Cancer Anorexia-cachexia Research Articles

MCG101-induced cancer anorexia-cachexia features altered expression of hypothalamic Nucb2 and Cartpt and increased plasma levels of cocaine- and amphetamine-regulated transcript peptides.

The aim of the present study was to explore central and peripheral host responses to an anorexia-cachexia producing tumor. We focused on neuroendocrine anorexigenic signals in the hypothalamus, brainstem, pituitary and from the tumor per se. Expression of mRNA for corticotropin-releasing hormone (CRH), cocaine- and amphetamine-regulated transcript (CART), nesfatin-1, thyrotropin (TSH) and the TSH receptor were explored. In addition, we examined changes in plasma TSH, CART peptides (CARTp) and serum amyloid P component (SAP). C57BL/6 mice were implanted with MCG101 tumors or sham-treated. A sham-implanted, pair‑fed (PF) group was included to delineate between primary tumor and secondary effects from reduced feeding. Food intake and body weight were measured daily. mRNA levels from microdissected mouse brain samples were assayed using qPCR, and plasma levels were determined using ELISA. MCG101 tumors expectedly induced anorexia and loss of body weight. Tumor-bearing (TB) mice exhibited an increase in nesfatin-1 mRNA as well as a decrease in CART mRNA in the paraventricular area (PVN). The CART mRNA response was secondary to reduced caloric intake whereas nesfatin-1 mRNA appeared to be tumor-specifically induced. In the pituitary, CART and TSH mRNA were upregulated in the TB and PF animals compared to the freely fed controls. Plasma levels for CARTp were significantly elevated in TB but not PF mice whereas levels of TSH were unaffected. The plasma CARTp response was correlated to the degree of inflammation represented by SAP. The increase in nesfatin-1 mRNA in the PVN highlights nesfatin-1 as a plausible candidate for causing tumor-induced anorexia. CART mRNA expression in the PVN is likely an adaptation to reduced caloric intake secondary to a cancer anorexia-cachexia syndrome (CACS)‑inducing tumor. The MCG101 tumor did not express CART mRNA, thus the elevation of plasma CARTp is host derived and likely driven by inflammation.

Anorexia-cachexia and obesity treatment may be two sides of the same coin: role of the TGF-b superfamily cytokine MIC-1/GDF15.

Anorexia-cachexia associated with cancer and other diseases is a common and often fatal condition representing a large area of unmet medical need. It occurs most commonly in advanced cancer and is probably a consequence of molecules released by tumour cells, or tumour-associated interstitial or immune cells. These may then act directly on muscle to cause atrophy and/or may cause anorexia, which then leads to loss of both fat and lean mass. Although the aetiological triggers for this syndrome are not well characterized, recent data suggest that MIC-1/GDF15, a transforming growth factor-beta superfamily cytokine produced in large amounts by cancer cells and as a part of other disease processes, may be an important trigger. This cytokine acts on feeding centres in the hypothalamus and brainstem to cause anorexia leading to loss of lean and fat mass and eventually cachexia. In animal studies, the circulating concentrations of MIC-1/GDF15 required to cause this syndrome are similar to those seen in patients with advanced cancer, and at least some epidemiological studies support an association between MIC-1/GDF15 serum levels and measures of nutrition. This article will discuss its mechanisms of central appetite regulation, and the available data linking this action to anorexia-cachexia syndromes that suggest it is a potential target for therapy of cancer anorexia-cachexia and conversely may also be useful for the treatment of severe obesity.

Prognostication of Survival in Patients With Advanced Cancer: Predicting the Unpredictable?

