Cancer Anorexia-cachexia Syndrome Research Articles

Ketone Bodies Attenuate Wasting in Models of Atrophy.

BackgroundCancer Anorexia Cachexia Syndrome (CACS) is a distinct atrophy disease negatively influencing multiple aspects of clinical care and patient quality of life. Although it directly causes 20% of all cancer‐related deaths, there are currently no model systems that encompass the entire multifaceted syndrome, nor are there any effective therapeutic treatments.MethodsA novel model of systemic metastasis was evaluated for the comprehensive CACS (metastasis, skeletal muscle and adipose tissue wasting, inflammation, anorexia, anemia, elevated protein breakdown, hypoalbuminemia, and metabolic derangement) in both males and females. Ex vivo skeletal muscle analysis was utilized to determine ubiquitin proteasome degradation pathway activation. A novel ketone diester (R/S 1,3‐Butanediol Acetoacetate Diester) was assessed in multifaceted catabolic environments to determine anti‐atrophy efficacy.ResultsHere, we show that the VM‐M3 mouse model of systemic metastasis demonstrates a novel, immunocompetent, logistically feasible, repeatable phenotype with progressive tumor growth, spontaneous metastatic spread, and the full multifaceted CACS with sex dimorphisms across tissue wasting. We also demonstrate that the ubiquitin proteasome degradation pathway was significantly upregulated in association with reduced insulin‐like growth factor‐1/insulin and increased FOXO3a activation, but not tumor necrosis factor‐α‐induced nuclear factor‐kappa B activation, driving skeletal muscle atrophy. Additionally, we show that R/S 1,3‐Butanediol Acetoacetate Diester administration shifted systemic metabolism, attenuated tumor burden indices, reduced atrophy/catabolism and mitigated comorbid symptoms in both CACS and cancer‐independent atrophy environments.ConclusionsOur findings suggest the ketone diester attenuates multifactorial CACS skeletal muscle atrophy and inflammation‐induced catabolism, demonstrating anti‐catabolic effects of ketone bodies in multifactorial atrophy.

The Effect ofCurcumin for Treatment of Cancer Anorexia-Cachexia Syndrome in Patients With Stage III-IV of Head and Neck Cancer

The Effect ofCurcumin for Treatment of Cancer Anorexia-Cachexia Syndrome in Patients With Stage III-IV of Head and Neck Cancer

A double-blind, placebo-controlled randomized phase II study: Evaluating the effect of curcumin for treatment of cancer anorexia-cachexia syndrome in solid cancer patients.

e23151 Background: Cancer anorexia–cachexia syndrome (CACS) is common among patients with advanced solid cancer and associated with poor prognosis. CACS is a hypercatabolic state, which comprises adipose tissue and skeletal muscle loss, which is characterized by negative protein and energy balance, loss of lean body mass and adipose tissue. Also, CACS increase systemic inflammation. The treatment of CACS is still unclear. Curcumin has been shown anti-cancer and anti-inflammatory effects, including attenuation of CACS in animal models. Therefore, clinical study of curcumin for CACS is required. Methods: This is randomized, double-blind, placebo-controlled phase ll study, 52 patients with CACS in solid malignancy were enrolled and randomized in 1:1 to receive oral curcumin (at a dose of 400 mg twice daily) or placebo for 8 weeks. The primary end point was body tissue composition and the secondary end points were body weight and body mass index, Hand grip muscle strengthening, safety and toxicity. Results: All parameters of body compositions were not statistically significant different between two groups: curcumin group and placebo group, which were consist body fat mass -0.9, SEM = 0.94 versus –1.65, SEM = 1 ( p-value = 0.58), skeletal muscle mass -0.17, SEM = 0.49 versus +0.4, SEM = 0.52 ( p-value = 0.42) and percent body fat –1.0, SEM = 0.65 versus -0.1, SEM = 0.68 ( p-value = 0.3) including with basal metabolic rate -5.3, SEM = 18 versus +18.3, SEM = 19 ( p-value = 0.37). The average of weight loss was also not statistically significant different between two groups, -1.04, SEM = 0.63 in curcumin group versus –1.15, SEM = 0.61 in placebo group, ( p-value = 0.9). Notably, patient with curcumin had less reduction of hand-grip muscle strength on both hands [right hand: -2.09 in curcumin versus -3.68 in placebo; p = 0.46], [left hand: -1.24 versus -5.04; p-value = 0.12], and basal metabolic rate than placebo group. Most adverse events were grade 1 on both groups similarly. Conclusions: Curcumin was not shown to be superior to placebo with regard to increasing the body composition in cancer patients with CACS. However, curcumin might show some clinical benefits, including slow progression of hand-grip muscle strength loss and basal metabolic rate. Further investigations should be explored.

