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Congress Report - 7th Cachexia Conference Kobe/Osaka, Japan, December 9−11, 2013

The 7th consecutive international meeting of the Society on Sarcopenia, Cachexia and Wasting Disorders (SCWD) was held in Kobe/Osaka, Japan, on December 9-11, 2013. More than 315 scientists and experts from 32 countries gathered to present and discuss the latest research and clinical developments in the field.

With a comprehensive program, many topics in the field of cachexia, sarcopenia and wasting were addressed. Beside the plenary sessions, the scientific program was split into a clinical and a basic science track to focus on specific aspects in the respective fields.
Presentations included keynote lectures, overview and research talks, young investigator award sessions, rapid-fire presentations and, of course, poster presentations. The scientific program also featured educational lectures and seminars on clinical and experimental methods to study body composition, metabolic pathways and pathologies of tissue wasting.
Some of the main clinical information on cancer cachexia that was discussed is reported here

Abstracts of the conference are available at http://link.springer.com/article/10.1007/s13539-013-0123-9 and http://link.springer.com/article/10.1007%2Fs13539-014-0129-y

Cachexia and muscle wasting in cancer

One of main focuses of the conference was the regulation, mechanisms and clinical features of cachexia and muscle wasting in cancer.

The clinical perspective on cancer cachexia was summarized by Professor Florian Strasser (St. Gallen, Switzerland). The detrimental impact of cancer cachexia on outcome, morbidity and quality of life, as well as on chemotherapy toxicity, was emphasized, making cachexia a core concern for oncologists. The complexity of cancer cachexia pathophysiology was outlined by Professor Ken Fearon (Edinburgh, UK) who presented the protocol of the MENAC study, a multicenter randomized phase 3 feasibility study comparing a multimodal intervention for cachexia prevention versus standard cancer care in patients with non-small-cell lung cancer or pancreatic cancer undergoing chemotherapy.

Professor Vickie Baracos (Edmonton, AB, Canada) discussed the difficulties of harmonizing the terminology and definitions of cancer cachexia and malnutrition. She identified more than 20 different definitions in 117 recent scientific publications.

Surgical cancer patients: prevalence of pre-cachexia and cachexia

Doctor Simone Lucia (Rome, Italy) presented a study suggesting that pre-cachexia and cachexia are highly prevalent in pre-surgical cancer patients.

According to recent criteria, cancer cachexia is defined as a multifactorial syndrome characterised by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment.1 Whereas pre-cachexia is defined based on the presence of an underlying chronic disease; an unintentional weight loss =5% of usual body weight during the last 6 months; chronic or recurrent systemic inflammatory response; anorexia or anorexia-related symptoms.2 Cachexia represents a spectrum through which not all patients will progress. At present there are no robust biomarkers to identify those pre-cachectic patients who are likely to progress further or the rate at which they will do so.1

Simone Lucia et al. have designed a study to evaluate whether the classification of surgical cancer patients according to the new criteria is reflected by changes in bio-impedance analysis measurements, and to assess the prevalence of pre-cachexia and cachexia in a population of surgical cancer patients.

42 cancer patients (tumour stage I-II: 26%, III-IV: 74%) were enrolled among those undergoing abdominal surgery from the MG Vannini Hospital (Rome, Italy) and St. Maria alle Scotte Hospital (Siena, Italy). Immediately before surgery, they were evaluated for the presence of pre-cachexia2 and cachexia.1 According to Fearon’s criteria, weight loss (WL) and BMI were sufficient to classify patients as cachectic in this cohort. All patients were given a bioelectrical impedance analysis and a handgrip muscle strength test was assessed in 20 patients.

Pre-cachexia was present in 14% of the patients, cachexia in 36%, while 50% had no pre-cachexia or cachexia. Diagnostic criteria, for pre-cachexia and cachexia allowed them to identify patients with decreased fat free mass and fat-free mass index (fig. 2). The use of bioelectrical impedance phase angle has been recommended as a prognostic tool in the clinical setting.3 In this study, changes in phase angle and its standardised values did not correlate with stages of cachexia, while significantly correlated with functional impairment, as assessed by the handgrip muscle strength test.

Patients with decreased fat free mass and fat-free mass index

Author information: Simone Lucia et al. (Department of Clinical Medicine, Sapienza University of Rome, Italy), 7th Cachexia Conference, Kobe, Japan, December 2013.

Advanced cancer & cachexia: The effect of melatonin on appetite and other symptoms

Prof. Egidio Del Fabbro (Richmond, VA, USA) presented interesting data on the effect of melatonin on appetite and other symptoms. In cachectic patients with advanced lung or gastrointestinal cancer, oral melatonin 20 mg at night did not improve appetite, weight, or quality of life compared with placebo.

