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Management of anorexia Clelia Madeddu Medical Oncology Department of Medical Sciences and Public Health University of Cagliari, Italy Session: Optimise nutritional strategies for excellent cancer care Disclosure I do not have any conflict of interest to declare. Nutritional status throughout the disease trajectory of cancer patients Malnutrition may develop at any time

and will usually be progressive. Throughout the trajectory screening for and assessment of malnutrition are recommended in all cancer patients as are appropriate nutrition interventions . Nearing the end of life treatment needs to focus on symptomatic support including alleviating hunger and thirst while all additional nutritional support may do more harm than goo

d . 2015 ASCO EDUCATIONAL BOOK e229 - 237 Incidence of cancer anorexia Cancer patients with cachexia develop anorexia at an incidence rate of 15 - 40%. STAT3 in the systemic inflammation of cancer cachexia. Seminars in Cell & Developmental Biology 2016; 54:28 – 41. Cancer cachexia results from an underlying chronic inflammatory status Evans WJ et al. Cachexia consensus c

onference . Cachexia : a new definition . Clin Nutr 2008 Hepcidin AIM: to evaluate the prevalence of cancer - related anemia in a large cohort of oncology patients and whether inflammation and malnutrition were predictive of its development and severity. The study included 888 patients with cancer at different sites Hemoglobin concentration was inversely correlated with

inflammatory markers, hepcidin, ferritin, erythropoietin and reactive oxygen species, and positively correlated with leptin, albumin, cholesterol and antioxidant enzymes. In multivariate analysis, stage, interleukin - 6 and leptin were independent predictors of hemoglobin concentration. Notably, hemoglobin was inversely dependent on modified Glasgow Prognostic Score. Ha

ematologica January 2015 100: 124 - 132 O 2 J Clin Invest 2016; 126: 2031 - 9 In presence of O 2 glucose is metabolised by aerobic glycolisis for the synthesis of ATP and peptides IRON Hemoglobin Heme group Glucose metabolism changes in cancer patients and energetic inefficiency Future Oncol 2015; 11: 2697 – 2710 Peripheral energy signals regulate appetite: role of l

eptin ghrelin Macciò A, et al. J Mol Med ( Berl ). 2013;91(12):1355 - 68 Leptin as a signal of the metabolic changes induced by cytokines J Cachexia Sarcopenia Muscle (2010) 1:135 – 145 Cytokines are capable of altering the function of central hunger regulatory systems Data indicate that food intake is suppressed when TNF a and IL1 are administered either centrally

or peripherally. These cytokines act on the ventromedial nucleus, a critical brain structure critical for the regulation of body mass, to stimulate early development of satiety. Early satiety may result from cytokine - mediated alterations in production of satiety - related hormones neuropeptide - Y (NPY, appetite stimulant) and proopiomelanocortin (POMC, appetite suppr

essant). Additionally, ciliary neurotrophic factor (CNF, a a neuronally - derived cytokine), is increased in the hypothalamus of tumor - carrying animals and subsequently causes anorexia by inhibiting gene expression of NPY and its receptors as well as NPY release. Meanwhile, POMC - derived appetite changes in cancer patients originate from elevations of hypothalamic s

erotonin and its precursor amino acid tryptophan . Ageing Res Rev. 2010 October ; 9(4): 369 – 383 Pro - inflammatory cytokines act on peripheral sensory neurons ( neural pathway ) and the blood - brain barrier ( humoral pathway ) leading to changes in the activity of key feeding - related brain sites distributed in the brainstem and hypothalamus. This neurobiological m

odel predicts that inflammation - associated anorexia can be modulated by several complementary approaches including to not limited to nutritional and pharmacological approaches. The most promising strategy to attenuate anorexia consists in modulating the melanocortin system by administrating orexigenic agents which are known to act on Arc neurons. Abbreviations : Acb ,

rostral nucleus accumbens; Arc , arcuate nucleus ; BBB, blood - brain barrier ; BST, nucleus of the stria terminalis ; CeA , central amygdala ; CVOs , circumventricular organs ; EP, prostaglandins receptors ; IL - 1, interleukin - 1; LHA, lateral hypothalamus ; LPS, lipopolysaccharide ; PGE2, prostaglandins E2; PVN, nucleus of the paraventricular hypothalamu

s ; pvt , paraventricular thalamus ; lPB , lateral parabrachial nucleus ; NTS, nucleus of the solitary tract . Ageing and inflammation Macciò A, Madeddu C. Management of Anemia of Inflammation in the Elderly. Anemia 2012: 563251 Pathogenesis of anorexia and reduced food intake in elderly cancer patients **Reversible causes of anorexia such as depression or poverty

need to be ruled out before pharmacological measures to improve appetite are considered ** Gastrointestinal symptom prevalence in cancer anorexia (N=95) Anorexia: early satiety, taste changes, and food aversions (N=95) A study by Seal and Cartwright showed that the number of reported symptoms correlates directly with age, with 5·7 symptoms in patients under 65 years and

