after liver transplantation requires further study. In this study, we aimed to establish whether sarcopenia predicts increased morbidity or mortality after liver transplantation. We analyzed 248 patients with cirrhosis who had a computed tomography (CT) scan including the third lumbar vertebra before liver transplantation. Data were recovered from medical charts, the skeletal muscle cross-sectional area was measured with CT, and sarcopenia was defined with previously published sex- and body mass index-specific cutoffs. One hundred sixty-nine patients (68%) were male, and the mean age at transplantation was 55 ± 1 years. The etiologies of cirrhosis were hepatitis C virus (51%), alcohol (19%), autoimmune liver diseases (15%), hepatitis B virus (8%), and other etiologies (7%). Sarcopenia was present in 112 patients (45%), and it was more frequent in males (P = 0.002), patients with ascites (P = 0.02), and patients with higher bilirubin levels (P = 0.05), creatinine levels (P = 0.02), international normalized ratios (P = 0.04), Child-Pugh scores (P = 0.002), and Model for End-Stage Liver Disease scores (P = 0.002). The median survival period after liver transplantation was 117 ± 17 months for sarcopenic patients and 146 ± 20 months for nonsarcopenic patients (P = 0.4). Sarcopenic patients had longer hospital stays (40 ± 4 versus 25 ± 3 days; P = 0.005) and a higher frequency of bacterial infections within the first 90 days after liver transplantation (26% versus 15%, P = 0.04) in comparison with nonsarcopenic patients. In conclusion, sarcopenia is one of the most common complications in patients with cirrhosis and is predictive of longer hospital stays and a higher risk of perioperative bacterial infections after liver transplantation, but it is not associated with increased mortality.

Assessment of nutritional status in cancer--the relationship between body composition and pharmacokinetics.

Several nutritional assessment tools have been used in oncology settings to monitor nutritional status and its associated prognostic significance. Body composition is fundamental for the assessment of nutritional status. Recently, the use of accurate and precise body composition tools has significantly added to the value of nutritional assessment in this clinical setting. Computerized tomography (CT) is an example of a technique which provides state-of-the-art assessment of body composition. With use of CT images, a great variability in body composition of cancer patients has been identified even in people with identical body weight or body mass index. Severe muscle depletion (sarcopenia) has emerged as a prevalent body composition phenotype which is predictive of poor functional status, shorter time to tumor progression, shorter survival, and higher incidence of dose-limiting toxicity. Variability in body composition of cancer patients may be a source of disparities in the metabolism of cytotoxic agents. Future clinical trials investigating dose reductions in patients with sarcopenia and dose-escalating studies based on pre-treatment body composition assessment have the potential to alter cancer treatment paradigms.

Body composition in chemotherapy: the promising role of CT scans.

PURPOSE OF REVIEW: Reducing cancer-treatment toxicity was a largely ignored research agenda, which is now emerging as an active area of investigation. Studies of human body composition using computerized tomography scans have provided proof-of-concept that variability in drug disposition and toxicity profiles may be partially explained by different features in body composition. RECENT FINDINGS: Collectively, studies suggest that skeletal muscle depletion (regardless of body weight) is an independent predictor of severe toxicity, affecting cancer treatment and its outcomes. Although precise mechanisms are unknown, pharmacokinetic parameters such as variations in volume of distribution and increased drug exposure may explain such findings. SUMMARY: Computerized tomography scans are readily available in clinical databases of diagnostic images and provide feasible, reliable, and highly differentiated measurements of body composition. These images should be used to optimize screening and management of patients in order to prevent severe toxicity, and to improve the efficacy and cost-efficiency of chemotherapy treatments.

Sarcopenia and physical function in overweight patients with advanced cancer.

