Assessing cachexia in obesity: contradiction or perfectly possible?

PURPOSE OF REVIEW: Existing definitions of clinically important weight loss in patients with cancer do not specifically address weight loss in patients who are obese at presentation. This review explores the clinical impact of weight loss and depletion of the skeletal muscle mass (i.e., criteria defining cancer cachexia), in patients with obesity. RECENT FINDINGS: Overweight and obese BMI values are shown by many recent studies to pose a survival advantage in patients with cancers of advanced stage, when compared with BMI in normal and underweight ranges. The classification of cancer-associated weight loss has evolved, and current grading schemes evaluate the impact of weight across the range of BMI values. Weight loss is associated with mortality in patients with BMI more than 30 kg/m2, however this is to a much lesser degree than in patients with lower BMI values. Diagnostic imaging permits the precise assessment of skeletal muscle index (SMI) in patients with cancer, and it has been clearly shown that while usually quite muscular, obese patients can have profound muscle depletion (i.e., sarcopenia), independent of the presence of weight loss. Muscle depletion associates strongly with mortality in obese patients, as well as with complications of cancer surgery and systemic therapy. SUMMARY: It would seem contradictory to diagnose concurrent obesity and cachexia, as these terms represent opposite ends of the weight spectrum. Weight loss can occur in anyone with cancer, however its priority for clinical management may be lesser in obese versus low body weight individuals. Sarcopenic obesity is strongly associated with a poor clinical outcome and deserves further research, diagnosis in clinical practice, and new strategies for mitigation.

Associations of nutrition impact symptoms with depression in patients with advanced cancer.

PURPOSE: Advanced cancer patients have nutrition impact symptoms (NISs), while many of them have depressive moods. This study aimed to determine the associations of NISs with depression. METHODS: This study was a secondary analysis. The dietary intake and 19 NISs in patients receiving palliative care were evaluated using 10-point scales, and the patients were categorized into two groups (non-depression and depression groups) using the cutoff based on the Patient Health Questionnaire-9 (PHQ-9). To determine associations between depression and the number of NISs with a score of ≥ 4, the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the logistic regression model were calculated. RESULTS: A total of 225 participants were divided into the non-depression group (n = 148) and the depression group (n = 77). The prevalence of depression was 34.2%. Dietary intake was lower, and the number of NISs with a score of ≥ 4 was higher in the depression group (both p < 0.001). All NISs were more severe in the depression group. Significant differences were observed in 15 of the 19 NISs. In the logistic regression model, significantly higher adjusted ORs were observed in the groups with 4-6 NISs and 7 or more NISs with a score of ≥ 4 (10.76 [95% CI, 2.07-55.91], p = 0.016; 17.02 [95% CI, 3.08-94.22], p < 0.001) than in the group with no NISs with a score of ≥ 4. CONCLUSION: Having four or more NISs with a score ≥ 4 was associated with depression.

Changes in Sarcopenia Status Predict Survival Among Patients with Resectable Esophageal Cancer.

BACKGROUND: Sarcopenia is a predictor of survival in patients with esophageal cancer. The objective of this research was to obtain insight into how changes in sarcopenia influence survival in resectable esophageal cancer. PATIENTS AND METHODS: A retrospective cohort of patients with esophageal cancer undergoing tri-modality therapy was selected. Body composition parameters from the staging, post-neoadjuvant, and 1-year surveillance computed tomography (CT) scans were calculated. Overall survival (OS) and disease-free survival (DFS) were evaluated using the Kaplan-Meier method and log-rank test, as well as multivariable Cox-proportional hazards models. RESULTS: Of 141 patients, 118 had images at all three timepoints. The median DFS and OS were 33.2 [95% confidence interval (CI) 19.1-73.7] and 34.5 (95% CI 23.1-57.6) months, respectively. Sarcopenia classified by the staging CT was present in 20 (17.0%) patients. This changed to 45 (38.1%) patients by the post-neoadjuvant scan, and 44 (37.3%) by the surveillance scan. In multivariable analysis, sarcopenia at the post-neoadjuvant scan was significantly associated with OS [hazards ratio (HR) 2.65, 95% CI 1.59-4.40; p < 0.001] and DFS (HR 1.80, 95% CI 1.03-3.13; p = 0.038). The net change in skeletal muscle index was associated with OS (HR 0.93, 95% CI 0.90-0.97; p < 0.001) and DFS (HR 0.94, 95% CI 0.91-0.98; p = 0.001). CONCLUSIONS: Patients who develop sarcopenia as a consequence of skeletal muscle wasting during neoadjuvant therapy are at risk for worse DFS and OS. Patients who have a net loss of muscle over time may be at high risk for early disease recurrence.