Pembrolizumab Exposure-Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance.

To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non-small cell lung cancer (NSCLC). PK dependencies in OS were evaluated across three pembrolizumab studies of either 200 mg or 2 to 10 mg/kg every 3 weeks (Q3W). Kaplan-Meier plots of OS, stratified by dose, exposure, and baseline clearance (CL0), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL0 subgroups. A total of 1,453 subjects were included: 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose independent from 2 to 10 mg/kg for pembrolizumab-treated melanoma [HR = 0.98; 95% confidence interval (CI), 0.94-1.02] and NSCLC (HR = 0.98; 95% CI, 0.95-1.01); however, a strong CL0-OS association was identified for both cancer types (unadjusted melanoma HR = 2.56; 95% CI, 1.72-3.80 and NSCLC HR = 2.64; 95% CI, 1.94-3.57). Decreased OS in subjects with higher pembrolizumab CL0 paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL0-OS association (multivariate-adjusted CL0 HR = 1.64; 95% CI, 1.06-2.52 for melanoma and HR = 1.88; 95% CI, 1.22-2.89 for NSCLC). These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg. An association of pembrolizumab CL0 with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure-response confounding may be a broader phenomenon generalizable to antineoplastic mAbs.See related commentary by Coss et al., p. 5787.

The management strategies of cancer-associated anorexia: a critical appraisal of systematic reviews

BackgroundCancer-related anorexia remains one of the most prevalent and troublesome clinical problems experienced by patients with cancer during and after therapy. To ensure high-quality care, systematic reviews (SRs) are seen as the best guide. Considering the methodology quality of SRs varies, we undertook a comprehensive overview, and critical appraisal of pertinent SRs.MethodsEight databases (between the inception of each database and September 1, 2017) were searched for SRs on the management of cancer-related anorexia. Two researchers evaluated the methodological quality of each SR by using the Revised Assessment of Multiple Systematic Reviews (R-AMSTAR) checklist. Characteristics of the “high quality” SRs were abstracted, included information on relevant studies numbers, study design, population, intervention, control, outcome and result.ResultsEighteen SRs met the inclusion criteria. The R-AMSTAR scores of methodological quality ranged from 18 to 41 out of 44, with an average score of 30. Totally eight SRs scored ≥31 points, which showed high methodological quality, and would be used for data extraction to make summaries. Anamorelin had some positive effects to relieve cancer anorexia-cachexia syndrome (CACS) and improve the quality of life (QoL). Megestrol Acetate (MA) could improve appetite, and was associated with slight weight gain for CACS. Oral nutritional interventions were effective in increasing nutritional intake and improving some aspects of QoL in patients with cancer who were malnourished or at nutritional risk. The use of thalidomide, Eicosapentaenoic Acid, and minerals, vitamins, proteins, or other supplements for the treatment of cachexia in cancer were uncertain, and there was inadequate evidence to recommend it to clinical practices, the same situation in Chinese Herb Medicine and acupuncture (acupuncture and related therapies were effective in improving QoL) for treating anorexia in cancer patients, warranting further RCTs in these areas.ConclusionsAnamorelin, MA, oral nutrition interventions, and acupuncture could be considered to be applied in patients with cancer-related anorexia. Future RCTs and SRs with high quality on the pharmaceutical or non-pharmaceutical interventions of anorexia in cancer patients are warranted.

Quality of life and anorexia/cachexia in lung cancer: validation of the Spanish version of the FAACT instrument.