Advanced cancer is associated with numerous metabolic abnormalities that may lead to significant body composition changes, particularly muscle loss or sarcopenia. Sarcopenia in cancer has been associated with poor clinical outcomes, including poor physical function. Accurate tools to assess body composition are expensive and not readily available in clinical settings. Unfortunately, little is known about the efficacy of affordable and portable techniques to assess functional status in patients with cancer. We investigated the prevalence of sarcopenia and its association with different portable and low-cost functional status measurement tools (i.e., handgrip strength testing, a two-minute walking test, and a self-report questionnaire) in overweight/obese patients (body mass index ≥ 25 kg/m²) with advanced cancer. Twenty-eight patients (68% men) aged 64.5 ± 9.5 years with advanced lung or colorectal cancer were included. Sarcopenia was assessed by measuring appendicular skeletal muscle (ASM) adjusted by height (ASM index), using dual energy X-ray absorptiometry. Approximately 36% of patients had sarcopenia. Average handgrip strength was greater in men without sarcopenia than in men with it (p=0.035). In men, ASM index was positively correlated with average (r=0.535, p=0.018) and peak handgrip strength (r=0.457, p=0.049). No differences were observed among female patients. Handgrip strength was associated with sarcopenia in male patients with advanced cancer, and therefore it may be used as a portable and simple nutritional screening tool.

Sarcopenia as a prognostic index of nutritional status in concurrent cirrhosis and hepatocellular carcinoma.

BACKGROUND AND AIMS: Abnormal body composition such as severe skeletal muscle depletion or sarcopenia has emerged as an independent predictor of clinical outcomes in a variety of clinical conditions. This study is the first study to report the frequency and prognostic significance of sarcopenia as a marker of nutritional status in patients with hepatocellular carcinoma (HCC). METHODS: We analyzed 116 patients with HCC who were consecutively evaluated for liver transplant. Skeletal muscle cross-sectional area was measured by CT. Sarcopenia was defined using previously established cutpoints. RESULTS: Ninety-eight patients were males (85%), and the mean age was 58±6 years. Sarcopenia was present in 35 patients (30%). By univariate Cox analysis, male sex (HR, 3.84; P=0.02), lumbar skeletal muscle index (HR, 0.97; P=0.04), INR (HR, 8.18; P<0.001), MELD score (HR, 1.19; P<0.001), Child-Pugh (HR, 3.95; P<0.001), serum sodium (HR, 0.84; P<0.001), TNM stage (HR, 2.59; P<0.001), treatment type (HR, 0.53; P<0.001), and sarcopenia (HR, 2.27; P=0.004) were associated with increased risks of mortality. By multivariate Cox regression analysis, only MELD score (HR, 1.08; P=0.04), Child-Pugh (HR, 2.14; P=0.005), sodium (HR, 0.89; P=0.01), TNM stage (HR, 1.92; P<0.001), and sarcopenia (HR, 2.04; P=0.02) were independently associated with mortality. Median survival for sarcopenic patients was 16±6 versus 28±3 months in nonsarcopenic (P=0.003). CONCLUSIONS: Sarcopenia is present in almost one third of patients with HCC, and constitutes a strong and independent risk factor for mortality. Our results highlight the importance of body composition assessment in clinical practice.

Nutritional status, cachexia and survival in patients with advanced colorectal carcinoma. Different assessment criteria for nutritional status provide unequal results.

BACKGROUND & AIMS: Different nutrition assessment tools and definitions are proposed for cancer-associated malnutrition and wasting (cachexia). We studied the associations between these assessments and overall survival in stage IV colorectal carcinoma patients. METHODS: Anthropometric measures, energy intake, biochemical variables, nutritional risk screening, assessment of malnutrition, cachexia and body composition from computed tomography images were analysed, in 77 patients from Norway and Canada. Results were dichotomized into presence or absence of nutritional risk, malnutrition, cachexia and sarcopenia (low muscle mass) and associated with survival. RESULTS: Overall, 22% up to 55% of the patients had cachexia according to different cachexia criteria: 34% were malnourished, 42% were at nutritional risk, and 39% were sarcopenic. Forty-four percent of the patients did not meet criteria for any of these conditions. Patients with cachexia defined by Cancer Cachexia Study Group (CCSG) had shorter survival in an unadjusted analysis, [Hazard ratio (HR) = 2.43; 95% confidence interval (CI) 1.32-4.47; P = 0.005]. After adjusting for nation, age and gender, cachexia (HR = 2.26; CI 1.18-4.32; P = 0.014) and malnutrition (HR = 1.83; CI 1.06-3.13; P = 0.029) remained significant predictors of survival. CONCLUSIONS: Nutritional depletion in up to 55% of the patients was found. The lack of concordance between the results obtained by different assessment criteria was obvious. CCSG's cachexia score was the best prognostic factor for overall survival.