Adverse effects of systemic cancer therapy on skeletal muscle: myotoxicity comes out of the closet.

PURPOSE OF REVIEW: Systemic cancer therapy-associated skeletal muscle wasting is emerging as a powerful impetus to the overall loss of skeletal muscle experienced by patients with cancer. This review explores the clinical magnitude and biological mechanisms of muscle wasting during systemic cancer therapy to illuminate this adverse effect. Emerging strategies for mitigation are also discussed. RECENT FINDINGS: Clinical findings include precise, specific measures of muscle loss over the course of chemotherapy, targeted therapy and immunotherapy. All these therapeutic classes associate with quantitatively important muscle loss, independent of tumor response. Parallel experimental studies provide understanding of the specific molecular basis of wasting, which can include inhibition of protein synthesis, proliferation and differentiation, and activation of inflammation, reactive oxygen species, autophagy, mitophagy, apoptosis, protein catabolism, fibrosis and steatosis in muscle. Strategies to mitigate these muscle-specific adverse effects of cancer therapy remain in the earliest stages of development. SUMMARY: The adverse side effect of cancer therapy on skeletal muscle has been largely ignored in the development of cancer therapeutics. Given the extent to which loss of muscle mass and function can bear on patients' function and quality of life, protection/mitigation of these side effects is a research priority.

Sarcopenia in Lung Cancer: A Narrative Review.

It has been over 10 years since the relationship between sarcopenia and lung cancer was first explored. Since then, sarcopenia research has progressed substantially, and the prognostic value of this condition is becoming increasingly apparent. Prior systematic reviews and meta-analyses have established sarcopenia to be negatively associated with disease-free and overall-survival, as well as a major risk factor for post-operative complications. The bulk of the literature has explored sarcopenia in the resectable setting, with less emphasis placed on studies evaluating this condition in advanced disease. In this up-to-date review, an examination of the literature exploring the association between sarcopenia and long-term outcomes in advanced lung cancer is provided. We further explore the association between adverse events of medical therapy and the role of sarcopenia as a predictor of tumor response. Finally, the interventions on sarcopenia and cancer cachexia are reviewed, with an emphasis placed on prospective studies.

Sarcopenia Determined by Skeletal Muscle Index Predicts Overall Survival, Disease-free Survival, and Postoperative Complications in Resectable Esophageal Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Sarcopenia has been identified as a prognostic factor among certain types of cancer. In esophageal cancer, patients are at increased risk of malnutrition and sarcopenia, ultimately contributing to poor outcomes. A systematic review was conducted to determine whether sarcopenia, defined by the skeletal muscle index, is predictive of overall survival, disease-free survival, and postoperative complications in resectable esophageal cancer. MATERIALS AND METHODS: A systematic search of MEDLINE, EMBASE, Scopus, Web of Science, and Cochrane Library was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines up until January 2021. The primary outcome was overall survival; secondary outcomes included disease-free survival, pulmonary complications, and anastomotic leak. RESULTS: Twenty-one studies (4 prospective; 17 retrospective; 3966 patients) were included. Sarcopenia was present in 1940 (48.1%) patients and was associated with lower overall survival [hazard ratio (HR): 1.56; 95% confidence interval (CI): 1.25-1.95; P <0.00001; I2 =71%] and disease-free survival (HR: 1.73; 95% CI: 1.04-2.87; P =0.03; I2 =51%). A decrease in skeletal muscle index, independent of sarcopenia status, was associated with lower overall survival (HR: 1.81; 95% CI: 1.20-2.73; P =0.005; I2 =92%). Sarcopenia was associated with increased odds of pulmonary complications (odds ratio: 1.86; 95% CI: 1.29-2.66; P =0.0008; I2 =41%) and increased odds of anastomotic leak (odds ratio: 1.46; 95% CI: 1.11-1.93; P =0.008; I2 =0%). CONCLUSIONS: Sarcopenia is a predictor of overall survival, disease-free survival, and postoperative complications in patients with resectable esophageal cancer. Studies on the modifiability of sarcopenia in the preoperative period will help determine the utility of nutritional interventions.