The cancer anorexia-cachexia syndrome (CACS) is highly prevalent in lung cancer (LC) patients (57-61%), and represents the direct cause of death in 20% of cases. Accurately quantifying CACS has been a challenging issue; consequently, this study presents the clinical validation of the Spanish version of the Functional Assessment of Anorexia-Cachexia Therapy (FAACT) scale in LC patients from Latin America. The Spanish version of the FAACT and the Mexican-Spanish version of the EORTC-QLQ-C30 instruments were applied to a cohort of patients with LC at the National Cancer Institute of Mexico. Reliability and validity tests were performed to assess the psychometric properties of the scales, and clinical validation was assessed considering the association of scales with subjective and objective clinical data. Two hundred patients were included. Questionnaire compliance rates were high (100%) and the instrument was well accepted in all cases; internal consistency tests demonstrated good convergent and divergent validity of the scale structure. Cronbach's α coefficient for three out of five basic multi-item scales was > 0.7 (0.55-0.86). FAACT scales presented significant associations with clinical parameters, including biochemical and nutritional variables (i.e., energy intake, p = 0.002), as well as strongly correlated with the appetite loss subscale of the QLQ-C30 questionnaire (r = - 0.624). Physical well-being (p < 0.0009), functional well-being (p = 0.004), anorexia/cachexia scale (p = 0.029), and FAACT total scores (p = 0.0009) were strongly associated to overall survival. The Spanish version of the FAACT questionnaire is reliable and valid for the assessment of health-related quality of life and CACS in LC patients and can be used in clinical trials.

Cancer Anorexia and Cachexia: Screening in an Ambulatory Infusion Service and Nutrition Consultation .

Cancer anorexia-cachexia syndrome compromises physical function and nutritional and emotional well-being. Systematic screening followed by nutrition referral for appropriate interventions is rare. . The purpose of this study was to pilot a screening process followed by nutritional assessment and intervention when warranted for patients with lung malignancies. . Adult patients with lung malignancies were invited to complete the 12-item Anorexia/Cachexia Scale (A/CS-12) on the day of chemotherapy initiation in ambulatory infusion. Those who scored at a preset threshold were referred to nutrition services for a comprehensive assessment and intervention plan. Those who scored better than the threshold completed the A/CS-12 at each infusion visit for as many as 16 weeks. . 90 participants enrolled, and 46 scored in a moderate-to-severe-risk category; of those, 42 were referred to nutrition services.

Fenofibrate prevents skeletal muscle loss in mice with lung cancer.

The cancer anorexia cachexia syndrome is a systemic metabolic disorder characterized by the catabolism of stored nutrients in skeletal muscle and adipose tissue that is particularly prevalent in nonsmall cell lung cancer (NSCLC). Loss of skeletal muscle results in functional impairments and increased mortality. The aim of the present study was to characterize the changes in systemic metabolism in a genetically engineered mouse model of NSCLC. We show that a portion of these animals develop loss of skeletal muscle, loss of adipose tissue, and increased inflammatory markers mirroring the human cachexia syndrome. Using noncachexic and fasted animals as controls, we report a unique cachexia metabolite phenotype that includes the loss of peroxisome proliferator-activated receptor-α (PPARα) -dependent ketone production by the liver. In this setting, glucocorticoid levels rise and correlate with skeletal muscle degradation and hepatic markers of gluconeogenesis. Restoring ketone production using the PPARα agonist, fenofibrate, prevents the loss of skeletal muscle mass and body weight. These results demonstrate how targeting hepatic metabolism can prevent muscle wasting in lung cancer, and provide evidence for a therapeutic strategy.

Brainstem GLP-1 signalling contributes to cancer anorexia-cachexia syndrome in the rat

The cancer anorexia-cachexia syndrome (CACS) is a frequent and severe condition in cancer patients. Currently, no pharmacological treatment is approved for the therapy of CACS. Centrally, glucagon-like peptide-1 (GLP-1) is expressed in the nucleus tractus solitarii (NTS) and is implicated in malaise, nausea and food aversion. The NTS is reciprocally connected to brain sites implicated in the control of energy balance including the area postrema (AP), which mediates CACS in certain tumour models. Given the role of GLP-1 as a mediator of anorexia under acute sickness conditions, we hypothesized that brainstem GLP-1 signalling might play a role in the mediation of CACS.Using hepatoma tumour-bearing (TB) rats, we first tested whether the chronic delivery of the GLP-1R antagonist exendin-9 (Ex-9) into the fourth ventricle attenuates CACS. Second, we investigated whether a genetic knockdown of GLP-1 expression in the NTS ameliorates CACS.Ex-9 attenuated anorexia, body weight loss, muscle and fat depletion compared to TB controls. Similarly, TB animals with a knockdown of GLP-1 expression in the NTS had higher food intake, reduced body weight loss, and higher lean and fat mass compared to TB controls.Our study identifies brainstem GLP-1 as crucial mediator of CACS in hepatoma TB rats. The GLP-1R represents a promising target against CACS and possibly other forms of disease-related anorexia/cachexia.