Prognosis is a key driver of clinical decision-making. However, available prognostication tools have limited accuracy and variable levels of validation. Principles of survival prediction and literature on clinician prediction of survival, prognostic factors, and prognostic models were reviewed, with a focus on patients with advanced cancer and a survival rate of a few months or less. The 4 principles of survival prediction are (a) prognostication is a process instead of an event, (b) prognostic factors may evolve over the course of the disease, (c) prognostic accuracy for a given prognostic factor/ tool varies by the definition of accuracy, the patient population, and the time frame of prediction, and (d) the exact timing of death cannot be predicted with certainty. Clinician prediction of survival is the most commonly used approach to formulate prognosis. However, clinicians often overestimate survival rates with the temporal question. Other clinician prediction of survival approaches, such as surprise and probabilistic questions, have higher rates of accuracy. Established prognostic factors in the advanced cancer setting include decreased performance status, delirium, dysphagia, cancer anorexia-cachexia, dyspnea, inflammation, and malnutrition. Novel prognostic factors, such as phase angle, may improve rates of accuracy. Many prognostic models are available, including the Palliative Prognostic Score, the Palliative Prognostic Index, and the Glasgow Prognostic Score. Despite the uncertainty in survival prediction, existing prognostic tools can facilitate clinical decision-making by providing approximated time frames (months, weeks, or days). Future research should focus on clarifying and comparing the rates of accuracy for existing prognostic tools, identifying and validating novel prognostic factors, and linking prognostication to decision-making.

Evidence for partial pharmaceutical reversal of the cancer anorexia-cachexia syndrome: the case of anamorelin.

A major component of the cancer anorexia-cachexia syndrome is a decline in food intake. Up until now none of the drugs that improve appetite also improve skeletal muscle. Recent studies have suggested that the oral ghrelin-analog, anamorelin, increased food intake and muscle mass. Unfortunately, it does not increase muscle power. Its regulatory future is uncertain, although it has important clinical effects.

Anorexia in human and experimental animal models: physiological aspects related to neuropeptides.

Anorexia, a loss of appetite for food, can be caused by various physiological and pathophysiological conditions. In this review, firstly, clinical aspects of anorexia nervosa are summarized in brief. Secondly, hypothalamic neuropeptides responsible for feeding regulation in each hypothalamic nucleus are discussed. Finally, three different types of anorexigenic animal models; dehydration-induced anorexia, cisplatin-induced anorexia and cancer anorexia-cachexia, are introduced. In conclusion, hypothalamic neuropeptides may give us novel insight to understand and find effective therapeutics strategy essential for various kinds of anorexia.

Nutritional support in Cancer Anorexia-Cachexia Syndrome: The reality in light of the facts

Cachexia develops in approximately 50% of cancer patients during their disease progression. In the International Consensus of Amsterdam cancer cachexia defined as a multifactorial syndrome characterized by ongoing loss of skeletal muscle mass that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. The consensus identified three stages of cachexia: precachexia, cachexia, and refractory cachexia. Severity is classified based on degree of depletion of energy stores, body protein mass and rate of ongoing weight loss. Cancer anorexia-cachexia syndrome (CACS) has negative impact on physical function, anticancer treatment response, quality of life and survival. The interactions between tumor and host are responsible not only for tumor progression, but also for chronic inflammation. The CACS associated changes in carbohydrate, protein and lipid metabolism are caused by the elevated level of inflammatory cytokines. In consistency with the multi-factorial pathogenesis of CACS, it is widely recognized that a multimodal treatment approach is necessary. Currently there is no guideline on clinical management of CACS. Although more and more drug targets are proposed based on research in animal models, only few pharmacological treatments have been translated into clinical practice. In this work we summarize the current nutritional and pharmacological approaches to treat CACS, and the results of clinical trials. However, it is undeniable that, there is a paradigm shift in CACS treatment. The traditional nutritional support is replaced by combination of pharmaceutical interventions, nutritional support and use of dietary supplements.

Current and future care of patients with the cancer anorexia-cachexia syndrome.

Many important advances have occurred in the field of cancer cachexia over the past decade, including progress in understanding the mechanisms of the cancer anorexia-cachexia syndrome (CACS) and the development of promising pharmacologic and supportive care interventions. However, no approved agents for cancer cachexia currently exist, emphasizing the unmet need for an effective pharmacologic therapy. This article reviews the key elements of CACS assessment in daily practice, the contribution of nutritional impact symptoms (NIS), the evidence for current pharmacologic options, and promising anticachexia agents in perclinical and clinical trials. It also proposes a model for multimodality therapy and highlights issues pertinent to CACS in patients with pancreatic, gastric, and esophageal cancer.

Health professionals' attitudes toward the detection and management of cancer-related anorexia-cachexia syndrome, and a proposal for standardized assessment.