Impact of Early Jejunostomy Tube Feeding on Clinical Outcome and Parameters of Body Composition in Esophageal Cancer Patients Receiving Multimodal Therapy.

BACKGROUND: Malnutrition commonly affects patients with esophageal cancer and has the potential to negatively influence treatment outcomes. The aim of this study was to investigate the impact of early (preoperative) jejunostomy tube feeding (JTF) in nutritionally 'high risk' patients receiving multimodal therapy for esophageal cancer. METHODS: Patients were selected to undergo early JTF during neoadjuvant chemoradiotherapy (nCRT) in accordance with European Society for Clinical Nutrition and Metabolism (ESPEN) and Enhanced Recovery after Surgery (ERAS®) Society guidelines. Clinical outcomes were compared with patients who received routine JTF from the time of esophagectomy. Body composition was determined from computed tomography (CT) images acquired at diagnosis, after nCRT, and ≥ 3 months after surgery. RESULTS: In total, 81 patients received early JTF and 91 patients received routine JTF. Patients who received early JTF had lower body mass index (BMI; 26.1 ± 4.6 vs. 28.4 ± 4.9; p = 0.002), greater weight loss, and worse performance status at diagnosis. Groups were otherwise well-matched for baseline characteristics. Rate of re-intubation (8.8% vs. 1.1%; p = 0.027), pulmonary embolism (5.0% vs. 0.0%; p = 0.046), and 90-day mortality (10.0% vs. 1.1%; p = 0.010) were worse in the early JTF group; however, overall survival was equivalent for both the early and routine JTF groups (p = 0.053). Wide variation in the degree of preoperative muscle loss and total adipose tissue loss was observed across the entire study cohort. Relative preoperative muscle and adipose tissue loss in patients with early and routine JTF was equivalent. CONCLUSIONS: In patients determined to be at 'high risk' of malnutrition, early JTF may prevent excess morbidity after esophagectomy with an associated relative preservation of parameters of body composition.

Psychological symptoms of illness and emotional distress in advanced cancer cachexia.

PURPOSE OF REVIEW: Cachexia induces both physical and psychological symptoms of illness in patients with advanced cancer and may generate emotional distress in patients and families. However, physical symptoms of cachexia received the most emphasis. The aims of this review are to elucidate a link between systemic inflammation underlying cachexia and psychological symptoms and emotional distress, and to advance care strategy for management of psychological symptoms and emotional distress in patients and families. RECENT FINDINGS: The main themes in the literature covered by this review are psychological symptoms in patients and emotional distress in patients and families. Studies of the underlying biology of cachexia identify the role of the central nervous system to amplify tumor-induced systemic inflammation. The brain mediates a cluster of symptoms, such as sleep disruption, anxiety, cognitive impairment, and reduction in motivated behavior (notably anorexia). These are distressing to patients as well as to families. SUMMARY: There is growing recognition that holistic multimodal interventions are needed to alleviate psychological symptoms and emotional distress and to improve quality of life in patients with cancer cachexia and families. This is an approach that addresses not only physical health but also psychological, emotional, and social well being issues.

Prognostic value of early changes in CT-measured body composition in patients receiving chemotherapy for unresectable pancreatic cancer.

OBJECTIVES: Skeletal muscle mass is a prognostic factor in pancreatic ductal adenocarcinoma (PDAC). However, it remains unclear whether changes in body composition provide an incremental prognostic value to established risk factors, especially the Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1). The aim of this study was to determine the prognostic value of CT-quantified body composition changes in patients with unresectable PDAC starting chemotherapy. METHODS: We retrospectively evaluated 105 patients with unresectable (locally advanced or metastatic) PDAC treated with FOLFIRINOX (n = 64) or gemcitabine-based (n = 41) first-line chemotherapy within a multicenter prospective trial. Changes (Δ) in skeletal muscle index (SMI), subcutaneous (SATI), and visceral adipose tissue index (VATI) between pre-chemotherapy and first follow-up CT were assessed. Cox regression models and covariate-adjusted survival curves were used to identify predictors of overall survival (OS). RESULTS: At multivariable analysis, adjusting for RECISTv1.1-response at first follow-up, ΔSMI was prognostic for OS with a hazard ratio (HR) of 1.2 (95% CI: 1.08-1.33, p = 0.001). No significant association with OS was observed for ΔSATI (HR: 1, 95% CI: 0.97-1.04, p = 0.88) and ΔVATI (HR: 1.01, 95% CI: 0.99-1.04, p = 0.33). At an optimal cutoff of 2.8 cm2/m2 per 30 days, the median survival of patients with high versus low ΔSMI was 143 versus 233 days (p < 0.001). CONCLUSIONS: Patients with a lower rate of skeletal muscle loss at first follow-up demonstrated improved survival for unresectable PDAC, regardless of their RECISTv1.1-category. Assessing ΔSMI at the first follow-up CT may be useful for prognostication, in addition to routine radiological assessment. KEY POINTS: • In patients with unresectable pancreatic ductal adenocarcinoma, change of skeletal muscle index (ΔSMI) in the early phase of chemotherapy is prognostic for overall survival, even after adjusting for Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1) assessment at first follow-up. • Changes in adipose tissue compartments at first follow-up demonstrated no significant association with overall survival. • Integrating ΔSMI into routine radiological assessment may improve prognostic stratification and impact treatment decision-making at the first follow-up.