Exploring the relationship of self-reported lack of appetite to patient characteristics and symptom burden.

187 Background: Cancer anorexia-cachexia syndrome (CACS) in patients is associated with decreases in lean body mass and body weight. Self-reported lack of appetite may be an important indicator for early identification of CACS. The current analyses examined the relationship of perceived lack of appetite to patient characteristics and overall symptom burden in a large mixed cancer sample referred to a palliative care clinic. Methods: We conducted a retrospective review of patients newly referred to an outpatient palliative care clinic over a two-year period. Data on demographic and clinical characteristics and patient-reported symptom scores on the Edmonton Symptom Assessment Scale (ESAS) were abstracted. Pearson’s correlations and ANOVAs were used to assess relationships between variables. Multiple regression analysis was used to evaluate the relative contribution of variables that were significantly correlated with lack of appetite at the univariate level. Results: Data on 544 patients ( M=53.7 years) showed that older age (r=12, p&lt;.01), not being married or in a marriage-like relationship (r=.09, p=.04), having insurance other than managed care insurance (r=.10, p=.02), lower body mass index (BMI; r=.11, p&lt;.01), marijuana use (r=.18, p&lt;.0001), and overall symptom burden (ESAS total score r=.52, p &lt; .0001) were associated with worse lack of appetite ( M=3.5, SD=3.1). Patients who were underweight (BMI &lt;18.5, 46.7%) reported significantly worse lack of appetite than patients who were normal weight, overweight, or obese ( M=3.9, SD=3.2, p&lt;.01). The final hierarchical regression model accounted for 34% of the variance in lack of appetite, with age, marital status, BMI, marijuana use, and total symptom burden remaining significant independent correlates (p’ s &lt;.01). Conclusions: Contrary to expectations, relatively few clinical correlates were associated with self-reported lack of appetite. Future research should explore inter-individual genetic factors to explain alterations in lean body mass and body weight that may contribute to poor appetite in patients. Such factors may be important indicators for early identification of CACS.

The role of hypothalamic inflammation, the hypothalamic-pituitary-adrenal axis and serotonin in the cancer anorexia-cachexia syndrome.

In cancer patients, the development of cachexia (muscle wasting) is frequently aggravated by anorexia (loss of appetite). Their concurrence is often referred to as anorexia-cachexia syndrome. This review focusses on the recent evidence underlining hypothalamic inflammation as key driver of these processes. Special attention is given to the involvement of hypothalamic serotonin. The anorexia-cachexia syndrome is directly associated with higher mortality in cancer patients. Recent reports confirm its severe impact on the quality of life of patients and their families.Hypothalamic inflammation has been shown to contribute to muscle and adipose tissue loss in cancer via central hypothalamic interleukine (IL)1β-induced activation of the hypothalamic-pituitary-adrenal axis. The resulting release of glucocorticoids directly stimulates catabolic processes in these tissues via activation of the ubiquitin-proteosome pathway. Next to this, hypothalamic inflammation has been shown to reduce food intake in cancer by triggering changes in orexigenic and anorexigenic responses via upregulation of serotonin availability and stimulation of its signalling pathways in hypothalamic tissues. This combination of reduced food intake and stimulation of tissue catabolism represents a dual mechanism by which hypothalamic inflammation contributes to the development and maintenance of anorexia and cachexia in cancer. Hypothalamic inflammation is a driving force in the development of the anorexia-cachexia syndrome via hypothalamic-pituitary-adrenal axis and serotonin pathway activation.