In 1999 a study by Lissoni et al, melatonin was proven to counteract chemotherapy toxicity, by acting as an anti-oxidant agent, and to promote apoptosis of cancer cells, so enhancing chemotherapy cytotoxicity. The aim of the study was to evaluate the effects of concomitant melatonin administration on toxicity and efficacy of several chemotherapeutic combinations in advanced cancer patients with poor clinical status. The study included 250 metastatic solid tumour patients. The 1-year survival rate and the objective tumour regression rate were significantly higher in patients concomitantly treated with melatonin than in those who received chemotherapy alone. Moreover, the concomitant administration of melatonin significantly reduced the frequency of thrombocytopenia, neurotoxicity, cardiotoxicity, stomatitis and asthenia. Thus, this study indicated that melatonin may enhance the efficacy of chemotherapy and reduce its toxicity, at least in advanced cancer patients with poor clinical status.4

In a pilot trial, approximately 63% of patients with advanced gastrointestinal cancer showed weight stabilisation or gain after combining melatonin and fish oil.5

In a systematic review of 10 randomised controlled trials of melatonin in solid tumour cancer patients, melatonin reduced the risk of death at 1 year; no severe adverse events were reported. Effects were consistent across melatonin dose, and type of cancer. This review suggested great potential for melatonin in treating cancer.6

Following the completion of this systematic review, two further randomised controlled trials with survival as the outcome were published by Lissoni et al.7,8 Both studies included patients with metastatic cancers of the lung or of the gastrointestinal tract. In the first study, patients best supportive care was compared with melatonin and with melatonin plus low-dose interleukin-2. The authors concluded that "the administration of interleukin-2 and the pineal hormone melatonin may induce a prolonged survival time in patients with metastatic solid tumours, for whom no other conventional anticancer therapy is available".
In the second study, patients received chemotherapy alone or chemotherapy plus melatonin. In this study again, the survival rate was higher in patients concomitantly treated with melatonin and the authors concluded that their results confirm the anticancer therapeutic properties of melatonin, which may enhance the efficacy of the standard anticancer chemotherapies.

Egidio Del Fabbro et al. evaluated the effect of melatonin on appetite and other symptoms in patients with metastatic or locally recurrent lung or gastrointestinal cancers and cachexia in a double-blind placebo-controlled trial (28-day of melatonin 20 mg at night vs placebo). After interim analysis of 48 patients, the study was closed because of its futility. There were no significant differences between groups for appetite (P = .78) or other symptoms, weight (P = .17), FAACT score (P = .95), toxicity, or survival from baseline to day 28 (Figure 3). Significant correlations were found in melatonin and placebo groups combined between percent weight change (from baseline to day 28) and appetite (P <.024) and depression (P < .03), no association between symptoms of appetite/fatigue and an increase or a decrease in CRP levels, weight (P = .17), Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire score (P = .95), toxicity, or survival from baseline to day 28 were found in the melatonin group.9

Ghrelin and ghrelin receptor agonists

Ghrelin as a central and potent regulator of nutritional intake and energy balance as well as a promising therapeutic target for anticatabolic intervention was a major focus of the conference, with multiple presentations and posters.

In the breakfast seminar, Professor Kenji Kangawa (Osaka, Japan), one of the discoverers of ghrelin, delivered a highly informative lecture on the discovery, development and pathophysiologic effects of ghrelin.

The endogenous ligand for growth-hormone secretagogue receptor was discovered in 1999 in the stomach and named "ghrelin," after the root word ("ghre") from Proto-Indo-European languages meaning "grow", since ghrelin stimulates growth hormone release from the pituitary gland. In addition, ghrelin stimulates appetite and increases food intake by acting on the hypothalamic arcuate nucleus, a region known to control food intake. Thus, ghrelin plays important roles for maintaining growth hormone release and energy homeostasis in vertebrates. The diverse functions of ghrelin raise the possibility of its clinical application for growth-hormone deficiency, eating disorder, gastrointestinal disease, cardiovascular disease, osteoporosis and aging, etc.

Peripheral ghrelin signaling, which travels to the nucleus tractus solitarius at least in part via the vagus nerve, increases noradrenaline in the arcuate nucleus of the hypothalamus, thereby stimulating feeding at least partially through alpha-1 and beta-2 noradrenergic receptors.
In addition, bilateral midbrain transections rostral to the nucleus tractus solitarius, or toxin-induced loss of neurons in the hindbrain that express dopamine beta hydroxylase (an noradrenergic synthetic enzyme), abolished ghrelin-induced feeding. These findings provide new evidence that the noradrenergic system is necessary in the central control of feeding behavior by peripherally administered ghrelin.

