Histopathologic Features of Mucosal Head and Neck Cancer Cachexia.

Objective: Determine the histopathologic features that correlate with head and neck cancer (HNC) cachexia. Methods: A single-institution, retrospective study was performed on adults with HPV-negative, mucosal squamous cell carcinoma of the aerodigestive tract undergoing resection and free flap reconstruction from 2014 to 2019. Patients with distant metastases were excluded. Demographics, comorbidities, preoperative nutrition, and surgical pathology reports were collected. Comparisons of histopathologic features and cachexia severity were made. Results: The study included 222 predominantly male (64.9%) patients aged 61.3 ± 11.8 years. Cachexia was identified in 57.2% patients, and 18.5% were severe (≥15% weight loss). No differences in demographics were identified between the groups. Compared to control, patients with severe cachexia had lower serum hemoglobin (p=0.048) and albumin (p < 0.001), larger tumor diameter (p < 0.001), greater depth of invasion (p < 0.001), and elevated proportions of pT4 disease (p < 0.001), pN2-N3 disease (p=0.001), lymphovascular invasion (p=0.009), and extranodal extension (p=0.014). Multivariate logistic regression identified tumor size (OR [95% CI] = 1.36 [1.08-1.73]), oral cavity tumor (OR [95% CI] = 0.30 [0.11-0.84]), and nodal burden (OR [95% CI] = 1.16 [0.98-1.38]) as significant histopathologic contributors of cancer cachexia. Conclusions: Larger, more invasive tumors with nodal metastases and aggressive histologic features are associated with greater cachexia severity in mucosal HNC.

Skeletal Muscle Proteome Modifications following Antibiotic-Induced Microbial Disturbances in Cancer Cachexia.

Cancer cachexia is an involuntary loss of body weight, mostly of skeletal muscle. Previous research favors the existence of a microbiota-muscle crosstalk, so the aim of the study was to evaluate the impact of microbiota alterations induced by antibiotics on skeletal muscle proteins expression. Skeletal muscle proteome changes were investigated in control (CT) or C26 cachectic mice (C26) with or without antibiotic treatment (CT-ATB or C26-ATB, n = 8 per group). Muscle protein extracts were divided into a sarcoplasmic and myofibrillar fraction and then underwent label-free liquid chromatography separation, mass spectrometry analysis, Mascot protein identification, and METASCAPE platform data analysis. In C26 mice, the atrogen mafbx expression was 353% higher than CT mice and 42.3% higher than C26-ATB mice. No effect on the muscle protein synthesis was observed. Proteomic analyses revealed a strong effect of antibiotics on skeletal muscle proteome outside of cachexia, with adaptative processes involved in protein folding, growth, energy metabolism, and muscle contraction. In C26-ATB mice, proteome adaptations observed in CT-ATB mice were blunted. Differentially expressed proteins were involved in other processes like glucose metabolism, oxidative stress response, and proteolysis. This study confirms the existence of a microbiota-muscle axis, with a muscle response after antibiotics that varies depending on whether cachexia is present.

Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia.

Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle atrophy. Increased skeletal muscle mitochondrial reactive oxygen species (ROS) is a contributing factor to loss of muscle mass in cachectic patients. Mice inoculated with Lewis lung carcinoma (LLC) cells lose weight, muscle mass, and have lower muscle sirtuin-1 (sirt1) expression. Nicotinic acid (NA) is a precursor to nicotinamide dinucleotide (NAD+) which is exhausted in cachectic muscle and is a direct activator of sirt1. Mice lost body and muscle weight and exhibited reduced skeletal muscle sirt1 expression after inoculation with LLC cells. C2C12 myotubes treated with LLC-conditioned media (LCM) had lower myotube diameter. We treated C2C12 myotubes with LCM for 24 h with or without NA for 24 h. C2C12 myotubes treated with NA maintained myotube diameter, sirt1 expression, and had lower mitochondrial superoxide. We then used a sirt1-specific small molecule activator SRT1720 to increase sirt1 activity. C2C12 myotubes treated with SRT1720 maintained myotube diameter, prevented loss of sirt1 expression, and attenuated mitochondrial superoxide production. Our data provides evidence that NA may be beneficial in combating cancer cachexia by maintaining sirt1 expression and decreasing mitochondrial superoxide production.

[Factors Associated with the Continuation of Anamorelin in Patients with Cancer-associated Cachexia: A Single-center Retrospective Study].