Oral Cavity and Oropharyngeal Cancer Surveillance and Control in Alberta: A Scoping Review.

OBJECTIVES: This scoping review provides a comprehensive overview of oral cavity cancer (OCC) and oropharyngeal cancer (OPC) in Alberta. METHODS: A database search was conducted up to 2018 using Web of Science, Scopus, Medline, PubMed and Embase, along with a manual search of gray literature. Data from the Alberta Cancer Foundation's dedicated fund for research, Cancer Surveillance and Reporting and Alberta Cancer Registry were also collected. RESULTS: Our review included 8 published papers and 14 other sources, including data on 3448 OCC and OPC patients from Surveillance and Reporting and Alberta Cancer Registry. Cancer registry data (2005-2017) showed that most OCC and OPC lesions were diagnosed at an advanced clinical stage, with a significantly large number of advanced OPC lesions in stage IV (OCC 45.2%, OPC 82.4%); 47.9% of these patients died. Survival rates were lowest in rural and First Nations areas. In Alberta, 35% of HPV-associated cancers were linked to OPCs, which were more prevalent in men and younger age groups. No routine public oral cancer screening program currently exists in Alberta. General practitioners and dentists refer patients to specialists, often with long waiting times. CONCLUSION: OCC and OPC patients in Alberta continue to be diagnosed in stage IV and experience high mortality rates.

Frequency, Timing, and Predictors of Palliative Care Consultation in Patients with Advanced Cancer at a Tertiary Cancer Center: Secondary Analysis of Routinely Collected Health Data.

INTRODUCTION: Early integration of palliative care (PC) with oncological care is associated with improved outcomes in patients with advanced cancer. Limited information exists on the frequency, timing, and predictors of PC consultation in patients receiving oncological care. The Cross Cancer Institute (CCI) is the sole tertiary cancer center serving the northern half of the Canadian province of Alberta, located in the city of Edmonton. The objectives of this study were to estimate the proportion of patients with advanced cancer at the CCI who received consultation by the CCI PC program and the comprehensive integrated PC program in Edmonton, and to determine the timing and predictors of consultation. MATERIALS AND METHODS: In this secondary analysis of routinely collected health data, adult patients who died between April 2013 and March 2014, and had advanced disease while under the care of a CCI oncologist, were eligible. Data from the Alberta Cancer Registry, electronic medical records, and Edmonton PC program database were linked. RESULTS: Of 2,253 eligible patients, 810 (36%) received CCI PC consultation. Median time between consultation and death was 2 months (range, 1.1-5.4). In multivariable logistic regression analysis, age, residence, income, cancer type, and interval from advanced cancer diagnosis to death influenced odds of receiving consultation. Among 1,439 patients residing in Edmonton, 1,121 (78%) were referred to the Edmonton PC program. CONCLUSION: A minority of patients with advanced cancer received PC consultation at the tertiary cancer center, occurring late in the disease trajectory. Frequency and timing of PC consultation varied significantly, according to multiple factors. IMPLICATIONS FOR PRACTICE: Clinical and demographic factors are associated with variations in frequency and timing of palliative care consultation at a cancer center and may, in some cases, reflect barriers to access that warrant attention.

Profiling Determinants of Resting Energy Expenditure in Colorectal Cancer.