Professor Jose M. Garcia (Houston, TX, USA) summarized the current state of knowledge on the therapeutic potential of ghrelin and ghrelin receptor agonists in patients with CACS (cancer anorexia-cachexia syndrome). In CACS, the tumour is associated with activation of pro-inflammatory and neuroendocrine responses. These result in reduced food intake and metabolic change. Adrenergic activation and tumour-related lipolytic factors lead to enhanced lipolysis. The effects of hypogonadism, insulin resistance, adrenergic activation, and systemic inflammation coupled with semi-starvation lead to muscle atrophy. Liver export protein synthesis is stimulated as part of the acute phase response. In addition, futile substrate cycles contribute to hypermetabolism.
Over the last few years, the discovery of several peripheral hormones that act on the appetite-regulating centre of the hypothalamus, leptin, peptide YY, ghrelin, have allowed a better understanding of how body weight is regulated. There is evidence now that there are multiple redundant pathways that play a role in the regulation of appetite, food intake and energy expenditure.

Ghrelin infusion increases food intake and "meal pleasantness" in cancer patients.
In an acute, randomized, placebo-controlled, cross-over clinical trial, NM Neary et al. have determined that ghrelin stimulates appetite in cancer patients with anorexia.
In an acute trial, a marked increase in energy intake (31± 7%; P = 0.005) was observed with ghrelin infusion compared with saline control in seven cancer patients who reported loss of appetite, and every patient ate more. No side effects were observed
The results of a long-term study suggest that daily, long-term provision of ghrelin to weight-losing cancer patients with solid tumours supports host metabolism, improves appetite, and attenuates catabolism.
Y Hiura et al. conducted a prospective, randomized phase 2 trial to evaluate the effects of exogenous ghrelin during cisplatin-based chemotherapy [cisplatin reduces plasma ghrelin levels through the 5-hydroxytryptamine (5-HT) receptor - this may cause cisplatin induced gastrointestinal disorders and hinders the continuation of chemotherapy]. Food intake and appetite VAS scores were significantly higher in the ghrelin group than in the placebo group. Also, patients in the ghrelin group had fewer adverse events during chemotherapy related to anorexia and nausea than patients in the control group.

Anamorelin, an oral mimetic of ghrelin, has been shown to increase body weight and anabolic hormone levels in healthy volunteers and is being investigated as a treatment for cancer cachexia. JM Garcia et al. designed a multicenter, double-blind, placebo-controlled, crossover study to evaluate the effects of anamorelin in 16 patients with different cancers and cachexia. Patients were randomly assigned to anamorelin 50 mg/day or placebo for 3 days. A 3-to7-day washout period followed and then treatments were switched. In this study, anamorelin significantly increased body weight compared with placebo (0.77 kg vs -0.33 kg). Food intake increased compared with placebo, but not significantly. Growth hormone levels significantly increased at all time-points. Insulin-like growth factor-1 significantly increased with anamorelin treatment compared with placebo; significant changes in insulin-like growth factor-binding protein 3 were found. Patient-reported symptoms, including appetite, significantly improved with anamorelin. Adverse events in four patients were possibly or probably related to anamorelin: hyperglycemia (two patients), nausea (one patient), and dizziness (one patient). Most adverse events were mild.

In the Prometheus keynote lecture, Professor Masayasu Kojima (Kurume, Japan) gave a comprehensive overview of current knowledge and hot issues in ghrelin research, both in experimental and clinical studies.

Few presentations were also given on rikkunshito (RKT), a Japanese herbal medicine, indicating that RKT may restore disturbed appetite and ghrelin secretion through the restoration of balance in the central autonomic nervous system. A study performed in rats indicated that RKT inhibits the NTS neuronal activity (solitary tract nucleus) suggesting that RKT inhibits vagal input from the periphery to central nerves. Also, activity of PVN (paraventricular nucleus of hypothalamus) is also suppressed possibly resulting in the decrease of the sympathetic outflow from the central nerve to the periphery.

Drug treatment options and results update

In the session called "Drug treatment options and results update" the two most advanced (phase III) treatment options discussed were anamorelin and enobosarm; results from a phase 2 study with espindolol were also presented.