Novel therapeutics in supportive cancer treatment

With constantly improving cancer therapies, patient’s quality of life, the management of potential side effects and treatment-related symptoms have also made considerable progress. Chemotherapy-induced nausea and vomiting (CINV) still constitutes a major problem for many patients. New developments in the field allow a more comfortable administration of guideline-based antiemetic therapy and may further improve the control of nausea. Therapeutic options for the cancer anorexia–cachexia syndrome (CACS), common in advanced cancers, are still limited and hampered by numerous side effects. Among these, targeting the ghrelin-receptor pathway could be a novel approach; however, data are still immature.

Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome: design, development, and potential place in therapy.

Cancer anorexia–cachexia syndrome (CACS) is a complex and largely untreatable paraneoplastic complication common in advanced cancer. It is associated with profoundly deleterious effects on quality of life and survival. Since its discovery over a decade ago, anamorelin hydrochloride (anamorelin), a mimetic of the growth hormone secretagogue ghrelin, has shown considerable promise in ameliorating components of CACS when administered to patients with advanced cancer, including loss of lean body mass and reversal of anorexia. This review summarizes the development of anamorelin and its safety and efficacy in clinical investigations. The potential future role of anamorelin in treating CACS is also discussed.

MABp1 for the treatment of colorectal cancer

ABSTRACTIntroduction: Inflammation is an established process in colorectal cancer development and a hallmark of progression, and pro-inflammatory cytokines have been implicated in the morbidity and functional compromise associated with malignancy. MABp1, described as a first-in-class true human antibody against interleukin-1α, has undergone clinical trial evaluation in a number of indications, recently completing late phase clinical trial testing under Fast Track designation for cancer anorexia-cachexia syndrome in colorectal cancer patients. To date, MABp1 has been evaluated as a novel therapeutic strategy to ameliorate phenotypic factors associated with poor prognosis in colorectal cancer patients.Areas covered: In this review, the authors discuss the clinical trial data available to date for this antibody in colorectal cancer, including novel clinical trial endpoints utilized to evaluate sarcopenia and inflammation, as well as the proposed role of interleukin-1α antagonism in leading to improved patient outcomes.Expert opinion: There is a multitude of antibodies in therapeutic development in oncology, and MABp1 is a novel class of antibody which has been safely tolerated to date. Clinical studies of this agent suggest a significant improvement in lean body mass, though additional results evaluating the impact of targeting inflammation as a strategy to delay disease progression in this population are awaited.

Oral Treatment with the Ghrelin Receptor Agonist HM01 Attenuates Cachexia in Mice Bearing Colon-26 (C26) Tumors.

The gastrointestinal hormone ghrelin reduces energy expenditure and stimulates food intake. Ghrelin analogs are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to investigate whether oral treatment with the non-peptidergic ghrelin receptor agonist HM01 counteracts CACS in colon-26 (C26) tumor-bearing mice. The C26 tumor model is characterized by pronounced body weight (BW) loss and muscle wasting in the absence of severe anorexia. We analyzed the time course of BW loss, body composition, muscle mass, bone mineral density, and the cytokines interleukin-6 (IL-6) and macrophage-inhibitory cytokine-1 (MIC-1). Moreover, we measured the expression of the muscle degradation markers muscle RING-finger-protein-1 (MuRF-1) and muscle atrophy F-box (MAFbx). After tumor inoculation, MIC-1 levels increased earlier than IL-6 and both cytokines were elevated before MuRF-1/MAFbx expression increased. Oral HM01 treatment increased BW, fat mass, and neuronal hypothalamic activity in healthy mice. In tumor-bearing mice, HM01 increased food intake, BW, fat mass, muscle mass, and bone mineral density while it decreased energy expenditure. These effects appeared to be independent of IL-6, MIC-1, MuRF-1 or MAFbx, which were not affected by HM01. Therefore, HM01 counteracts cachectic body weight loss under inflammatory conditions and is a promising compound for the treatment of cancer cachexia in the absence of severe anorexia.