Background: Understanding resting energy expenditure (REE) is important for determining energy requirements; REE might be altered in individuals with cancer. The objective of this study was to characterize determinants of REE in patients with stages II-IV colorectal cancer (CRC).Methods: REE was measured via indirect calorimetry in patients with newly diagnosed CRC. Computerized tomography images from medical records ascertained skeletal muscle and total adipose tissue cross-sectional areas, which were then transformed to lean soft tissue (LST) and fat mass (FM) values (in kg). Linear regression assessed determinants of REE.Results: 86 patients were included (n = 55, 64.0% male; 60 ± 12 years old; median body mass index: 27.6, interquartile range: 24.3-31.2 kg/m2), with most (n = 40) having stage III disease. Age, sex, and weight were significant predictors of REE [R2 = 0.829, standard error of the estimate (SEE): 128 kcal/day, P < 0.001]. Replacing weight with LST and FM yielded a similar model, with age, sex, LST, and FM predictive of REE (R2 = 0.820, SEE: 129 kcal/day, p < 0.001).Conclusion: Age, sex, weight, LST, and FM were the main contributors to REE. Further investigation of REE changes over time and its relationship to total energy expenditure, dietary intake, and clinical outcomes should be explored.

Thigh Ultrasound Used to Identify Frail Elderly Patients with Sarcopenia Undergoing Surgery: A Pilot Study.

BACKGROUND: Computed tomography (CT) scan quantifying skeletal muscle mass is the gold standard tool to identify sarcopenia. Unfortunately, high cost, limited availability, and radiation exposure limit its use. We suggest that ultrasound of the thigh muscle could be an objective, reproducible, portable, and risk-free tool, used as a surrogate to a CT scan, to help identify frail patients with sarcopenia. MATERIALS AND METHODS: We included 49 patients over 64 y old, referred to the acute care surgery service. An ultrasound of thigh muscle thickness was standardized to patient thigh length (U/Swhole/L). CT skeletal muscle index (SMI) was calculated using skeletal muscle surface area of the L3 region divided by height2. Frailty status was assessed using the Canadian Study of Healthy Aging Clinical Frailty Scale. RESULTS: The mean (SD) age was 76 (8) y, and 34% (n = 17) were men. CT-defined sarcopenia was identified in 65% (n = 11) of men and 75% (n = 24) of women. In general, women had longer stay in hospital than men (mean + SD 14 ± 9 versus 7 ± 3 d, P = 0.003). There was a significant positive correlation between thigh U/Swhole/L and CT SMI. There was an inverse correlation between thigh U/Swhole/L and frailty score; a similar relationship was observed between CT SMI and frailty. There was an association between U/Swhole/L and postoperative major complications. CONCLUSIONS: This prospective observational study illustrates that the U/Swhole/L index can be used as a surrogate to CT scan, whereby it can identify elderly frail patients with sarcopenia. Thigh ultrasound should be further tested as an objective tool to assess for stratifying frailty.

Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia.

Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat. How tumours induce brown fat activity is unknown. Here, using a Lewis lung carcinoma model of cancer cachexia, we show that tumour-derived parathyroid-hormone-related protein (PTHrP) has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of PTHrP in tumour-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Our results demonstrate that PTHrP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia. Thus, neutralization of PTHrP might hold promise for ameliorating cancer cachexia and improving patient survival.

Visceral adiposity increases risk for hepatocellular carcinoma in male patients with cirrhosis and recurrence after liver transplant.

Visceral adipose tissue (VAT) is a metabolically active organ, associated with higher risk of malignancies. We evaluated whether VAT is associated with the risk of hepatocellular carcinoma (HCC) in patients presenting with cirrhosis as well as HCC recurrence after liver transplantation (LT). Patients with cirrhosis (n = 678; 457 male) who were assessed for LT (289 with HCC) were evaluated for body composition analysis. Patients who underwent LT (n = 247, 168 male) were subsequently evaluated for body composition, and 96 of these patients (78 male) had HCC. VAT, subcutaneous adipose tissues, and total adipose tissues were quantified by computed tomography at the level of the third lumbar vertebra and reported as indexes (cross-sectional area normalized for height [square centimeters per square meter]). At the time of LT assessment, the VAT index (VATI) was higher in male patients with HCC compared to non-HCC patients (75 ± 3 versus 60 ± 3 cm2 /m2 , P = 0.001). The VATI, subcutaneous adipose tissue index, and total adipose tissue index were higher in male patients with HCC compared to non-HCC patients. By multivariate analysis, male patients with VATI ≥65 cm2 /m2 had a higher risk of HCC (hazard ratio, 1.90; 95% confidence interval, 1.31-2.76; P = 0.001). In male patients with HCC who underwent LT, a VATI ≥65 cm2 /m2 adjusted for Milan criteria was independently associated with higher risk of HCC recurrence (hazard ratio, 5.34; 95% confidence interval, 1.19-23.97; P = 0.03). CONCLUSION: High VATI is an independent risk factor for HCC in male patients with cirrhosis and for recurrence of HCC after LT. (Hepatology 2018;67:914-923).