Anamorelin
The efficacy and safety data from a phase 2 trial of the ghrelin receptor agonist anamorelin in patients with non-small cell lung cancer (NSCLC) was also reported by John Friend (Helsinn Therapeutics, Bridgewater, USA). Treatment with anamorelin resulted in significant body weight increase as well as improvement in functional (handgrip strength) and quality of life measures. The drug was well tolerated and no dose-limiting adverse effects were noted. Continued phase 3 studies are under way.

Enobosarm
Mitchell Steiner (GTx, Memphis, USA) reported on the latest data from two international phase 3 trials on the selective androgen receptor modulator (SARM) GTx-024 (enobosarm). The POWER1 and POWER2 trials investigated the ability of GTx-024 to prevent and treat muscle wasting in non-small cell lung cancer (NSCLC) patients in different chemotherapy regimens (platinum plus taxane and platinum plus non-taxane, respectively). The treatment effect to improve lean body mass (LBM) and functional capacity (stair climb power) was observed in both trials, but differences in effect size were considered to result from different chemotherapies and different analysis. The data was presented according to two different statistical methods (responders analysis and MMRM slopes – Mixed Model Repeated Measures) and by study (thus by concomitant chemotherapy: platinum +/- taxane). In the POWER1 study (enobosarm + platinum + taxane), LBM was significantly different in both statistical analysis methods used. Functional endpoint was significantly different only in the MMRM statistical analysis. In the POWER2 study (enobosarm + platinum + non taxane), LBM was statistically significant only in the MMRM statistical analysis. Functional endpoint was non statistically significant in either methods used.

Espindolol
Results from a phase 2 study with espindolol (ACT-ONE) was reported  by Andrew JS Coats (Melbourne, Australia). In preclinical studies using a rat cancer cachexia model, espindolol has been shown to have superior effects upon cachectic signs and overall survival when compared to other beta-blockers. This phase 2 study included patients with a confirmed diagnosis of stage III or IV non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) and who met the consensus definition of cachexia (>5% weight loss). Patients were randomized  to high dose espindolol (HD=10 mg bd), low dose espindolol (LD=2,5 mg bd) or matching placebo (P) and treated for 16 weeks. Efficacy was demonstrated for high dose espindolol compared to placebo. For the primary endpoint in the ITT population, the slope of weight change (Kg per 4 weeks) in the HD group demonstrated a positive slope of 0.42 compared to a negative slope of -0.37 in the P group (p<0,0001).

Definitions and treatment targets: a debate

A panel discussion on the novel and emerging therapeutic compounds on cachexia and sarcopenia triggered a vivid and enlightening debate.

Ken Fearon (Edinburgh, United Kingdom) pointed out that cancer cachexia is likely to be the first target for testing the efficacy of such novel compounds, with cachexia in other diseases or sarcopenia then following. Trial design issues are still under debate as are approvable endpoints and safety endpoints. John Beadle (PsiOxus Therapeutics, Abingdon, United Kingdom) emphasized that the debate on definitions and treatment targets are still on the table as muscle bulk and function may be the foremost targets to be improved, but also other aspects of cachexia may be relevant targets such as inflammatory activation or fat-tissue wasting. Stefan Anker (Berlin, Germany) reminded the audience that regulatory requirements are also important with regard to implementation of such treatments and that differences in regulatory demands and constraints in Europe (by the EMA) and in the USA (by the FDA) may lead to regionally different ways this is pursued with regard to endpoints, treatment targets and safety profiles.

Novel methodological concepts

As a new type of session, a rapid-fire clinical science session was brought into the program with concise presentation on novel methodological concepts and clinical research data. Outstanding poster presenters were given the opportunity to present and discuss their data in front of a larger audience.

Annemie Schols (Maastricht, Netherlands) reported on the close relationship between body composition, physical performance and exercise in patients with COPD. Nadja Scherbakov (Berlin, Germany) showed novel data on a promising biomarker candidate for muscle wasting: the C-terminal fragment of the glycoprotein agrin that is involved in the regulation of neuromuscular synaptic formation. Nicolaas Deutz (College Station, TX, USA) presented a new method to quantify fat and fat-free mass by D2O dilution and gas chromatography-mass spectroscopy technique. Validating this new method against DEXA, he showed the accuracy and easy-to-use applicability of the method. New insights into the processes of autophagy in cancer cachexia were summarized by Geir Bjorkoy (Trondheim, Norway). Vincenzo Musolino (Berlin, Germany) presented experimental data on the anti-cachectic effects of the combined ß-blocker/5-HT1A agonist espindolol with potent effects leading to an improved outcome in a hepatoma cancer mouse model.

Abstracts of the conference are available at http://link.springer.com/article/10.1007/s13539-013-0123-9 and http://link.springer.com/article/10.1007%2Fs13539-014-0129-y

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