Cancer Anorexia Research Articles

Pathophysiology of anorexia in the cancer cachexia syndrome.

Anorexia is commonly present in persons with cancer and a major component of cancer cachexia. There are multiple causes of anorexia in cancer. Peripherally, these can be due to (i) substances released from or by the tumour, e.g. pro-inflammatory cytokines, lactate, and parathormone-related peptide; (ii) tumours causing dysphagia or altering gut function; (iii) tumours altering nutrients, e.g. zinc deficiency; (iv) tumours causing hypoxia; (v) increased peripheral tryptophan leading to increased central serotonin; or (vi) alterations of release of peripheral hormones that alter feeding, e.g. peptide tyrosine tyrosine and ghrelin. Central effects include depression and pain, decreasing the desire to eat. Within the central nervous system, tumours create multiple alterations in neurotransmitters, neuropeptides, and prostaglandins that modulate feeding. Many of these neurotransmitters appear to produce their anorectic effects through the adenosine monophosphate kinase/methylmalonyl coenzyme A/fatty acid system in the hypothalamus. Dynamin is a guanosine triphosphatase that is responsible for internalization of melanocortin 4 receptors and prostaglandin receptors. Dynamin is up-regulated in a mouse model of cancer anorexia. A number of drugs, e.g. megestrol acetate, cannabinoids, and ghrelin agonists, have been shown to have some ability to be orexigenic in cancer patients.

OR018: Cancer Anorexia: Assessment of Hypothalamic Dysfunction by Functional Magnetic Resonance Imaging (FMRI) and Its Association with Inflammation, Ghrelin, and Leptin in Lung Cancer Patients

OR018: Cancer Anorexia: Assessment of Hypothalamic Dysfunction by Functional Magnetic Resonance Imaging (FMRI) and Its Association with Inflammation, Ghrelin, and Leptin in Lung Cancer Patients

A preliminary study of attitudes toward the assessment and management of cancer cachexia among medical oncologists and nurses.

44 Background: A recent international consensus on the definition and classification of the cancer anorexia / cachexia syndrome (CACS) will facilitate clinical trial design, development of practice guidelines, and routine clinical management. Non-pharmacological interventions such as dietary counseling and promising new drugs have demonstrated improved outcomes in preliminary trials. Management of nutritional impact symptoms such as severe pain, depression, early satiety and chronic nausea also produce weight gain. These important advances contrast with the apparent low priority given to this condition by oncological societies worldwide. Our objective was to evaluate the attitudes of medical oncologists and nurses in the assessment and management of CACS in non-small cell lung cancer. Methods: Surveys were administered electronically to US-based, community medical oncologists (n=76 respondents) and oncology nurses (n=25), members of the Sermo research database which includes over 275,000 active healthcare providers, pre-qualified through telephone or online screening. A proprietary MedPulse tool achieved random geographic distribution of respondents through a staged query–response process. Results: 67% of medical oncologists selected weight loss as the most important criterion for diagnosing CACS in their daily practice, consistent with the consensus definition. However, only 4% of respondents described CACS as inevitable or very likely to develop in patients maintaining good performance status through first-line therapy. Community providers identified the management of symptoms that affect appetite as very important (58.8%), important (31.4%) or somewhat important (7.8%), but only 9.8% indicated they currently use a formal tool to evaluate these symptoms. 72% would consider using a brief assessment tool in clinical practice. Conclusions: Our surveys suggest community oncologists recognize the core criteria for the diagnosis of CACS, although there may be under-recognition of the condition’s prevalence. There is considerable interest in adopting a brief symptom assessment tool for screening, management and referral of affected or at-risk patients.

Hypothalamic S1P/S1PR1 axis controls energy homeostasis

Sphingosine 1-phosphate receptor 1 (S1PR1) is a G-protein-coupled receptor for sphingosine-1-phosphate (S1P) that has a role in many physiological and pathophysiological processes. Here we show that the S1P/S1PR1 signalling pathway in hypothalamic neurons regulates energy homeostasis in rodents. We demonstrate that S1PR1 protein is highly enriched in hypothalamic POMC neurons of rats. Intracerebroventricular injections of the bioactive lipid, S1P, reduce food consumption and increase rat energy expenditure through persistent activation of STAT3 and the melanocortin system. Similarly, the selective disruption of hypothalamic S1PR1 increases food intake and reduces the respiratory exchange ratio. We further show that STAT3 controls S1PR1 expression in neurons via a positive feedback mechanism. Interestingly, several models of obesity and cancer anorexia display an imbalance of hypothalamic S1P/S1PR1/STAT3 axis, whereas pharmacological intervention ameliorates these phenotypes. Taken together, our data demonstrate that the neuronal S1P/S1PR1/STAT3 signalling axis plays a critical role in the control of energy homeostasis in rats.