The Impact of Muscle and Adipose Tissue on Long-term Survival in Patients With Stage I to III Colorectal Cancer.

BACKGROUND: Computed tomography-derived body composition parameters are emerging prognostic factors in colorectal cancer. OBJECTIVE: This study aimed to determine the roles of sarcopenia, myosteatosis, and obesity as independent and overlapping parameters in stage I to III colorectal cancer. DESIGN: This is a retrospective cohort study from a prospectively collected database. Multivariate Cox proportional hazards models were performed to assess the associations between body composition parameters and survival. SETTINGS: All patients were seen in a tertiary care cancer center. PATIENTS: Adult patients with stage I to III colorectal cancer, undergoing curative resection from 2007 to 2009, were included. INTERVENTION: Computed tomography-derived quantification of skeletal muscle and adipose tissues was used to determine population-specific cutoffs for sarcopenia, myosteatosis, and total adiposity. MAIN OUTCOME MEASURES: Primary outcome measures were overall, recurrence-free, and cancer-specific survival. RESULTS: In the 968 patients included, there were a total of 254 disease recurrences and 350 deaths. Body mass index and CT-derived measures of adiposity did not result in worse survival outcomes. Sarcopenia was independently predictive of worse overall (HR, 1.45; 95% CI, 1.16-1.84), recurrence-free (HR, 1.32; 95% CI, 1.00-1.75), and cancer-specific survival (HR, 1.46; 95% CI, 1.09-1.94) in a multivariate model. Myosteatosis was also independently predictive of overall survival (HR, 1.53; 95% CI, 1.19-1.97). In a model considering joint effects of sarcopenia and myosteatosis, the presence of both predicted the worst overall (HR, 2.23; 95% CI, 1.62-3.06), recurrence-free (HR, 1.53; 95% CI, 1.06-2.21), and cancer-specific survival (HR, 2.40; 95% CI, 1.69-3.42) in a multivariate model. LIMITATIONS: The limitations of this study are inherent in retrospective observational studies. CONCLUSIONS: Sarcopenia and myosteatosis are independent predictors of worse survival in stage I to III colorectal cancer, and their joint effect is highly predictive of reduced overall, recurrence-free, and cancer-specific survival. See Video Abstract at http://links.lww.com/DCR/A923.

Undiagnosed cardiac deficits in non-small cell carcinoma patients in the candidate population for anti-cachexia clinical trials.

PURPOSE: Currently, there is no approved therapy for cancer cachexia. According to European and American regulatory agencies, physical function improvements would be approvable co-primary endpoints of new anti-cachexia medications. As physical functioning is in part dependent on cardiac functioning, we aimed to explore the cardiac status of a group of patients meeting current criteria for inclusion in cachexia clinical trials. METHODS: Seventy treatment-naive patients with metastatic NSCLC [36 (51.4%) male; 96% ECOG 0-1; eligible for carboplatin-based therapy and meeting eligibility criteria for cachexia clinical trials] were recruited before the start of first-line carboplatin-based chemotherapy. Patients were evaluated by echocardiography, electrocardiography, and scales for fatigue and dyspnea. Computed tomography cross-sectional images were utilized for body composition analysis. RESULTS: In 9/70 patients (12.8%), echocardiography allowed discovery of clinically relevant cardiac disorders [seven patients with left ventricular ejection fraction (LVEF) 32%-47%; one patient with severe right ventricular dilation and severe pulmonary hypertension and one patient with severe pericardial effusion warranted hospitalization and drainage]. Another 10/70 (14.3%) patients had diastolic dysfunction with preserved LVEF. The cardiac conditions were associated with aggravated fatigue (p < 0.05), dyspnea (p < 0.05), and anemia (p = 0.06). Five out of seven patients with LVEF < 50% were sarcopenic and one was borderline sarcopenic. CONCLUSION: Baseline cardiac status of the metastatic NSCLC patients adds potential heterogeneity for anti-cachexia clinical trials. Detailed cardiac screening data might be useful for inclusion/exclusion criteria, randomization, and post hoc analysis.