Practical and theoretical implications of weight gain in advanced non-small cell lung cancer patients

Involuntary weight loss occurs frequently in individuals with many types of cancers and was shown to be associated with inferior survival almost 40 years ago (1). More recently, there is evidence that weight loss prior to initiation of systemic anti-cancer therapies is associated with increased treatment related side effects (2,3). The majority of these patients are suffering from the cancer anorexia cachexia syndrome. In 2011, a panel of cancer cachexia experts published a consensus statement which defined and classified cancer cachexia (4). This group pointed out that the predominant feature of this syndrome includes loss of skeletal muscle mass which cannot be reversed by conventional nutritional support and which may or may not be accompanied by loss of body fat. Their consensus for diagnostic criteria for cancer cachexia are weight loss greater than 5% in individuals with body mass index (BMI) of ≥20 during the preceding 6 months and 2% weight loss in individuals with BMI <20. They also defined stages of cachexia as pre cachexia (<5% weight loss), cachexia as defined above, and refractory cachexia which is usually associated with progressive cancer and poor performance status.

Plasma Ghrelin Levels Are Associated with Anorexia but Not Cachexia in Patients with NSCLC.

Background and Aims: The ghrelin receptor is one of the new therapeutic targets in the cancer anorexia-cachexia syndrome. Previous studies revealed that plasma ghrelin levels were high in patients with anorexia nervosa and low in obese subjects. We studied to what extent ghrelin levels are related with anorexia and cachexia in patients with cancer.Materials and Methods: Fasted ghrelin levels were determined as well as anorexia and cachexia in patients with stage III/IV non-small cell lung cancer before chemotherapy. Total plasma ghrelin was measured by radioimmunoassay. Anorexia was measured with the FAACT-A/CS questionnaire (cut-off value ≤ 37). Cachexia was determined as >5% weight loss (WL) in 6 months or >2% WL in 6 months in combination with low BMI or low muscle mass. The Kruskal-Wallis test was performed to assess differences in plasma ghrelin levels between four groups: patients with (+) or without (−) anorexia (A) or cachexia (C). Multiple regression analyses were performed to assess differences in plasma ghrelin levels between patients C+ and C− and patients with A+ and A− (adjusted for age and sex).Results: Forty patients with stage III (33%) or stage IV (68%) were recruited, of which 50% was male. Mean age was 59.6 ± 10.3 years. Sixteen patients had no anorexia or cachexia (A−C−), seven patients had both anorexia and cachexia (A+C+), ten patients had anorexia without cachexia (A+C−) and seven patients had cachexia without anorexia (A−C+). The levels of total plasma ghrelin were significantly different between the four groups of patients with or without anorexia or cachexia (p = 0.032): the A+C− patients had significantly higher ghrelin levels [median (IQR): 1,754 (1,404–2,142) compared to the A−C+ patients 1,026 (952–1,357), p = 0.003]. A+ patients had significantly higher ghrelin levels compared A− patients (C+ and C− combined, β: 304, p = 0.020). Plasma ghrelin levels were not significantly different in C+ patients compared to C− patients (A+ and A− combined, β: −99, p = 0.450).Conclusions: Patients with anorexia had significantly higher ghrelin levels compared to patients without anorexia. We therefore hypothesize that patients with cancer anorexia might benefit from treatment with a ghrelin receptor agonist to prevent WL and deterioration in physical functioning.

Protein calorie malnutrition, nutritional intervention and personalized cancer care

Cancer patients often experience weight loss caused by protein calorie malnutrition (PCM) during the course of the disease or treatment. PCM is expressed as severe if the patient has two or more of the following characteristics: obvious significant muscle wasting, loss of subcutaneous fat; nutritional intake of <50% of recommended intake for 2 weeks or more; bedridden or otherwise significantly reduced functional capacity; weight loss of >2% in 1 week, 5% in 1 month, or 7.5% in 3 months. Cancer anorexia-cachexia syndrome (CACS) is a multifactorial condition of advanced PCM associated with underlying illness (in this case cancer) and is characterized by loss of muscle with or without loss of fat mass. Cachexia is defined as weight loss of more than 5% of body weight in 12 months or less in the presence of chronic disease. Hence with a chronic illness on board even a small amount of weight loss can open the door to cachexia. These nutritional challenges can lead to severe morbidity and mortality in cancer patients. In the clinic, the application of personalized medicine and the ability to withstand the toxic effects of anti-cancer therapies can be optimized when the patient is in nutritional homeostasis and is free of anorexia and cachexia. Routine assessment of nutritional status and appropriate intervention are essential components of the effort to alleviate effects of malnutrition on quality of life and survival of patients.