Dietary patterns of patients with advanced lung or colorectal cancer.

The purpose of this study was to identify dietary patterns among patients with advanced cancer. Differences between cancer groups are described, and food groups contributing higher proportions to overall caloric intake are identified. Patients with advanced cancer (n=51) were recruited from a regional cancer centre and completed a three-day dietary record. Food items were categorized according to macronutrient content. After adjustment for body weight, substantial variation in energy intake was observed (range: 13.7 to 55.4 kcal/kg/day). For 49% of patients, protein intake was below recommendations. Overall, patients consumed the largest proportion of their calories from meat (16%), other foods (11%), dessert (9%), fruit (9%), white bread (7%), and milk (7%). Only 5% of patients consumed meal replacement supplements. The results of this descriptive study provide important insights into the dietary habits of patients with advanced cancer. These insights could be translated into the development of effective recommendations for maintaining or improving health and quality of life.

Muscle wasting is associated with mortality in patients with cirrhosis.

BACKGROUND & AIMS: Sarcopenia, defined as a low level of muscle mass, occurs in patients with cirrhosis. We assessed its incidence among cirrhotic patients undergoing evaluation for liver transplantation to investigate associations between sarcopenia and mortality and prognosis. METHODS: We studied 112 patients with cirrhosis (78 men; mean age, 54 ± 1 years) who were consecutively evaluated for liver transplantation and had a computed tomography scan at the level of the third lumbar (L3) vertebrae to determine the L3 skeletal muscle index; sarcopenia was defined by using previously published, sex-specific cutoffs. RESULTS: Of the patients studied, 45 (40%) had sarcopenia. Univariate Cox analysis associated mortality with ascites (hazard ratio [HR], 2.12; P = .04), encephalopathy (HR, 1.99; P = .04), level of bilirubin (HR, 1.007; P < .01), international normalized ratio (HR, 7.69; P < .001), level of creatinine (HR, 1.01; P = .005), level of albumin (HR, 94; P = .008), serum level of sodium (HR, 89; P < .001), Model for End-Stage Liver Disease (MELD) score (HR, 1.14; P < .01), Child-Pugh score (HR, 2.84; P < .001), and sarcopenia (HR, 2.18; P = .006). By multivariate Cox analysis, only Child-Pugh (HR, 1.85; P = .04) and MELD scores (HR, 1.08; P = .001) and sarcopenia (HR, 2.21; P = .008) were independently associated with mortality. The median survival time for patients with sarcopenia was 19 ± 6 months, compared with 34 ± 11 months among nonsarcopenia patients (P = .005). There was a low level of correlation between L3 skeletal muscle index and MELD (r = -0.07; P = .5) and Child-Pugh scores (r = -0.14; P = .1). CONCLUSIONS: Sarcopenia is associated with mortality in patients with cirrhosis. It does not correlate with the degree of liver dysfunction evaluated by using conventional scoring systems. Scoring systems should include evaluation of sarcopenia to better assess mortality among patients with cirrhosis.

Prediction of skeletal muscle and fat mass in patients with advanced cancer using a metabolomic approach.

Urine and plasma metabolites originate from endogenous metabolic pathways in different organs and exogenous sources (diet). Urine and plasma were obtained from advanced cancer patients and investigated to determine if variations in lean and fat mass, dietary intake, and energy metabolism relate to variation in metabolite profiles. Patients (n = 55) recorded their diets for 3 d and after an overnight fast they were evaluated by DXA and indirect calorimetry. Metabolites were measured by NMR and direct injection MS. Three algorithms were used [partial least squares discriminant-analysis, support vector machines (SVM), and least absolute shrinkage and selection operator] to relate patients' plasma/urine metabolic profile with their dietary/physiological assessments. Leave-one-out cross-validation and permutation testing were conducted to determine statistical validity. None of the algorithms, using 63 urine metabolites, could learn to predict variations in individual's resting energy expenditure, respiratory quotient, or their intake of total energy, fat, sugar, or carbohydrate. Urine metabolites predicted appendicular lean tissue (skeletal muscle) with excellent cross-validation accuracy (98% using SVM). Total lean tissue correlated highly with appendicular muscle (Pearson r = 0.98; P < 0.0001) and gave similar cross-validation accuracies. Fat mass was effectively predicted using the 63 urine metabolites or the 143 plasma metabolites, exclusively. In conclusion, in this population, lean and fat mass variation could be effectively predicted using urinary metabolites, suggesting a potential role for metabolomics in body composition research. Furthermore, variation in lean and fat mass potentially confounds metabolomic studies attempting to characterize diet or disease conditions. Future studies should account or correct for such variation.