The identification and management of patients with cancer anorexia-cachexia syndrome (CACS) can be a challenge despite recent international consensus on the definition of the condition. To describe the current views and practice patterns of community oncologists and oncology nurses in regard to CACS and to propose a standardized, pragmatic assessment of CACS for oncological practice. Responses from 151 community oncologists and nurses obtained across 5 surveys were analyzed. Questions addressed CACS in general and in patients with non-small-cell lung cancer (NSCLC). Surveys 1-3 were directed at physicians, and surveys 4 and 5 were directed at nurses. Surveys 1, 2, 4, and 5 focused on the recognition and monitoring of CACS, and Survey 3 on symptom management. 67% of medical oncologists in Survey 3 selected weight loss as the most important criterion for diagnosing CACS and cited declining appetite and performance status (PS) as the most bothersome effects for patients and families. Weight maintenance/gain was the primary treatment objective for oncologists. Respondents to surveys 1 and 2 acknowledged the risk for CACS is high (60%) in NSCLC but considered the risk much lower (4%) in patients completing a first course of therapy with good PS. 91% of oncologists in Survey 3 reported that symptoms that had an impact on calorie intake were important/very important, and 73% were willing to consider a symptom assessment instrument that included appetite. Nurses in surveys 4 and 5 reported weight loss and appetite were most commonly used to identify cachexia. They considered responsibility for the initial assessment of cachexia was the oncologist's (32%), followed by the nurse practitioner (28%), and the nurse (16%). Most oncologists and nurses recognize the core criteria for the CACS, although there may be under-recognition of the condition's prevalence, particularly earlier in the course of treatment. There is considerable interest in adopting a brief assessment tool for screening, management, and referral of patients who are affected by or at-risk of CACS.

What bothers lung cancer patients the most? A prospective, longitudinal electronic patient-reported outcomes study in advanced non-small cell lung cancer.

Patients with advanced non-small cell lung cancer (aNSCLC) face a significant symptom burden. Little is known about the frequency and severity of symptoms over time, so we longitudinally characterized patients' symptoms using the Patient Care Monitor (PCM) version 2.0, an electronic symptom-assessment tool. Ninety-seven patients with aNSCLC completed the PCM at up to four clinic visits. We analyzed symptom data by incidence, severity, type (functional vs. nonfunctional), proximity to death, and cancer anorexia-cachexia syndrome status (CACS). Functional concerns predominated, even in the non-CACS group. Average severity among the top 5 symptoms was worse for functional than nonfunctional items (mean difference 0.62, 95% CI 0.22-1.01, P = 0.003). Severe dyspnea and fatigue were the most prevalent nonfunctional symptoms; moderate/severe dyspnea was reported by at least 29% of patients, and fatigue by over 50%. Depression was reported infrequently, with over half of patients at each visit reporting "none"; moderate or severe depression was reported in only 2.5-9.3 and 3.4-6.2% of patients, respectively. The average number of moderate/severe symptoms increased with proximity to death; 84% reported moderate/severe fatigue in the last 3 months of life, compared to 48% at ≥ 12 months from death (P = 0.007). Patients with aNSCLC face a significant symptom burden, which increases with proximity to death. Symptom type and severity vary by proximity to death, but even patients without overt CACS report significant functional symptoms throughout. We recommend an individualized approach to palliative symptom intervention in advanced lung cancer, based on detailed symptom assessment and tracking.

Validation and real-world assessment of the Functional Assessment of Anorexia-Cachexia Therapy (FAACT) scale in patients with advanced non-small cell lung cancer and the cancer anorexia-cachexia syndrome (CACS).

Patients with cancer anorexia-cachexia syndrome (CACS) suffer a significant symptom burden, impaired quality of life (QoL), and shorter survival. Measurement of QoL impairments related to CACS is thereby important both in clinical practice and in research. We aimed to further validate the Functional Assessment of Anorexia-Cachexia Therapy (FAACT) scale in an advanced lung cancer population. We tested the performance of the FAACT and its anorexia-cachexia subscale (ACS) within a dataset of patients with advanced non-small cell lung cancer (aNSCLC), using standard statistical methods. We then compared the performance of commonly used QoL measures stratified by CACS status and by patient self-report of appetite and weight loss. The FAACT and its ACS demonstrate internal validity consistent with acceptable published ranges for other QoL scales (Cronbach alpha = 0.9 and 0.79, respectively). Correlation coefficients demonstrate moderate correlations in the expected directions between FAACT and ACS and scales that measure related constructs. Comparing patients with and without CACS, the ACS is more sensitive to change than other QoL instruments (mean score 33.1 vs. 37.2, p = 0.011, ES = 0.58). In patients with aNSCLC, the FAACT and its ACS performed well compared with other instruments, further supporting their validity and value in clinical research. FAACT and ACS scores covaried with symptoms and other QoL changes that are typical hallmarks of CACS, lending further support to their use as QoL endpoints in clinical trials among patients with CACS.