7·4 in those over 85 years. Moreover, despite having more symptoms, elderly patients were less likely to report their symptoms as very distressing — a finding attributed to the development of coping mechanisms resulting from the long - term presence of symptoms. Early assesment and monitoring Evaluation of nutritional symptoms and risk of malnutrition in elderly cancer

patients Evaluating the older patient with cancer : understanding frailty and geriatric assessment . CA Cancer J Clin 2010;60:120 – 132 Primary anorexia (i.e. central nervous system level) and secondary anorexia (impairment to oral intake ) cause: ❖ reduced food intake and as a consequence : - insufficient caloric intake * and malnutrition ------ �

unintentional weight loss and sarcopenia - sarcopenia due to low aminoacid availability and subsequent decrease in protein synthesis - protein energy malnutrition in turn compromise muscle mass and strength and quality of life ❖ Loss of eating pleasure ❖ inability to enjoy meals with family members Ageing Res Rev. 2010 October ; 9(4): 369 – 383 *Partial reduction

in food intake also results in large caloric deficits overtime and, in this instance , consideration should be given to the percent daily deficit (e�.g.25%�,50%, o�r75% of energy requirements ), the expected duration , as well as the degree of depletion of body reserves . ESPEN guidelines on nutrition in cancer patients . Clinical Nutrition

2017; 36:11 - 48 CONSEQUENCES OF ANOREXIA A multi - center Japanese study of 702 bereaved family members found high levels of eating - related distress and a need for education and support. About half of family members were distressed by the patient’s disappointment at their inability to eat, and 1 in 10 felt it was “useless” to consult medical staff about a daily di

et. Psychological intervention and teaching cognitive reframing strategies also encourages patients to take control over eating habits, empowering the patient. A shift to conscious control over eating may be useful by reframing eating as a necessity (rather than a pleasure) for promoting positive outcomes such as slowing disease progression, tolerating side - effects of che

motherapy, and maintaining strength and stamina. Caregivers and psychosocial distress induced by anorexia Shragge JE, Wismer WV, Olson KL, et al. Shifting toconscious control: psychosocial and dietary management of anorexia by patients with advanced cancer. Palliat Med 2007;21:227 - 33. APPROACH TO ANOREXIA AND RELATED MALNUTRITION The collective derangements of dieta

ry intake are generally approached with nutrition therapy Nutrition interventions aim to : - maintain or improve food intake - maintain body weight , skeletal muscle mass and physical performance - reduce the risk of reductions or interruptions of scheduled anticancer treatments - improve quality of life Therapies for cancer - associated malnutrition include the follow

ing : 1) Nutrition counselling by a health care professional is regarded as the 1st line of nutrition therapy 2) Oral nutritional supplements : commercially available homogeneous and usually nutritionally complete nutrient mixtures for oral consumption recommended to supplement volitional food intake 3) Artificial nutrition : non - volitional application of nutrient

s via enteral tubes ( enteral nutrition ) or parenteral infusions ( parenteral nutrition ) 4) Drug therapy : pharmacologic orexygenic agents to stimulate appetite Bozzetti F. Tailoring the nutritional regimen in the elderly cancer patient . Nutrition . 2015;31(4):612 - 4. Nutrition. 2015 Apr;31(4):605 - 7 The net phenylalanine balance PheNB) of muscle protein in the p

ostabsorptive condition and after ingestion of essential amino acids (EAA) EICOSAPENTAENOIC ACID SUPPLEMENTATION 26 Several small clinical trials (4 RCT), including between 13 and 92 patients and using fish oil supplements or oral nutritiona l supplements (containing 0.4 - 2.2 g/day of EPA) in patients with advanced cancer, reported improvements in appetite, energy intake,

body weight, lean body mass, and/or in physical activity. Beneficial effects of fish oil were observed especially in tri als studying patients undergoing chemotherapy; this included improvements in physical activity and quality of life (RCT; n=40; 2 g/d ay EPA), appetite as well as intake of energy and protein, body weight and lean body mass. However, several randomized t

rials, including from 60 to 518 patients did not demonstrate a benefit associated with supplemental intake of fish oil EPA ethyl est er. EICOSAPENTAENOIC ACID SUPPLEMENTATION: Meta - analyses Three systematic reviews conducted in 2007, 2009, and 2012 concluded that there was insufficient evidence to support a recommendation for long chain omega - 3 fatty acids to treat cance

r cachexia. Another systematic review published in 2007 included non - randomized clinical trials in addition to RCT and concluded that an intake of �1.5 g/day of long - chain fatty acids improved appetite, bodyweight, post - surgical morbidity, and quality of life in weight - losing cancer patients. A systematic review published in 2015 assessed supplementation wit

h long - chain N - 3 fatty acids in cancer patients during chemo - and/or radiotherapy and reported beneficial effects when compared to a control arm, most prominently a conservation of body composition. Dewey A, et al. Cochrane Database Syst Rev 2007 Jan 24;1:CD004597. Mazzotta P, Jeney CM. J Pain Symptom Manage 2009;37: 1069e77. Ries A, et al. Palliat Med 2012;26:29