Cancer-associated cachexia, a multifactorial syndrome involving loss of muscle mass and anorexia, affects the survival of cancer patients. Anamorelin was the first drug approved in Japan for the treatment of cachexia. However, cases in which anamorelin is discontinued within 3 weeks are often observed in clinical practice. This study aimed to explore the factors associated with continued anamorelin dosing. We retrospectively reviewed records of patients with lung, gastric, pancreatic, and colorectal cancer who started anamorelin at Fukuoka University Hospital from April 2021 to November 2022. Patients were divided into two groups based on the duration of anamorelin administration: 15 patients were classified into the <3 weeks group and 22 were classified into the ≥3 weeks group. The primary objective was to explore the potential factors associated with the continuation of anamorelin, and the secondary objectives were to compare survival and nutritional indices. In the univariate analysis, there were significant differences between the two groups in terms of cancer type (p=0.007) and serum albumin level (p=0.026). In the multivariate analysis, gastric cancer and albumin 2.7 g/dL or less were associated with the continuation of anamorelin. Survival was significantly shorter in the <3 weeks group (p=0.019). This study suggests that the continuation of anamorelin may be influenced by specific tumor types and serum albumin levels. Furthermore, the duration of anamorelin administration may affect patient survival.

[Efficacy of Anamorelin for the Treatment of Cancer Cachexia and Factors Associated with Weight Gain].

Cancer cachexia causes anorexia and metabolic disorders, eventually leading to sarcopenia, which in turn contributes to the development of functional disabilities. Although anamorelin hydrochloride tablets are marketed to treat cancer cachexia, their efficacy varies significantly among patients. Here, we investigated the efficacy of anamorelin and the factors associated with weight gain. The factors that contributed to weight gain in patients before starting anamorelin were as follows: the patients' disease stage had not progressed to refractory cachexia based on the cancer cachexia classification of the European Palliative Care Research Collaborative; the patients had received fewer lines of anticancer treatment at the start of oral administration of anamorelin; and the patients had not met all the criteria for starting treatment with anamorelin, namely, C-reactive protein level >0.5 mg/dL, hemoglobin level <12 g/dL, and albumin level <3.2 g/dL. These results suggest that early administration of anamorelin hydrochloride tablets may increase the response rate when cancer cachexia is diagnosed.

Prognostic value of body composition in patients with digestive tract cancers: A prospective cohort study of 8,267 adults from China.

BACKGROUND & AIMS: The characterization and prognostic value of body composition parameter/phenotype based on computed tomography (CT) in patients with digestive tract cancers remain incomplete. This study aimed to investigate the relationship between parameter/phenotype and clinical outcomes in patients with digestive tract cancers. METHODS: In this prospective cohort study, 8267 patients with digestive tract cancers were assessed using CT scans to determine body composition. Body composition data, including areas of skeletal muscle (SM), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT), were collected at the third lumbar level on CT images obtained within 30 days before surgery. Body composition phenotypes (sarcopenia, cancer cachexia, sarcopenic obesity) were determined based on SM, SAT, and VAT areas. The primary endpoint was overall survival, obtained from electronic medical records and telephone follow-up surveys. Kaplan-Meier and log-rank analyses were employed to compare unadjusted survival, while multivariate survival analyses were conducted using a proportional hazards model adjusted for age, gender, and cancer-node-metastasis (TNM) stages. RESULTS: Adjusted hazard ratios (HRs) for all-cause mortality were calculated for the second (Q2), third (Q3), and fourth (Q4) quantiles relative to the first quantile (Q1) for SM areas, revealing adjusted summary HRs of 0.575 (95% CI, 0.361-0.916), 0.419 (95% CI, 0.241-0.729), and 0.384 (95% CI, 0.203-0.726), respectively. Sarcopenia-adjusted summary HRs were 1.795 (95% CI: 1.012-3.181) for male patients and 1.925 (95% CI: 1.065-3.478) for female patients. Cancer cachexia-adjusted summary HRs were 1.542 (95% CI: 1.023-2.324) for male patients and 1.569 (95% CI: 0.820-3.001) for female patients. Sarcopenic obesity-adjusted summary HRs were 1.122 (95% CI: 0.759-1.657) for male patients and 1.303 (95% CI: 0.623-2.725) for female patients. Subgroup analyses indicated varying prognostic values of body composition parameter/phenotype among different cancer types. CONCLUSIONS: Our findings suggest a large SM area is a favorable prognostic indicator, while cancer cachexia and sarcopenia signify poor prognosis in patients with digestive tract cancers. These findings have important implications for the personalized preoperative assessment of body composition in patients with digestive tract cancers.

Malnutrition and cachexia are associated with poor CAR T-cell therapy outcomes including survival.