Two faces of drug therapy in cancer: drug-related lean tissue loss and its adverse consequences to survival and toxicity.

PURPOSE OF REVIEW: A common feature of cancer patients is loss of lean tissue, specifically skeletal muscle, which may be the result of the tumor or a side-effect of chemotherapy or other drugs. Lean tissue loss in turn has important adverse implications for toxicity of antineoplastic therapy and, hence, cancer prognosis. RECENT FINDINGS: Contemporary cancer populations have heterogeneous proportions of lean tissue, regardless of body weight. Wasting of lean tissue during the cancer trajectory has been associated with tumor progression. Lean tissue depletion is an independent predictor of severe toxicity in patients treated with chemotherapeutic agents of diverse classes. Patients with lean tissue depletion behave as if overdosed and have toxicity of sufficient magnitude to require dose reductions, treatment delays or definitive termination of treatment. Muscle loss may occur due to a specific effect of a chemotherapy agent (i.e. sorafenib), androgen suppression therapy or other drugs (i.e. statins such as atorvastatin). SUMMARY: Lean tissue wasting occurs due to cancer progression and may be exacerbated by several drug classes. This loss of lean tissue is not proportional to changes in body weight and is prognostic of enhanced treatment toxicity and reduced survival.

An exploratory study of body composition as a determinant of epirubicin pharmacokinetics and toxicity.

PURPOSE: Although body composition has emerged as an important predictor of drug efficacy and toxicity, explanations for this association are unclear. Our goal was to investigate relationships between lean body mass (LBM), liver size/function and epirubicin pharmacokinetics (PK) and toxicity. METHODS: Data from a clinical study (n = 24) of patients with breast cancer receiving adjuvant intravenous FE(100)C chemotherapy were used to examine relationships between LBM, liver size, and epirubicin clearance. Muscle tissue and liver mass were measured by analysis of computerized tomography cross-sectional images, and an extrapolation of muscle mass to total LBM compartment was employed. Population PK analysis of epirubicin was undertaken to test effects of body composition on epirubicin clearance and area under the curve (AUC). RESULTS: Estimated LBM was extremely variable in this cohort ranging from 32.9 to 67.3 kg. LBM was associated with neutrophil nadir (r = 0.5, P = 0.023), and mean LBM was lower for patients presenting with toxicity compared to those where toxicity was absent (41.6 vs. 56.2 kg, P = 0.002); 33% of variance in clearance was explained by LBM and aspartate aminotransferase (AST). Liver mass was not related to epirubicin clearance likely due to larger livers presenting with larger fat content, but liver attenuation (degree of fat infiltration) and AST were associated with AUC. CONCLUSION: To our knowledge, this is the first study to examine relationships between LBM, liver mass/function and epirubicin PK and toxicity. This exploratory work investigates the notion of organs and tissues having distinctive contributions to the distribution and metabolism of antineoplastic drugs.

The emerging role of computerized tomography in assessing cancer cachexia.

PURPOSE OF REVIEW: The present review represents an overview of the potential opportunistic use of computerized tomography (CT) to enhance our understanding of abnormal body composition, specifically lean and adipose tissue changes in cancer cachexia. RECENT FINDINGS: One of the characteristics of cancer cachexia is the depletion of muscle with or without adipose tissue loss. Therefore, a body composition tool that specifically distinguishes between these tissues is essential in assessing this syndrome. Cancer patients are routinely evaluated by high resolution imaging such as CT for the purpose of diagnosis and follow-up. Recent work exploiting CT images for body composition analysis has revealed the natural history of cancer cachexia, including progressive alterations in skeletal muscle, adipose tissue, organs, and tumor mass. CT-based quantification of skeletal muscle has permitted identification of individuals with sarcopenia, and links between sarcopenia and functional status, chemotherapy toxicity, time to tumor progression, and mortality. SUMMARY: CT images routinely acquired from health records of cancer patients can be used to quantify specific lean and adipose tissues, to interpret body composition in population-based studies, and to evaluate individual patients in a clinical and therapeutic decision-making setting.