PP088-SUN: Evaluation of Hypothalamic Activity in Cancer Anorexia by Functional Magnetic Resonance

PP088-SUN: Evaluation of Hypothalamic Activity in Cancer Anorexia by Functional Magnetic Resonance

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...

Effect of Sipjeondaebo-tang on cancer-induced anorexia and cachexia in CT-26 tumor-bearing mice.

Cancer-associated anorexia and cachexia are a multifactorial condition described by a loss of body weight and muscle with anorexia, asthenia, and anemia. Moreover, they correlate with a high mortality rate, poor response to chemotherapy, poor performance status, and poor quality of life. Cancer cachexia is regulated by proinflammatory cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α). In addition, glucagon like peptide-1 (GIP-1), peptide YY (PYY), ghrelin, and leptin plays a crucial role in food intake. In this study, we investigated the therapeutic effects of one of the traditional herbal medicines, Sipjeondaebo-tang (Juzen-taiho-to in Japanese; SJDBT), on cancer anorexia and cachexia in a fundamental mouse cancer anorexia/cachexia model, CT-26 tumor-bearing mice. SJDBT was more significantly effective in a treatment model where it was treated after anorexia and cachexia than in a prevention model where it was treated before anorexia and cachexia on the basis of parameters such as weights of muscles and whole body and food intakes. Moreover, SJDBT inhibited a production of IL-6, MCP-1, PYY, and GLP-1 and ameliorated cancer-induced anemia. Therefore, our in vivo studies provide evidence on the role of SJDBT in cancer-associated anorexia and cachexia, thereby suggesting that SJDBT may be useful for treating cancer-associated anorexia and cachexia.

Drugs in development for treatment of patients with cancer-related anorexia and cachexia syndrome [Retraction

Drugs in development for treatment of patients with cancer-related anorexia and cachexia syndrome [Retraction] The Editor-in-Chief, Dr Pilch, of Drug Design, Development and Therapy has been alerted to unacceptable levels of duplication between a previously published paper: Macciò A, Madeddu C, Mantovani G. Current pharmacotherapy options for cancer anorexia and cachexia. Expert Opin. Pharmacotherapy 2012 13(17) 2453–2472 and one published subsequently in Drug Design, Development and Therapy: Mantovani G, Madeddu C, Macciò A. Drugs in development for treatment of patients with cancer-related anorexia and cachexia syndrome. Drug Design, Development and Therapy 2013:7 645–656.