BACKGROUND & AIMS: Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a revolutionary treatment for patients with refractory or relapsed B-cell malignancies. However, a significant proportion of patients experience negative outcomes, including severe inflammatory toxicities and relapse. Cachexia and malnutrition are known secondary syndromes in many cancer patients, attributed to the effects of active malignancy, systemic inflammation, and cumulative treatment burden; however, further research is required to accurately characterise these issues in CAR T-cell patients. The aims of this service evaluation were to explore the changes in nutritional status (malnutrition and cachexia) in CAR T-cell therapy patients and the potential impact on patient outcomes including survival. Additionally, we describe the utilisation of dietetic resources in this specific patient population in a London tertiary referral centre. METHODS: Adult haematology patients receiving licensed CD19-targeting CAR T-cell therapy at University College London Hospital between 01/04/19 and 01/09/21 were included. Data were collected from the time of treatment consent, and throughout admission to day of discharge: body weight (BW), C-reactive protein, albumin, lactate dehydrogenase, nutrition-risk screening scores (hospital-specific) and dietetic input. Clinical outcomes such as 12-month all-cause mortality, intensive care unit (ICU) admission, high-grade toxicities, and length of hospital stay (LoS) were also recorded. Cachexia and malnutrition were defined using the modified Glasgow Prognostic Score (mGPS) and Global Leadership Initiative on Malnutrition (GLIM) consensus, respectively. RESULTS: 114 patients (55.6 ± 15.1 years; 57% males) with B-cell non-Hodgkin's lymphoma (n = 109) and B-cell acute lymphoblastic leukaemia (n = 5), receiving axicabtagene ciloleucel (n = 89) and tisagenlecleucel (n = 25) were included. Median LoS for treatment was 34 (27-38) days. Prior to treatment, 31.5% of patients developed malnutrition, with pre-cachexia/refractory cachexia (mGPS) identified in 43.6% of patients. This altered nutritional status pre-treatment was significantly associated with adverse patient outcomes post-infusion; mGPS was independently associated with inferior overall survival (HR = 3.158, CI = 1.36-7.323, p = 0.007), with malnutrition and mGPS associated with increased LoS (p = 0.037), sepsis (p = 0.022) and ICU admission (p = 0.039). During admission, patients experienced significant BW loss (-5.6% (-8.8 to -2.4); p=<0.001), with 68.4% developing malnutrition. Malnutrition screening during admission identified 57% patients at-risk, with 66.6% of patients referred to dietetics; however, there was a lack of malnutrition screening and dietetic referrals prior to treatment. CONCLUSION: Pre-treatment malnutrition and cachexia was significantly associated with adverse CAR T patient outcomes, including mGPS cachexia status independently associated with inferior overall survival. Further research in this novel space is essential to confirm the extent and impact of nutritional issues, to assist with implementing dietetic pathways, and to identify potential interventions with a view to optimising outcomes.

Area postrema neurons mediate interleukin-6 function in cancer cachexia.

Interleukin-6 (IL-6) has been long considered a key player in cancer cachexia. It is believed that sustained elevation of IL-6 production during cancer progression causes brain dysfunctions, which ultimately result in cachexia. However, how peripheral IL-6 influences the brain remains poorly understood. Here we show that neurons in the area postrema (AP), a circumventricular structure in the hindbrain, is a critical mediator of IL-6 function in cancer cachexia in male mice. We find that circulating IL-6 can rapidly enter the AP and activate neurons in the AP and its associated network. Peripheral tumor, known to increase circulating IL-6, leads to elevated IL-6 in the AP, and causes potentiated excitatory synaptic transmission onto AP neurons and AP network hyperactivity. Remarkably, neutralization of IL-6 in the brain of tumor-bearing mice with an anti-IL-6 antibody attenuates cachexia and the hyperactivity in the AP network, and markedly prolongs lifespan. Furthermore, suppression of Il6ra, the gene encoding IL-6 receptor, specifically in AP neurons with CRISPR/dCas9 interference achieves similar effects. Silencing Gfral-expressing AP neurons also attenuates cancer cachectic phenotypes and AP network hyperactivity. Our study identifies a central mechanism underlying the function of peripheral IL-6, which may serve as a target for treating cancer cachexia.

Circulating myostatin as a biomarker of muscle mass and strength in individuals with cancer or obesity.