Sarcopenia as a determinant of chemotherapy toxicity and time to tumor progression in metastatic breast cancer patients receiving capecitabine treatment.

PURPOSE: Body composition has emerged as an important prognostic factor in cancer patients. Severe depletion of skeletal muscle (sarcopenia) and, hence, of overall lean body mass may represent an occult condition in individuals with normal or even high body weight. Sarcopenia has been associated with poor performance status, 5-fluorouracil toxicity, and shortened survival in cancer patients. Here, we prospectively studied patients with metastatic breast cancer receiving capecitabine treatment in order to determine if sarcopenia was associated with a higher incidence of toxicity and a shorter time to tumor progression (TTP). EXPERIMENTAL DESIGN: Fifty-five women with metastatic breast cancer resistant to anthracycline and/or taxane treatment were included. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured by computerized tomography, and sarcopenia was defined using a previously published cutoff point. Toxicity was assessed after cycle 1 of treatment, and TTP was determined prospectively. RESULTS: Approximately 25% of patients were classified as sarcopenic, and this feature was seen in normal weight, overweight, and obese individuals. Toxicity was present in 50% of sarcopenic patients, compared with only 20% of nonsarcopenic patients (P = 0.03), and TTP was shorter in sarcopenic patients (101.4 days; confidence interval, 59.8-142.9) versus nonsarcopenic patients (173.3 days; confidence interval, 126.1-220.5; P = 0.05). CONCLUSION: Sarcopenia is a significant predictor of toxicity and TTP in metastatic breast cancer patients treated with capecitabine. Our results raise the potential use of body composition assessment to predict toxicity and individualize chemotherapy dosing.

A viscerally driven cachexia syndrome in patients with advanced colorectal cancer: contributions of organ and tumor mass to whole-body energy demands.

BACKGROUND: Cancer cachexia-associated weight loss is poorly understood; energetically demanding tissues (eg, organ and tumor mass) and resting energy expenditure (REE) are reported to increase with advanced cancer. OBJECTIVE: The objective was to quantify the potential contribution of increasing masses of energetically demanding tissues to REE with colorectal cancer cachexia progression. DESIGN: A longitudinal computed tomography (CT) image review was performed to quantify organ size (liver, including metastases, and spleen) and peripheral tissues (skeletal muscle and adipose tissue) during colorectal cancer cachexia progression (n = 34). Body composition was prospectively evaluated by CT and dual-energy X-ray absorptiometry, and REE was determined by indirect calorimetry in advanced colorectal cancer patients (n = 18). RESULTS: Eleven months from death, the liver (2.3 +/- 0.7 kg) and spleen (0.32 +/- 0.2 kg) were larger than reference values. One month from death, liver weight increased to 3.0 +/- 1.5 kg (P = 0.010), spleen showed a trend to increase (P = 0.077), and concurrent losses of muscle (4.2 kg) and fat (3.5 kg) (P < 0.05) were observed. The estimated percentage of fat-free mass (FFM) occupied by the liver increased from 4.5% to 7.0% (P < 0.001). The most rapid loss of peripheral tissues and liver and metastases gain occurred within 3 mo of death. A positive linear relation existed between liver mass and measured whole-body REE (r(2) = 0.35, P = 0.010); because liver accounted for a larger percentage of FFM, measured REE . kg FFM(-1) . d(-1) increased (r(2) = 0.35, P = 0.010). CONCLUSIONS: Increases in mass and in the proportion of high metabolic rate tissues, including liver and tumor, represented a cumulative incremental REE of approximately 17,700 kcal during the last 3 mo of life and may contribute substantially to cachexia-associated weight loss.