Anamorelin for cancer anorexia-cachexia syndrome: a systematic review and meta-analysis.

The aim of this study was to evaluate the therapeutic effects of Anamorelin on patients with cancer anorexia-cachexia syndrome (CACS) based on a meta-analysis of published randomized trials. We searched PubMed, Embase, Medline, and the Cochrane Central Register of Controlled Trials databases. Data from each selected study were evaluated individually. All continuous outcomes were calculated by the mean difference or standardized mean difference with 95% confidence interval for each study. Heterogeneity was assessed by using the Chi2 test at a significance level of P<0.1, in addition to the I 2 statistic (I 2>50% indicated substantial heterogeneity). At last, four studies were included from 284 records. In three studies, lean body mass was reported and there was a significant difference between placebo and Anamorelin groups (P<0.00001), without significant heterogeneity (I 2=0%). All the four studies reported the body weight change from baseline, and there was significant difference between placebo and Anamorelin groups (P=0.007), but with high heterogeneity (I 2=97%). Two studies reported Anderson Symptom Assessment Scale (ASAS) score, and Anamorelin significantly increased the total ASAS score of CACS patients (P<0.00001), without any heterogeneity (I 2=0%). Three studies reported non-dominant handgrip strength, and there was no significant difference between Anamorelin and placebo groups (P=0.16). Three studies reported insulin-like growth factor-1 level, and there was significant difference between Anamorelin and placebo groups (P=0.02), but with high heterogeneity (I 2=96%). Three studies reported IGF binding protein-3 concentration. Anamorelin significantly increased such concentration compared with placebo did (P<0.00001). However, there was still higher heterogeneity (I 2=59%). All the included studies reported adverse events. Compared with placebo, Anamorelin induced fewer adverse events, but there was no significant difference between the two groups (RR=0.07, P=0.35). In the included studies, Anamorelin had some positive effects to relieve the symptoms and improved the quality of life. However, the heterogeneity was apparent, so the clinical effects of Anamorelin should be further validated by increasing the sample size, varying the range of doses during treatment, and observing other outcomes. We are still confident for the future application of Anamorelin in phase III clinical trials.

Anorexia-cachexia syndrome in hepatoma tumour-bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC-1/GDF15.

BackgroundThe cancer‐anorexia‐cachexia syndrome (CACS) negatively affects survival and therapy success in cancer patients. Inflammatory mediators and tumour‐derived factors are thought to play an important role in the aetiology of CACS. However, the central and peripheral mechanisms contributing to CACS are insufficiently understood. The area postrema (AP) and the nucleus tractus solitarii are two important brainstem centres for the control of eating during acute sickness conditions. Recently, the tumour‐derived macrophage inhibitory cytokine‐1 (MIC‐1) emerged as a possible mediator of cancer anorexia because lesions of these brainstem areas attenuated the anorectic effect of exogenous MIC‐1 in mice.MethodsUsing a rat hepatoma tumour model, we examined the roles of the AP and of vagal afferents in the mediation of CACS. Specifically, we investigated whether a lesion of the AP (APX) or subdiaphragmatic vagal deafferentation (SDA) attenuate anorexia, body weight, muscle, and fat loss. Moreover, we analysed MIC‐1 levels in this tumour model and their correlation with tumour size and the severity of the anorectic response.ResultsIn tumour‐bearing sham‐operated animals mean daily food intake significantly decreased. The anorectic response was paralleled by a significant loss of body weight and muscle mass. APX rats were protected against anorexia, body weight loss, and muscle atrophy after tumour induction. In contrast, subdiaphragmatic vagal deafferentation did not attenuate cancer‐induced anorexia or body weight loss. Tumour‐bearing rats had substantially increased MIC‐1 levels, which positively correlated with tumour size and cancer progression and negatively correlated with food intake.ConclusionsThese findings demonstrate the importance of the AP in the mediation of cancer‐dependent anorexia and body weight loss and support a pathological role of MIC‐1 as a tumour‐derived factor mediating CACS, possibly via an AP‐dependent action.