BACKGROUND & AIMS: Our study aims to determine whether myostatin (MSTN) is associated with muscle mass and strength in individuals with cancer or obesity, as well as with cancer cachexia (CC) or sarcopenic obesity (SO). METHODS: The ACTICA study included individuals with CC (n = 70) or without CC (NC, n = 73). The MYDIASECRET study included individuals with obesity evaluated before (T0) and 3 months (T3) after bariatric surgery (n = 62). Body composition was assessed using bioelectrical impedance analysis (BIA). Skeletal muscle mass (SMM) and appendicular SMM (ASMM) were calculated from Janssen's and Sergi's equations, respectively, and expressed as indexes (SMMI and ASMMI). Handgrip strength (HGS) was assessed using a Jamar hand-held dynamometer. MSTN plasma levels were measured using ELISA. Spearman's coefficient was used to correlate MSTN with muscle mass and strength. Receiver operating characteristic (ROC) curve analysis was performed to identify an optimal MSTN cutoff level for the prediction of CC or SO. RESULTS: In the ACTICA study, muscle mass and strength were lower in CC individuals than in NC individuals (SMMI: 8.0 kg/m2vs 9.0 kg/m2, p = 0.004; ASMMI: 6.2 kg/m2vs 7.2 kg/m2, p < 0.001; HGS: 28 kg vs 38 kg, p < 0.001). MSTN was also lower in CC individuals than in NC individuals (1434 pg/mL vs 2149 pg/mL, p < 0.001). Muscle mass and strength were positively correlated with MSTN (SMMI: R = 0.500, p < 0.001; ASMMI: R = 0.479, p < 0.001; HGS: R = 0.495, p < 0.001). ROC curve analysis showed a MSTN cutoff level of 1548 pg/mL (AUC 0.684, sensitivity 57%, specificity 75%, p < 0.001) for the prediction of CC. In the MYDIASECRET study, muscle mass and strength were reduced at T3 (SMMI: -8%, p < 0.001; ASMMI: -12%, p < 0.001; HGS: -6%, p = 0.005). MSTN was also reduced at T3 (1773 pg/mL vs 2582 pg/mL, p < 0.001). Muscle mass and strength were positively correlated with MSTN at T0 and T3 (SMMI-T0: R = 0.388, p = 0.002; SMMI-T3: R = 0.435, p < 0.001; HGS-T0: R = 0.337, p = 0.007; HGS-T3: R = 0.313, p = 0.013). ROC curve analysis showed a MSTN cutoff level of 4225 pg/mL (AUC 0.835, sensitivity 98%, specificity 100%, p = 0.014) for the prediction of SO at T3. CONCLUSIONS: MSTN is positively correlated with muscle mass and strength in individuals with cancer or obesity, suggesting its potential use as a biomarker of muscle mass and strength. The ROC curve analysis suggests the potential use of MSTN as a screening tool for CC and SO.

Tumor metabolic activity is associated with subcutaneous adipose tissue radiodensity and survival in non-small cell lung cancer.

BACKGROUND: Cachexia-associated body composition alterations and tumor metabolic activity are both associated with survival of cancer patients. Recently, subcutaneous adipose tissue properties have emerged as particularly prognostic body composition features. We hypothesized that tumors with higher metabolic activity instigate cachexia related peripheral metabolic alterations, and investigated whether tumor metabolic activity is associated with body composition and survival in patients with non-small-cell lung cancer (NSCLC), focusing on subcutaneous adipose tissue. METHODS: A retrospective analysis was performed on a cohort of 173 patients with NSCLC. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scans obtained before treatment were used to analyze tumor metabolic activity (standardized uptake value (SUV) and SUV normalized by lean body mass (SUL)) as well as body composition variables (subcutaneous and visceral adipose tissue radiodensity (SAT/VAT radiodensity) and area; skeletal muscle radiodensity (SM radiodensity) and area). Subjects were divided into groups with high or low SAT radiodensity based on Youden Index of Receiver Operator Characteristics (ROC). Associations between tumor metabolic activity, body composition variables, and survival were analyzed by Mann-Whitney tests, Cox regression, and Kaplan-Meier analysis. RESULTS: The overall prevalence of high SAT radiodensity was 50.9% (88/173). Patients with high SAT radiodensity had shorter survival compared with patients with low SAT radiodensity (mean: 45.3 vs. 50.5 months, p = 0.026). High SAT radiodensity was independently associated with shorter overall survival (multivariate Cox regression HR = 1.061, 95% CI: 1.022-1.101, p = 0.002). SAT radiodensity also correlated with tumor metabolic activity (SULpeak rs = 0.421, p = 0.029; SUVpeak rs = 0.370, p = 0.048). In contrast, the cross-sectional areas of SM, SAT, and VAT were not associated with tumor metabolic activity or survival. CONCLUSION: Higher SAT radiodensity is associated with higher tumor metabolic activity and shorter survival in patients with NSCLC. This may suggest that tumors with higher metabolic activity induce subcutaneous adipose tissue alterations such as decreased lipid density, increased fibrosis, or browning.

Berberine Improves Cancer-Derived Myocardial Impairment in Experimental Cachexia Models by Targeting High-Mobility Group Box-1.