Anamorelin for patients with cancer cachexia: an integrated analysis of two phase 2, randomised, placebo-controlled, double-blind trials

Cancer anorexia-cachexia syndrome is associated with increased morbidity and mortality. Anamorelin is an oral ghrelin-receptor agonist with appetite-enhancing and anabolic activity. We assessed the effects of anamorelin on body composition, strength, quality of life, biochemical markers, and safety in patients with cancer anorexia-cachexia. Data were pooled, a priori, from two completed phase 2, multicentre, placebo-controlled, double-blind trials in patients with advanced or incurable cancer and weight loss of 5% or more. Patients were stratified by weight loss severity (5-15%, >15%) and randomly allocated (1:1) with a computer-generated randomisation schedule to anamorelin hydrochloride 50 mg or placebo once-daily for 12 weeks. Primary outcome was lean body mass by dual-energy x-ray absorptiometry over the 12 week treatment period in eligible patients who had at least one dose of study drug and post-treatment efficacy assessment. We assessed safety in all patients who received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT00219817 and NCT00267358. Between June 29, 2005, and Oct 26, 2006, we enrolled 44 patients in the anamorelin group and 38 patients in the placebo group. 74 patients were eligible for the efficacy analyses. Over 12 weeks, lean body mass increased in 38 patients in the anamorelin group by a least-squares mean of 1.89 kg (95% CI 0.84 to 2.95) compared with a decrease of a least-squares mean of -0.20 kg (-1.23 to 0.83) for 36 patients in the placebo group (difference 2.09 kg [0.94-3.25]; p=0.0006). 42 (95%) of 44 patients treated with anamorelin and 33 (87%) of 38 patients treated with placebo had adverse events. The most common grade 3-4 adverse events (treatment-related or not) in the anamorelin group were fatigue, asthenia, atrial fibrillation, and dyspnoea (two [5%] each); in the placebo group, such events were pneumonia (three [8%]) and anaemia, thrombocytopenia, abdominal pain, anxiety, and dyspnoea (two [5%] each). Anamorelin treatment for 12 weeks had a favourable clinical response profile in patients with cancer anorexia-cachexia syndrome. These findings support further investigation in this setting. Helsinn Therapeutics (US), Helsinn Healthcare SA.

Correlation Between the International Consensus Definition of the Cancer Anorexia-Cachexia Syndrome (CACS) and Patient-Centered Outcomes in Advanced Non-Small Cell Lung Cancer

ContextThe cancer anorexia-cachexia syndrome (CACS) is common in patients with advanced solid tumors and is associated with adverse outcomes including poor quality of life (QOL), impaired functioning, and shortened survival. ObjectivesTo apply the recently posed weight-based international consensus CACS definition to a population of patients with advanced non-small cell lung cancer (NSCLC) and explore its impact on patient-reported outcomes. MethodsNinety-nine patients participated in up to four study visits over a six-month period. Longitudinal assessments included measures of physical function, QOL, and other clinical variables such as weight and survival. ResultsPatients meeting the consensus CACS criteria at Visit 1 had a significantly shorter median survival (239.5 vs. 446 days; hazard ratio, 2.06, P < 0.05). Physical function was worse in the CACS group (mean Karnofsky Performance Status score 68 vs. 77, Eastern Cooperative Oncology Group Performance Status score 1.8 vs. 1.3, P < 0.05 for both), as was QOL (Functional Assessment of Cancer Therapy-General [FACT-G] Lung Cancer subscale of 17.2 vs. 19.9, Anorexia/Cachexia subscale of 31.4 vs. 37.9, P < 0.05 for both). Differences in the FACT-G and the Functional Assessment of Chronic Illness Therapy-Fatigue subscale approached but did not reach statistical significance. Longitudinally, all measures of physical function and QOL worsened regardless of CACS status, but the rate of decline was more rapid in the CACS group. ConclusionThe weight-based component of the recently proposed international consensus CACS definition is useful in identifying patients with advanced NSCLC who are likely to have significantly inferior survival and who will develop more precipitous declines in physical function and QOL. This definition may be useful for clinical screening purposes and identify patients with high palliative care needs.