English

Introduction Diabetes and cancer are prevalent diseases whose incidence is globally increasing. Type 2 diabetes mellitus is an independent risk factor for the development of several different types of cancer, including that of the colon and pancreas both in men and women, breast cancer in women and cancer of the liver and bladder in men. Nutritional assessment is an essential step in the global management of diabetic cancer patients. Malnutrition occurs due to a variety of mechanisms, involving the tumour, the host response to the tumour and anticancer therapies (surgery, radiotherapy and chemotherapy). In diabetic patients with cancer, malnutrition is a significant cause of morbidity, with high rate of toxicities during chemotherapy and radiotherapy, increased hospital length of stay, increased treatment costs and altered quality of life. Further, in diabetic cancer people, anorexia and cachexia can co-exist to determine the anorexia–cachexia syndrome, which acts synergistically to impact patients’ morbidity and mortality. Indeed, the concurrence of diabetes and cancer results in profound changes in the protein, lipid and glucose metabolism, in turn causing inefficient use of the energy and plastic substrates. The aim of this paper was to discuss nutrition in diabetic people with cancer. Conclusion The best way to treat cancer cachexia is to cure the cancer, although unfortunately this remains an infrequent achievement among adults with advanced solid tumours. Introduction Diabetes and cancer are prevalent diseases whose incidence is globally increasing1. Epidemiologic evidence suggests that type 2 diabetes mellitus (T2DM) is an independent risk factor for the development of several different types of cancer including that of the colon and pancreas both in men and women, breast cancer in women and cancer of the liver and bladder in men. The link between T2DM and certain types of cancer was first postulated many years ago and it was believed that the relationship could be entirely attributable to the direct effects of diabetes, such as hyperglycemia1,2. Current thinking suggests that diabetes is a possible marker of altered cancer risk due to changes in underlying metabolic conditions, including insulin resistance, hyperinsulinaemia and hyperglycaemia, via their influence on neoplastic processes2. Nutritional assessment is an essential step in the global management of diabetic cancer patients, in order to distinguish malnourished and non-malnourished patients3. The American Society for Parenteral and Enteral Nutrition guidelines defined malnutrition as an involuntary loss or gain of > 10% of usual body weight in 6 months or > 5% in one month4. Malnutrition occurs due to a variety of mechanisms, involving the tumour, the host response to the tumour and anticancer therapies (surgery, radiotherapy, chemotherapy)5. In diabetic patients with cancer, malnutrition is a significant cause of morbidity, with high rate toxicities during chemotherapy and radiotherapy, increased hospital length of stay, increased treatment costs, decreased performance status and altered quality of life6. Cachexia is more common in elderly patients and becomes more pronounced as the disease progresses. The prevalence of cachexia increases from 50% to more than 80% before death and in more than 20% of patients, cachexia is the main cause of death7. In diabetic cancer patients, anorexia and cachexia can co-exist to determine the ‘anorexia–cachexia syndrome’8 that acts synergistically to impact patients’ morbidity, mortality and quality of life9. The presence and severity of anorexia–cachexia syndrome reduce overall survival, contribute to the occurrence of postoperative complications, increase the toxicity induced by radio-chemotherapy, while reducing the sensitivity of tumour cells to antineoplastic treatment. In addition, it lowers the immune response and ultimately becomes the source of psychological stress for the patient and family. This paper discusses the management of diabetic cancer patients including the attempt to address and possibly solve typical diabetes and tumour metabolic changes, reduced caloric intake secondary to the presence of cancer anorexia and specific nutritional requirements by the tumour itself. Discussion The ‘anorexia–cachexia syndrome’ in diabetic cancer patients For a long time, the nutritional problems of diabetic cancer patients * Corresponding author Email: ottavio.giampietro@med.unipi.it Clinical Nutrition Unit, Department of Clinical and Experimental Medicine, University of Pisa

Clinical Trials of Cancer Cachexia Therapy, Now and Hereafter

In the article accompanying this editorial, a clinical trial of melatonin for the treatment of cancer cachexia is reported by Del Fabbro et al. Melatonin can be purchased over the counter or on the internet and thus is one of the many putative therapies for cancer cachexia that can be freely obtained by patients without consultation with a health care professional. The vast majority of such integrative therapies lack any evidence in support of their efficacy, other than anecdotal findings. The results of Del Fabbro et al are important because patients use these therapies at some expense and potentially some risk. The absence of either positive or negative findings at least means that patients are unlikely to experience any detriment from undertaking melatonin therapy, and at best these placebo-controlled and double-blinded findings would discourage their future use. Cancer anorexia in particular is subject to substantial placebo effects, and it cannot be underestimated how important it is to conduct well-stratified, randomized, blinded, and controlled trials. The context of the Del Fabbro et al study was within a program where there was excellent attention to pain and symptom management while patients were evaluated for eligibility and eventually included in the trial. This means that the standard of care for symptom management was not as much of a wild card as they might otherwise have been, especially as in multicenter studies with disparate standards of care. The melatonin story is a good example of how optimistic results in open label and uncontrolled trials are deflated by the first controlled investigation. Preclinical studies may also inflate the hopes for a new cachexia therapy. On the surface of it, the evidence in animal models sounds quite compelling for pleiotropic beneficial actions of melatonin on appetite, intestinal transit, nutrient absorption, inflammation, and even antitumor effects. However, several of these findings were observed in healthy animals, in nonmalignant disease or a single cancer model. Indeed, there was no evidence as to whether melatonin has these effects in the presence of tumor and systemic inflammation, or whether it would be equally effective at early, intermediate, and late stages of cachexia. During the time the study in the current report was developed and completed, there has been a thoughtful reconsideration of cancer cachexia by within the clinical cancer research community. This introspection has in part been motivated by the fact that there have been approximately 100 randomized clinical investigations of therapies for cancer cachexia and anorexia, yet many of them, like the present one, have been negative and have not resulted in approved therapies. Research on the underlying biology of cancer cachexia has expanded dramatically, especially in relation to its characteristic pronounced catabolism of skeletal muscle. Cachexia is now the subject of a series of biannual international conferences, a journal, and a Society on Cachexia and Wasting Disorders. International consensus groups have convened to address lack of consistency in defining cachexia, in the use of diagnostic criteria for cachexia and in the design of cachexia-related clinical trials. These consensus building efforts herald a paradigm shift in the design of clinical trials on cancer-associated cachexia. Here are some of the new concepts that current and future cancer cachexia clinical trials are incorporating into their designs:

Erlotinib Plus Parenteral Nutrition

This case study details the poor performance status of a patient with non-small cell lung cancer and cancer anorexia-cachexia syndrome got through the hardest days of high tumor burden and malnutrition, by using a combined therapy of lung cancer-targeted therapy drug and parenteral nutrition. The related literatures were reviewed.

Timing of antioxidant supplementation is critical in improving anorexia in an experimental model of cancer

Increased oxidative stress may contribute to cancer anorexia, which could be ameliorated by antioxidant supplementation. methylcholanthrene (MCA) sarcoma-bearing Fisher rats were studied. After tumour inoculation, rats were randomly assigned to standard diet (CTR group, n = 6), or to an antioxidant-enriched diet (AOX group, n = 8). Eight more rats (STD-AOX group) switched from standard to antioxidant diet when anorexia developed. At the end of the study, food intake (FI, g/d), body weight and tumour weight (g) were recorded, and plasma samples were obtained. On day 16, anorexia has appeared only in CTR and STD-AOX animals. At the end of the study, FI in AOX animals was still higher than in the other groups (p = 0.08). No differences in body and tumour weights were observed among groups. However, hydrogen peroxide and interleukin-1β levels were significantly reduced only in AOX rats. Data obtained suggest that early antioxidant supplementation improves cancer anorexia, ameliorates oxidative stress and reduces inflammation.

The Potential of Ghrelin in Cancer Anorexia–Cachexia

The cancer anorexia–cachexia syndrome (CACS) is often seen in patients with incurable malignancies and is associated with increased mortality, decreased efficacy of anticancer treatments and poor quality of life. However, there are currently no effective therapies for CACS. Since CACS is a multifactorial syndrome with a complex pathophysiology, therapeutic interventions for CACS might potentially include anabolic agents as well as anti-inflammatory effects. Ghrelin affects numerous key pathways in the regulation of body weight and body composition through increased appetite and growth hormone (GH) secretion. Preliminary clinical data indicate that the administration of ghrelin and ghrelin receptor agonist such as anamorelin have beneficial effects on appetite and body weight in patients with CACS. Anamorelin is currently in phase III clinical trials.

Cannabidiol in Humans—The Quest for Therapeutic Targets

Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, is attracting growing attention in medicine for its anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, up to this point, a comprehensive literature review of the effects of CBD in humans is lacking. The aim of the present systematic review is to examine the randomized and crossover studies that administered CBD to healthy controls and to clinical patients. A systematic search was performed in the electronic databases PubMed and EMBASE using the key word “cannabidiol”. Both monotherapy and combination studies (e.g., CBD + ∆9-THC) were included. A total of 34 studies were identified: 16 of these were experimental studies, conducted in healthy subjects, and 18 were conducted in clinical populations, including multiple sclerosis (six studies), schizophrenia and bipolar mania (four studies), social anxiety disorder (two studies), neuropathic and cancer pain (two studies), cancer anorexia (one study), Huntington’s disease (one study), insomnia (one study), and epilepsy (one study). Experimental studies indicate that a high-dose of inhaled/intravenous CBD is required to inhibit the effects of a lower dose of ∆9-THC. Moreover, some experimental and clinical studies suggest that oral/oromucosal CBD may prolong and/or intensify ∆9-THC-induced effects, whereas others suggest that it may inhibit ∆9-THC-induced effects. Finally, preliminary clinical trials suggest that high-dose oral CBD (150–600 mg/d) may exert a therapeutic effect for social anxiety disorder, insomnia and epilepsy, but also that it may cause mental sedation. Potential pharmacokinetic and pharmacodynamic explanations for these results are discussed.