Cardiac disorders in cancer patients pose significant challenges to disease prognosis. While it has been established that these disorders are linked to cancer cells, the precise underlying mechanisms remain elusive. In this study, we investigated the impact of cancerous ascites from the rat colonic carcinoma cell line RCN9 on H9c2 cardiomyoblast cells. We found that the ascites reduced mitochondrial volume, increased oxidative stress, and decreased membrane potential in the cardiomyoblast cells, leading to apoptosis and autophagy. Although the ascites fluid contained a substantial amount of high-mobility group box-1 (HMGB1), we observed that neutralizing HMGB1 with a specific antibody mitigated the damage inflicted on myocardial cells. Our mechanistic investigations revealed that HMGB1 activated both nuclear factor κB and phosphoinositide 3-kinases-AKT signals through HMGB1 receptors, namely the receptor for advanced glycation end products and toll-like receptor-4, thereby promoting apoptosis and autophagy. In contrast, treatment with berberine (BBR) induced the expression of miR-181c-5p and miR-340-5p while suppressing HMGB1 expression in RCN9 cells. Furthermore, BBR reduced HMGB1 receptor expression in cardiomyocytes, consequently mitigating HMGB1-induced damage. We validated the myocardial protective effects of BBR in a cachectic rat model. These findings underscore the strong association between HMGB1 and cancer cachexia, highlighting BBR as a promising therapeutic agent for myocardial protection through HMGB1 suppression and modulation of the signaling system.

Testosterone replacement therapy in patients with cachexia: a contemporary review of the literature.

INTRODUCTION: Patients with long-term chronic illnesses frequently present with hypogonadism, which is primarily managed through exogenous testosterone. These same patients also experience a high degree of cachexia, a loss of skeletal muscle and adipose tissue. OBJECTIVE: To perform a contemporary review of the literature to assess the effectiveness of testosterone replacement therapy (TRT) for managing chronic disease-associated cachexia. METHODS: We performed a PubMed literature search using MeSH terms to identify studies from 2000 to 2022 on TRT and the following cachexia-related chronic medical diseases: cancer, COPD, HIV/AIDS, and liver cirrhosis. RESULTS: From the literature, 11 primary studies and 1 meta-analysis were selected. Among these studies, 3 evaluated TRT on cancer-associated cachexia, 3 on chronic obstructive pulmonary disease, 4 on HIV and AIDS, and 2 on liver cirrhosis. TRT showed mixed results favoring clinical improvement on each disease. CONCLUSIONS: Cachexia is commonly observed in chronic disease states. Its occurrence with hypogonadism, alongside the shared symptoms of these 2 conditions, points toward the management of cachexia through the administration of exogenous testosterone. Robust data in the literature support the use of testosterone in increasing lean body mass, improving energy levels, and enhancing the quality of life for patients with chronic disease. However, the data are variable, and further studies are warranted on the long-term efficacy of TRT in patients with cachexia.

Withaferin A as a Potential Therapeutic Target for the Treatment of Angiotensin II-Induced Cardiac Cachexia.

In our previous studies, we showed that the generation of ovarian tumors in NSG mice (immune-compromised) resulted in the induction of muscle and cardiac cachexia, and treatment with withaferin A (WFA; a steroidal lactone) attenuated both muscle and cardiac cachexia. However, our studies could not address if these restorations by WFA were mediated by its anti-tumorigenic properties that might, in turn, reduce the tumor burden or WFA's direct, inherent anti-cachectic properties. To address this important issue, in our present study, we used a cachectic model induced by the continuous infusion of Ang II by implanting osmotic pumps in immunocompetent C57BL/6 mice. The continuous infusion of Ang II resulted in the loss of the normal functions of the left ventricle (LV) (both systolic and diastolic), including a significant reduction in fractional shortening, an increase in heart weight and LV wall thickness, and the development of cardiac hypertrophy. The infusion of Ang II also resulted in the development of cardiac fibrosis, and significant increases in the expression levels of genes (ANP, BNP, and MHCß) associated with cardiac hypertrophy and the chemical staining of the collagen abundance as an indication of fibrosis. In addition, Ang II caused a significant increase in expression levels of inflammatory cytokines (IL-6, IL-17, MIP-2, and IFNγ), NLRP3 inflammasomes, AT1 receptor, and a decrease in AT2 receptor. Treatment with WFA rescued the LV functions and heart hypertrophy and fibrosis. Our results demonstrated, for the first time, that, while WFA has anti-tumorigenic properties, it also ameliorates the cardiac dysfunction induced by Ang II, suggesting that it could be an anticachectic agent that induces direct effects on cardiac muscles.

Anamorelin for the Treatment of Cancer Anorexia-Cachexia Syndrome.

PURPOSE OF REVIEW: The following review will highlight the development of anamorelin to treat cancer anorexia-cachexia syndrome (CACS) including the potential benefits, limitations, and future directions. RECENT FINDINGS: Ghrelin, a 28-amino acid peptide hormone, is secreted by the stomach mucosa and regulates appetite, promotes lipogenesis, increases body weight, improves gastric motility, reduces catabolic wasting and inflammation. Several randomized, double-blind, placebo-controlled clinical trials evaluating anamorelin, a ghrelin agonist, for the treatment of CACS have reported improvement in appetite and body composition including both lean body and fat mass; however, most studies noted no improvement in physical function as assessed by measuring non-dominant hand-grip strength. Common adverse effects of anamorelin include the development of diabetes mellitus, hyperglycemia, and less frequently, hepatic abnormalities and cardiovascular events including conduction abnormalities, hypertension, and ischemic cardiomyopathy. Anamorelin has the potential to stimulate appetite, improve gastric movement, and may have anti-inflammatory effects on patients with CACS. In patients with cancer, studies involving anamorelin combined with other multimodal treatments including nutrition counseling (branched chain amino acids, omega 3 fatty acids, and other nutrients), exercise, treatment of hormonal abnormalities including hypogonadism and hypovitaminosis D, and anti-inflammatory agents are needed. Compliance with multimodality treatment has been a barrier and future studies may need to incorporate motivational counseling to promote adherence.