4e304. Colomer R, et al. Br J Nutr 2007;97:823e31. de Aguiar Pastore Silva J, Emilia de Souza Fabre M, Waitzberg DL. Clin Nutr 2015;34:359e66. Current and future care of patients with CACS Egidio del Fabbro. ASCO Educational Book 2015 Arends J., et al. ESPEN guidelines on nutrition in cancer patients Clinical Nutrition 2017;36:11 - 48 DRUGS: CORTICOSTEROIDS AND PROGESTAGENS

Ruiz Garcia V, Lopez - Briz E, Carbonell Sanchis R, Gonzalvez Perales JL, Bort - Marti S. Megestrol acetate for treatment of anorexia - cachexia syndrome. Cochrane Database Syst Rev 2013;28(3):CD004310. Meta - analysis showed a benefit of Megestrol Acetate (MA) compared with placebo, particularly with regard to appetite improvement and weight gain in cancer, AIDS and

other underlying conditions, and lack of benefit in the same patients when MA was compared to other drugs. There was insufficient information to define the optimal dose of MA, but higher doses were more related to weight improvement than lower doses. Oedema , thromboembolic phenomena and deaths were more frequent in the patients treated with MA . No improvement in appeti

te DRUGS: CANNABINOIDS Ghrelin agonists as target intervention for cancer - related anorexia Pharmacological approach: ghrelin receptor agonists Beside appetite, ghrelin influences also the muscle protein metabolism , adipose tissue metabolism , and energy expenditure . Anamorelin is a novel ghrelin receptor agonist , recently tested in a large ramdomized trial fo

r the treatment of cachexia in non small cell lung cancer . Zhang H, garcia JM. Anamorelin hydrocloride for the treatment of cancer - anorexia - cachexia in NSCLC. Expert Opin Pharmacother 2015; 1 - 9 . Nausea/vomiting Tratto da: Int. J. Mol. Sci. 2017, 18(4), 798 KEY MESSAGE: The ROMANA 3 safety extension study shows anamorelin’s safety and efficacy for a prolo

nged exposure period (24 weeks) in patients with non - small cell lung cancer , thus highlighting its potential as a novel , effective treatment option. Investigational agents Muscle wasting as main evidence of energy impairment in cancer cachexia: future therapeutic approaches . Madeddu C, Mantovani G, Gramignano G, Astara G, Macciò A. Future Oncol. 2015 Sep 17. A ran

domized phase III clinical trial of a combined treatment for cachexia in patients with gynecologic cancers: evaluating t he impact on inflammatory and metabolic profile s and quality of life Macciò A, Madeddu C, Gramignano G, Mulas C, Floris C, Sanna E, Cau MC, Panzone F, Mantovani G. Advanced gynecological cancer patients (no. 104) were randomized to receive a combined tre

atment with L - carnitine+celecoxib+antioxidants (alpha lipoic acid and carboxycysteine )+MA (arm 1) vs. MA alone (arm 2). ARM 1 ARM 2 The combination arm was more effective than arm 2 with respect to LBM, REE, fatigue, and global QoL. As for the secondary efficacy endpoints, patient appetite increased, and ECOG PS decreased significantly in both arms. The inflammation a

nd oxidative stress parameters decreased significantly in arm 1, while no significant change was observed in arm 2 The fragmented approach of various disciplines to the patient ’s CACS care, resulting in undertreatment , delayed and burdensome visits , and patient and caregiver frustration and emotional distress . The mounting problems that arise for the patient

over time exemplify the absence of a shared mental model among the various providers , patient , and caregiver for the care of CACS. Each provider was responsive to individual symptoms , rather than conceptualizing the constellation of symptoms as a syndrome that warrants coordinated care among clinicians . Hopkinson JB, Richardson A. A mixed - methods qualitative

research study to develop a complex intervention for weight loss and anorexia in advanced cancer : the Family Approach to Weight and Eating . Palliat Med . 2015;29:164 - 76 The proposed psychosocial approach was found to aid family talk about food , feelings and reciprocity Bruera et al. J Clin Oncol 2009; 27:3052 - 3058 address the multiple issues that cause s

uffering for patients and their families and impact their life quality Psychosocial approach to anorexia Grazie per l’attenzione Hypothalamic activation after oral intake in anorexic cancer patients is reduced respect and responds differently to oral challenges . This suggests a dysregulation of the central control of appetite during cancer anorexia , before , and