The importance of communication about cachexia as experienced by patients and caregivers: A qualitative cross-cultural study.

37 Background: Cancer Anorexia-Cachexia Syndrome (CACS) is a multifactorial condition defined by an ongoing loss in body weight that cannot be fully reversed through conventional nutritional support and leads to progressive functional impairment. This condition has for a long time been misrecognized and underdiagnosed. Furthermore, the burden of CACS as experienced and depicted by patients and caregivers has not been deeply explored so far. Methods: This was a narrative qualitative cross-cultural study (IT, ES, UK, DE, US) based on the collection of 30 weekly emotional diaries followed by 30 semi-structured in-depth interviews to caregivers (i.e. relatives, partners, close friends) of patients diagnosed with CACS. The aim was to understand how the disease is experienced by patients and caregivers, their feelings and unmet needs. Results: Caregivers and patients demonstrate a poor knowledge of CACS: while they spontaneously refer to a pattern of CACS symptoms, they do not verbalize the term “cachexia”. The awareness and levels of engagement in managing CACS by caregivers appear to be dependent on the degree and timing of communication on this condition with the physician: those who express a higher sense of powerlessness and despair also report that their doctor has never explicitly mentioned CACS, nor indicated any strategies to manage it. On the other hand, those who appear more confident and engaged in managing CACS report a more detailed and earlier communication on the subject. Conclusions: Scarce and/or late communication on CACS and its management options with patients and caregivers may result in a sense of powerlessness and ignorance on how to manage its symptoms. In line with the recently reported importance of an early CACS recognition [(Aapro M et al, Ann Oncol (2014). 2014 May 2)], an earlier and thorough discussion about CACS with patients and caregivers would improve their level of engagement and help relieve some of their distress.

Anamorelin for the Treatment of Cancer Anorexia-Cachexia in Advanced NSCLC Patients: Results From ROMANA 1, a Pivotal Phase 3 Study: Supportive Care/Palliation/Nursing

Anamorelin for the Treatment of Cancer Anorexia-Cachexia in Advanced NSCLC Patients: Results From ROMANA 1, a Pivotal Phase 3 Study: Supportive Care/Palliation/Nursing

Therapeutic potential of phytocannabinoids in cancer anorexia-cachexia syndrome

Therapeutic potential of phytocannabinoids in cancer anorexia-cachexia syndrome

Anamorelin HCl (ONO-7643), a novel ghrelin receptor agonist, for the treatment of cancer anorexia-cachexia syndrome: preclinical profile.

BackgroundAnamorelin HCl (ANAM) is a novel, orally active, ghrelin receptor agonist in clinical development for the treatment of cancer cachexia. We report in vitro and in vivo studies evaluating the preclinical pharmacologic profile of ANAM.MethodsFluorescent imaging plate reader and binding assays in HEK293 and baby hamster kidney cells determined the agonist and antagonist activity of ANAM, and its affinity for the ghrelin receptor. Rat pituitary cells were incubated with ANAM to evaluate its effect on growth hormone (GH) release. In vivo, rats were treated with ANAM 3, 10, or 30 mg/kg, or control orally, once daily for 6 days to evaluate the effect on food intake (FI) and body weight (BW), and once to assess GH response. In pigs, single (3.5 mg/kg) or continuous (1 mg/kg/day) ANAM doses were administered to assess GH and insulin-like growth factor (IGF-1) response.ResultsANAM showed significant agonist and binding activity on the ghrelin receptor, and stimulated GH release in vitro. In rats, ANAM significantly and dose-dependently increased FI and BW at all dose levels compared with control, and significantly increased GH levels at 10 or 30 mg/kg doses. Increases in GH and IGF-1 levels were observed following ANAM administration in pigs.ConclusionANAM is a potent and highly specific ghrelin receptor agonist with significant appetite-enhancing activity, leading to increases in FI and BW, and a stimulatory effect on GH secretion. These results support the continued investigation of ANAM as a potential treatment of cancer anorexia-cachexia syndrome.