Body weight and composition endpoints in cancer cachexia clinical trials: Systematic Review 4 of the cachexia endpoints series.

Significant variation exists in the outcomes used in cancer cachexia trials, including measures of body composition, which are often selected as primary or secondary endpoints. To date, there has been no review of the most commonly selected measures or their potential sensitivity to detect changes resulting from the interventions being examined. The aim of this systematic review is to assess the frequency and diversity of body composition measures that have been used in cancer cachexia trials. MEDLINE, Embase and Cochrane Library databases were systematically searched between January 1990 and June 2021. Eligible trials examined adults (≥18 years) who had received an intervention aiming to treat or attenuate the effects of cancer cachexia for >14 days. Trials were also of a prospective controlled design and included body weight or at least one anthropometric, bioelectrical or radiological endpoint pertaining to body composition, irrespective of the modality of intervention (e.g., pharmacological, nutritional, physical exercise and behavioural) or comparator. Trials with a sample size of <40 patients were excluded. Data extraction used Covidence software, and reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. This review was prospectively registered (PROSPERO: CRD42022276710). A total of 84 clinical trials, comprising 13 016 patients, were eligible for inclusion. Non-small-cell lung cancer and pancreatic cancer were studied most frequently. The majority of trial interventions were pharmacological (52%) or nutritional (34%) in nature. The most frequently reported endpoints were assessments of body weight (68 trials, n = 11 561) followed by bioimpedance analysis (BIA)-based estimates (23 trials, n = 3140). Sixteen trials (n = 3052) included dual-energy X-ray absorptiometry (DEXA)-based endpoints, and computed tomography (CT) body composition was included in eight trials (n = 841). Discrepancies were evident when comparing the efficacy of interventions using BIA-based estimates of lean tissue mass against radiological assessment modalities. Body weight, BIA and DEXA-based endpoints have been most frequently used in cancer cachexia trials. Although the optimal endpoints cannot be determined from this review, body weight, alongside measurements from radiological body composition analysis, would seem appropriate. The choice of radiological modality is likely to be dependent on the trial setting, population and intervention in question. CT and magnetic resonance imaging, which have the ability to accurately discriminate tissue types, are likely to be more sensitive and provide greater detail. Endpoints are of particular importance when aligned with the intervention's mechanism of action and/or intended patient benefit.

The relationship between LDH and GLIM criteria for cancer cachexia: Systematic review and meta-analysis.

INTRODUCTION: Cancer cachexia is a clinical condition characterized by recognizable "sickness behaviors" accompanied by loss of lean body tissue. The Global Leadership on Malnutrition (GLIM) has proposed phenotypic (unintentional weight loss, low body mass index and low muscle mass) and aetiologic (reduced food intake and inflammation or disease burden) diagnostic criteria. Recent work has suggested serum lactate dehydrogenase (LDH) might represent a 3rd aetiologic criteria. Little is known of its relationship with GLIM. A systematic review and meta-analysis of their comparative prognostic value and association was performed. METHODS: A search of electronic databases (PubMed, Medline, Ovid, Cochrane) up to February 2023 was used to identify studies that compared the prognostic value of LDH and components of the GLIM criteria in cancer. An analysis of the relationship between LDH and the components of GLIM was undertaken where this data was available. RevMan 5.4.1 was used to perform a meta-analysis for each diagnostic criteria that had 3 or more studies which reported hazard ratios with a 95 per cent confidence interval for overall survival (OS). RESULTS: A total of 119 studies were reviewed. Advanced lung cancer was the most studied population. Included in the meta-analysis were 6 studies (n=2165) on LDH and weight loss, 17 studies (n=7540) on LDH and low BMI, 5 studies (n=758) on LDH and low muscle mass, 0 studies on LDH and food intake and 93 studies (n=32,190) on LDH and inflammation. There was a significant association between elevated serum LDH and each of low BMI (OR 1.39, 1.09 - 1.77; p=0.008), elevated NLR (OR 2.04, 1.57 - 2.65; p<0.00001) and elevated CRP (OR 2.58, 1.81 - 3.67; p<0.00001). There was no association between elevated serum LDH and low muscle mass. Only one study presented data on the association between LDH and unintentional weight loss. Elevated LDH showed a comparative OS (HR 1.86, 1.57 - 2.07; p<0.00001) to unintentional weight loss (HR 1.57, 1.23 - 1.99; p=0.0002) and had a similar OS (HR 2.00, 1.70 - 2.34; p<0.00001) to low BMI (HR 1.57, 1.29-2.90; p<0.0001). LDH also showed an OS (HR 2.25, 1.76 - 2.87; p<0.00001) congruous with low muscle mass (HR 1.93, 1.14 - 3.27; p=0.01) and again, LDH conferred as poor an OS (HR 1.77, 1.64-1.90; p<0.00001) as elevated NLR (HR 1.61, 1.48 - 1.77; p<0.00001) or CRP (HR 1.55, 1.43 - 1.69; p<0.00001). CONCLUSION: Current literature suggests elevated serum LDH is associated with inflammation in cancer (an aetiologic GLIM criterion), however more work is required to establish the relationship between LDH and the phenotypic components of GLIM. Additionally, elevated serum LDH appears to be a comparative prognosticator of overall survival in cancer when compared to the GLIM criteria.