Change in Skeletal Muscle Following Resection of Stage I-III Colorectal Cancer is Predictive of Poor Survival: A Cohort Study.

BACKGROUND: Sarcopenia at time of diagnosis predicts worse survival outcomes. It is currently unknown how changes in muscle mass over time interact with sarcopenia in colorectal patients treated with curative intent. Objectives of this study were to quantify sarcopenia and skeletal muscle loss from time of diagnosis to end of surveillance and determine its effect on survival outcomes after completion of 2 years of surveillance. METHODS: Retrospective cohort study of stage I-III colorectal cancer patients from 2007-2009, who underwent resection and had preoperative and 2-year surveillance computed tomography scans, without recurrence during that time. Body composition analysis was done at both time points to determine lumbar skeletal muscle index, radiodensity and adiposity. Change over time was standardized as a percentage per year. Cox proportional hazard regression modeling was used for survival analysis. RESULTS: Of 667 patients included, median survival from surgery was 7.96 years, with 75 recurrences occurring after 2 years. On average patients lost muscle mass (-0.415%/year; CI -0.789, -0.042) and radiodensity (-5.76 HU/year; CI -6.74, -4.80), but gained total adipose tissue (7.06%/year; CI 4.34, 9.79). Patients with sarcopenia at diagnosis (HR 1.80; CI 1.13, 2.85) or muscle loss over time (HR 1.55; CI 1.01, 2.37) had worse overall survival, with significantly worse joint effect (HR 2.73; CI 1.32, 5.65). CONCLUSIONS: Sarcopenia at diagnosis combined with ongoing skeletal muscle loss over time resulted in significantly worse survival. Patients with these features who are recurrence-free at 2 years are more likely to have a non-colorectal cancer cause of death.

A prospective study examining cachexia predictors in patients with incurable cancer.

BACKGROUND: Early intervention against cachexia necessitates a predictive model. The aims of this study were to identify predictors of cachexia development and to create and evaluate accuracy of a predictive model based on these predictors. METHODS: A secondary analysis of a prospective, observational, multicentre study was conducted. Patients, who attended a palliative care programme, had incurable cancer and did not have cachexia at baseline, were amenable to the analysis. Cachexia was defined as weight loss (WL) > 5% (6 months) or WL > 2% and body mass index< 20 kg/m2. Clinical and demographic markers were evaluated as possible predictors with Cox analysis. A classification and regression tree analysis was used to create a model based on optimal combinations and cut-offs of significant predictors for cachexia development, and accuracy was evaluated with a calibration plot, Harrell's c-statistic and receiver operating characteristic curve analysis. RESULTS: Six-hundred-twenty-eight patients were included in the analysis. Median age was 65 years (IQR 17), 359(57%) were female and median Karnofsky performance status was 70(IQR 10). Median follow-up was 109 days (IQR 108), and 159 (25%) patients developed cachexia. Initial WL, cancer type, appetite and chronic obstructive pulmonary disease were significant predictors (p ≤ 0.04). A five-level model was created with each level carrying an increasing risk of cachexia development. For Risk-level 1-patients (WL < 3%, breast or hematologic cancer and no or little appetite loss), median time to cachexia development was not reached, while Risk-level 5-patients (WL 3-5%) had a median time to cachexia development of 51 days. Accuracy of cachexia predictions at 3 months was 76%. CONCLUSION: Important predictors of cachexia have been identified and used to construct a predictive model of cancer cachexia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01362816 .

Computed tomography-defined muscle and fat wasting are associated with cancer clinical outcomes.

Cancer cachexia (i.e., skeletal muscle wasting with or without fat loss) relates to several adverse outcomes. Computed tomography (CT) cross-sectional images serve as an efficient biomarker for assessment of cachexia in cancer patients. We systematically reviewed literature reporting quantitative evaluation of the cross sectional area of the main tissues implicated in cancer cachexia, muscle and visceral, subcutaneous and inter-muscular fat in CT scans at the 3rd lumbar vertebra. Our main goal was to summarize CT-defined variation of muscle and fat and the relationship between these features and cancer outcomes such as chemotherapy toxicity, post-surgery complications and survival.