Anamorelin for the Treatment of Cancer Anorexia-Cachexia in Nsclc: Results from the Phase 3 Studies Romana 1 and 2

ABSTRACT Background: Cancer anorexia-cachexia syndrome is a common debilitating condition, characterized by decreased body weight, mainly lean body mass (LBM) and negatively impacts quality of life and prognosis. Anamorelin HCl (ANAM) is a novel selective ghrelin receptor agonist with appetite-enhancing and anabolic activity. Methods: These were two international, double-blind, Phase 3 trials assessing ANAM efficacy and safety in patients with unresectable Stage III/IV NSCLC, ECOG 0-2 and cachexia (≥5% weight loss within prior 6 months or BMI Results: There were no within-study population differences for ROMANA 1 (N = 484) and ROMANA 2 (N = 495). Over 12 weeks, ANAM significantly increased LBM vs placebo (p Conclusions: In two global, large-scale Phase 3 studies, ANAM for 12 weeks was well tolerated, and significantly improved LBM, body weight, and anorexia-cachexia symptoms/concerns in advanced NSCLC patients with cachexia. Disclosure: K. Fearon: has received research funding from Helsinn; L. Gleich: is an employee of Medpace, Inc. Y. Yan and J. Friend: is an employee of Helsinn Therapeutics (US), Inc.; A. Abernethy: Received research funding from DARA, Celgene, Helsinn, Bristol-Myers Squibb (BMS), Dendreon, GSK, Pfizer; has consulting agreements with BMS and ACORN Research; is on the Board of Directors of athenahealth (a health information technology company).All other authors have declared no conflicts of interest.

Anamorelin for the treatment of cancer anorexia-cachexia: Baseline characteristics from three phase III clinical trials (the ROMANA program).

e20694 Background: Cancer anorexia-cachexia (CACS) is a frequent, debilitating and life-threatening multifactorial syndrome in which altered metabolism, inflammation, and reduced food intake contri...

Correlation between the international consensus definition of the cancer anorexia cachexia syndrome (CACS) and patient outcomes in advanced non-small cell lung cancer (NSCLC).

e19042 Background: CACS is a problematic clinical syndrome, difficult to objectively define. A consensus-derived, weight-based definition has been proposed. An observational study was analyzed to e...

Relationship of guarana (Paullinia cupana) on anorexia in patients with advanced cancer.

e20532 Background: Anorexia is prevalent in cancer patients with advanced disease. There are currently some treatments for cancer anorexia-cachexia syndrome (CACS), including corticosteroids, progestogens, cannabinoids and anabolic steroids. However, none of these treatments alone increases appetite and weight with few side effects. In this pilot phase II, open label, non-randomized trial, we evaluated the efficacy and safety of guarana (Paullinia cupana) in patients with cancer and weight loss. Methods: We included advanced cancer patients with decreased appetite and weight loss of more than 5% from their baseline in the past 6 months. All of the patients received 50 mg of the crude dry extract of guarana twice a day for 4 weeks. The trial was designed in 2 phases (Simon model). We considered a positive response in the first phase to be at least 5% weight gain or a 3-point improvement in the appetite scale in at least 3 of the first 18 evaluable patients. Results: Of the 34 eligible patients, 30 were included and 18 completed the protocol. Only 1 patient abandoned the protocol due to toxicity (grade II arthralgia). There were no grade 3 or 4 toxicities. There were no significant differences in nausea, weight loss and quality of life (FACT-G). Only 2 of the 18 patients who completed the study had weight gain above 5% from their baseline, whereas 6 patients had at least a 3-point improvement in the visual appetite scale. The M.D. Anderson Symptom Inventory (MDASI) was used to evaluate several symptoms, and we observed a significant decrease in lack of appetite (p=0.02) and in somnolence (p=0.0142). Conclusions: We concluded that the weight stabilization and increased appetite we observed in this study justify further studies of guarana in this patient population. Clinical trial information: NCT01540019.