Biomarker endpoints in cancer cachexia clinical trials: Systematic Review 5 of the cachexia endpoint series.

Regulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve drugs. Biomarkers are often considered surrogate endpoints. In cancer cachexia trials, the measurement of biomarkers features frequently. The aim of this systematic review was to assess the frequency and diversity of biomarker endpoints in cancer cachexia trials. A comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990-2023) was completed. Eligible trials met the following criteria: adults (≥18 years), prospective design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a biomarker(s) as an endpoint. Biomarkers were defined as any objective measure that was assayed from a body fluid, including scoring systems based on these assays. Routine haematology and biochemistry to monitor intervention toxicity were not considered. Data extraction was performed using Covidence, and reporting followed PRISMA guidance (PROSPERO: CRD42022276710). A total of 5975 studies were assessed, of which 52 trials (total participants = 6522) included biomarkers as endpoints. Most studies (n = 29, 55.7%) included a variety of cancer types. Pharmacological interventions (n = 27, 51.9%) were most evaluated, followed by nutritional interventions (n = 20, 38.4%). Ninety-nine different biomarkers were used across the trials, and of these, 96 were assayed from blood. Albumin (n = 29, 55.8%) was assessed most often, followed by C-reactive protein (n = 22, 42.3%), interleukin-6 (n = 16, 30.8%) and tumour necrosis factor-α (n = 14, 26.9%), the latter being the only biomarker that was used to guide sample size calculations. Biomarkers were explicitly listed as a primary outcome in six trials. In total, 12 biomarkers (12.1% of 99) were used in six trials or more. Insulin-like growth factor binding protein 3 (IGFBP-3) and insulin-like growth factor 1 (IGF-1) levels both increased significantly in all three trials in which they were both used. This corresponded with a primary outcome, lean body mass, and was related to the pharmacological mechanism. Biomarkers were predominately used as exploratory rather than primary endpoints. The most commonly used biomarker, albumin, was limited by its lack of responsiveness to nutritional intervention. For a biomarker to be responsive to change, it must be related to the mechanism of action of the intervention and/or the underlying cachexia process that is modified by the intervention, as seen with IGFBP-3, IGF-1 and anamorelin. To reach regulatory approval as an endpoint, the relationship between the biomarker and clinical benefit must be clarified.

Cancer cachexia as a predictor of adverse outcomes in patients with non-small cell lung cancer: A meta-analysis.

INTRODUCTION: Cancer cachexia is a complex problem characterized by weight loss due to skeletal muscle and adipose tissue reduction. The purpose of this meta-analysis is to examine the association between cancer cachexia and adverse outcomes in patients with non-small cell lung cancer (NSCLC). METHODS: A comprehensive search was conducted in the PubMed, Web of Science, and Embase databases from their inception to January 15, 2024. Retrospective or prospective studies that investigated the cancer cachexia as a predictor of overall survival (OS), progression-free survival (PFS), overall response rate (ORR), or disease control rate (DCR) in NSCLC patients were included in this analysis. RESULTS: Sixteen studies, comprising 5919 NSCLC patients, were identified. The pooled prevalence of cachexia in NSCLC patients was 39%, with individual studies reporting rates ranging from 19% to 63.8%. A meta-analysis using a random effects model showed that cachexia was associated with reduced OS (hazard ratio [HR] 1.84; 95% confidence interval [CI] 1.54-2.21) and PFS (HR 1.49; 95% CI 1.27-1.73). Subgroup analysis indicated that cancer cachexia significantly predicted OS, regardless of study design, NSCLC subtypes, cancer stage, definitions of cachexia, or follow-up duration. However, there was no clear association between cancer cachexia and ORR or DCR. CONCLUSIONS: Cancer cachexia emerges is a negative prognostic factor for OS and PFS in NSCLC patients. Assessing cancer cachexia can improve risk classification for survival outcomes in this patient population.