Carnitine Administration Reduces Cytokine Levels, Improves Food Intake, and Ameliorates Body Composition in Tumor-Bearing Rats

Increased cytokine expression contributes to the pathogenesis of cancer anorexia–cachexia syndrome. Carnitine may reduce inflammation in chronic diseases. We tested the effects of L-propionylcarnitine (PC group) or saline (C group) on food intake (FI), body composition, and inflammatory status of MCA-sarcoma-bearing rats. On tumor appearance, rats were randomly assigned to daily i.p. injection of L-propionylcarnitine (250 mg/kgBW/d; n = 8) or saline (equal volume; n = 8). FI and fat-free mass wasting improved in PC rats only (p < .01 vs. controls). Cytokines’ levels decreased in PC rats vs. controls (p < .02). Results suggest that carnitine may ameliorate cancer anorexia–cachexia, via reduction of the inflammatory status.

Cancer anorexia–cachexia: When all you can eat is yourself

Cancer anorexia–cachexia: When all you can eat is yourself

Neural pathophysiology of cancer anorexia

Approximately two thirds of cancer patients at advanced stages of the disease suffer from anorexia. Defined as the loss of the desire to eat, anorexia lower the energy intake which further exacerbates a progressive deterioration of the patient nutritional status. Malnutrition has a large impact on morbidity and mortality affecting the quality of life. Cancer anorexia etiology is multifactorial including complex interactions among the tumor, host metabolism and antineoplastic treatment. New related theories include peripheral and brain mechanisms affecting hypothalamic pathways; inducing behavioral and metabolic failure of responses to energy balance. The aim of this review is to describe actual concepts involved in the pathogenesis of cancer anorexia with special interest in brain mechanisms. Anorexia and reduced food intake are important issues in the management of cancer patients, more knowledge about pathogenic mechanism is needed to improve therapeutic options, prognosis and quality of life in cancer patients.

Observaciones sobre la patogénesis de la anorexia asociada a cáncer y su regulación por el sistema nervioso central

Introduction: Approximately two thirds of cancer patients at advanced stages of the disease suffer from anorexia. Defined as the loss of the desire to eat, anorexia lower the energy intake which further exacerbates a progressive deterioration of the patient nutritional status. Malnutrition has a large impact on morbidity and mortality affecting the quality of life. Cancer anorexia etiology is multifactorial including complex interactions among the tumor, host metabolism and antineoplastic treatment. New related theories include peripheral and brain mechanisms affecting hypothalamic pathways; inducing behavioral and metabolic failure of responses to energy balance. The aim of this review is to describe actual concepts involved in the pathogenesis of cancer anorexia with special interest in brain mechanisms. Conclusions: Anorexia and reduced food intake are important issues in the management of cancer patients, more knowledge about pathogenic mechanism is needed to improve therapeutic options, prognosis and quality of life in cancer patients.

The emotional aspects of cancer anorexia

To discuss the psychosocial support of people affected by cancer anorexia, drawing on recent publications. Recent studies describe the problem of distress in response to cancer anorexia. There are propositions of appropriate support and calls for the development of psychosocial interventions to relieve cachexia-related distress. Preliminary work is now testing these ideas. Psychosocial support for cancer anorexia is a new and promising field of study. The prevention or alleviation of the anorexia of cachexia would relieve much eating-related suffering experienced by patients and their families. However, whilst the scientific community works to achieve this goal there is another task to be addressed: to help people with cancer anorexia to adapt and live with the symptom. Despite accounts over many years of the distress caused by poor appetite, little attention has been paid to the potential for psychosocial support to aid self-management of the symptom. Emergent thinking is that psychosocial support for cancer anorexia can have benefit for both patients and their family members.

Animal models of the cancer anorexia–cachexia syndrome

Cancer cachexia, a complex wasting syndrome, is common in palliative medicine. Animal models expand our understanding of its mechanisms. A review of cancer cachexia and anorexia animal models will help investigators make an informed choice of the study model. Cancer-anorexia cachexia animal models are numerous. No one is ideal. The choice should depend on the research question. To investigate cancer-anorexia cachexia independent of pro-inflammatory cytokine effects, the MAC16 ADK and XK1 are useful. MAC16 ADK helps study the host's tumor metabolic effects, independent of any anorexia or inflammation. XK1 is both anorectic and cachectic, but data about it is limited. All other models induce a host inflammatory response. The Walker 256 ADK and MCG 101 are best avoided due to excessive tumor growth. Since individual models do not address all aspects of the syndrome, use of a combination seems wise. Suggested combinations: MAC16-ADK (non-inflammatory and non-anorectic) with YAH-130 (inflammatory, anorectic, and cachectic), Lewis lung carcinoma (slow onset anorexia) or prostate adenocarcinoma (inflammatory, anorectic but not cachectic) with YAH-130.