Real-world safety and effectiveness of anamorelin for cancer cachexia: Interim analysis of post-marketing surveillance in Japan.

BACKGROUND: Anamorelin was approved in Japan in 2021 to treat cancer cachexia associated with non-small cell lung, gastric, pancreatic, or colorectal cancers. Post-marketing surveillance is being conducted to evaluate the real-world safety and effectiveness of anamorelin. METHODS: This prospective, observational surveillance registered all patients who started treatment with anamorelin after April 21, 2021. Hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were defined as main safety specifications. Body weight (BW) and appetite were assessed as effectiveness specifications. RESULTS: This analysis was based on data as of January 21, 2023. The safety and effectiveness analysis sets included 6016 and 4511 patients, respectively. Treatment-related adverse events in ≥1% of patients were hyperglycemia (3.9%) and nausea (2.6%). The incidences of hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were 4.8%, 1.2%, and 1.1%, respectively. The mean changes (standard error [SE]) in BW from baseline to weeks 3, 12, 24, and 52 were 0.64 (0.05) kg, 1.19 (0.12) kg, 1.40 (0.21) kg, and 1.42 (0.39) kg, respectively. The mean changes (SE) in Functional Assessment of Anorexia/Cachexia Treatment 5-item Anorexia Symptom Scale total scores from baseline to weeks 3, 12, 24, and 52 were 3.2 (0.09), 4.8 (0.18), 5.2 (0.30), and 5.3 (0.47), respectively, exceeding the clinically meaningful improvement score (2.0 points). CONCLUSION: The overall safety of anamorelin raised no new safety concerns, although continued caution may be required for hyperglycemia and nausea. Improvements in BW and appetite were also observed in real-world clinical settings.

Relationships of emerging biomarkers of cancer cachexia with quality of life, appetite, and cachexia.

PURPOSE: Quality of life (QoL), appetite, cachexia, and biomarkers [albumin, hemoglobin (Hb), neutrophils, lymphocytes, platelets, C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6), interleukin 8 (IL-8), C-X-C motif chemokine ligand 5 (CXCL5) and citrullinated histoneH3 (H3Cit)] were compared for 40 cases with advanced cancer and 40 healthy controls. Baseline differences and significant relationships were explored for biomarkers with QoL, appetite, and cachexia. METHODS: In a prospective case-control, age and sex matched study, the European Organisation for the Research and Treatment of Cancer Quality of Life-C30 questionnaire (EORTC-QLQ-C30) for QoL, the Functional Assessment of Anorexia and Cachexia Therapy assessment (FAACT A/CS-12) for appetite, and a five-factor cachexia assessment tool for cachexia assessment were performed. Routine hematological measurements and blood chemistry analyses together with ELISA procedures and a Multiplex® bead array platform, were used for biomarker analysis. Descriptive statistics and regression analyses were undertaken. P < 0.05 defined statistical significance. RESULTS: Global health status (QL-G), functional scales (QL-FS), and symptom scales (QL-SS) differed for cases and controls (p < 0.01). In cases, differences were observed for QL-G (p < 0.01), QL-FS (p < 0.01), and QL-SS (p = 0.01) compared to standardized references values. FAACT A/CS-12 scores differed significantly between cases and controls (p < 0.01) and 30% of cases scored "poor" appetites. Cachexia was present in 60% of cases. Albumin, lymphocytes, platelets, Hb, platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), CRP, TNFα, all at p < 0.01, neutrophil to lymphocyte ratio (NLR) (p = 0.02), IL-6 (p < 0.04), and IL-8 (p = 0.02) differed significantly between cases and controls. No difference was found for CXCL5 or H3Cit. Albumin NLR, Hb, PLR, SII, TNFα, IL-8, and CRP showed significant relationships with all aspects of QoL. QL-FS was significantly related to CXCL5 (p = 0.04), significant relationships with FAACT A/CS-12 included: NLR (p = 0.002), Hb (p < 0.001), and PLR (p < 0.01). NLR, PLR, SII, TNFα, IL-6, IL-8, and CRP correlated positively to cachexia and albumin while Hb and lymphocyte count correlated negatively to cachexia. CONCLUSION: CXCL5 and H3Cit were not reliable biomarkers for cancer cachexia, nor significantly related to QoL, appetite or cachexia. Albumin, NLR, Hb, PLR, SII, TNFα, IL-8, and CRP were reliable indicators of QoL, appetite, and cachexia. Future research should include other novel biomarkers namely growth differentiation factor-15 (GDF-15), fibroblast growth factor 21 (FGF-21), fractakline, interferon gamma (IFN-y), IL-16, macrophage colony stimulating factor (M-CSF), and macrophage procoagulant-inducing factor (MPIF).