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ANORESSIA e CACHESSIA Clelia Madeddu Oncologia Medica Università degli Studi di Cagliari

Mediterranean School of Oncology Corso “ Supportive and Palliative Care in the Elderly ” Roma 19 Ottobre 2012. ANORESSIA e CACHESSIA Clelia Madeddu Oncologia Medica Università degli Studi di Cagliari. DEFINITION OF CACHEXIA.

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ANORESSIA e CACHESSIA Clelia Madeddu Oncologia Medica Università degli Studi di Cagliari

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  1. Mediterranean School of Oncology Corso “Supportive and Palliative Care in the Elderly” Roma 19 Ottobre 2012 ANORESSIA e CACHESSIA Clelia Madeddu Oncologia Medica Università degli Studi di Cagliari

  2. DEFINITION OF CACHEXIA Cachexia is a multifactorial syndrome characterized by tissue wasting, loss of body weight, particularly of lean body (muscle) mass and to a lesser extent adipose tissue, metabolic alterations, fatigue, reduced performance status, very often accompanied by anorexia leading to a reduced food intake: it accompanies the end stage of many chronic diseases

  3. UP- to- date DEFINITION OF CACHEXIA Multi-factorial syndrome defined 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. Agreed diagnostic criteria are: weight loss>5% or >2% in individuals already showing depletion of body weight (BMI<20 kg/m2) or skeletal muscle (sarcopenia). Assessment for classification and clinical management should include the following domains: anorexia/reduced food intake, catabolic drive, muscle mass and strength, functional and psychosocial impairment. Cachexia: a newdefinition.LancetOncology 2010

  4. ETIOLOGY OF WEIGHT LOSS IN THE ELDERLY Reduced basal hunger, dysgeusia, decreased gastric emptying time, failure to adjust food intake after a period of overfeeding or underfeeding NORMAL AGING Hyperthyroidism, hyperparathyroidism and hypoadrenalism ENDOCRINE DISORDERS Theophylline, lithium, digoxin, chemotherapy, antibiotics, etc…. MEDICATIONS Dementia, depression, anorexia nervosa, alcoholism, and paranoia (late-life) PSYCHIATRIC CHRONIC DISEASE COPD, CHF, rheumatoid arthritis, AIDS, cancer Acute and chronic infections, gastritis, cholecystitis INFECTIONS Stroke, Parkinson’s disease, sclerodermia SYSTEM DISEASES From Morley J Am Geriatr Soc 1994

  5. FACTORS INVOLVED IN AGEING WEIGHT LOSS

  6. CAUSES OF BODY WEIGHT LOSS IN THE ELDERLY Thomas DR. Clinical Nutrition 2007

  7. Anorexia in the aging

  8. Biological mechanisms of anorexia in the aging

  9. MECHANISMS OF AGE-RELATED MUSCLE WASTING Cachexia defines a distinct clinical syndrome where the activation of proinflammatory cytokines have a direct effect on muscle metabolism and anorexia

  10. ETIOLOGY OF SARCOPENIA

  11. SKELETAL MUSCLE ALTERATIONS LEADING TO SARCOPENIA

  12. AGING ↓ SEX STEROIDS ↑ CATHECOLAMINE IL-6 FUNCTIONAL DISABILITY INCREASED MORBIDITY AND MORTALITY PHYSICAL DISABILITY (ADL) COGNITIVE IMPAIRMENT DECREASED HEMOGLOBIN LEVELS

  13. CONDITION ASSOCIATED WITH CACHEXIA CACHEXIA IS BEST VIEWED AS THE CYTOKINE-ASSOCIATED WASTING OF PROTEIN AND ENERGY STORES DUE TO EFFECTS OF DISEASE. CHRONIC INFLAMMATION Thomas DR. Clinical Nutrition 2007

  14. SYMPTOMS OF CANCER-RELATED CACHEXIA • nausea/vomiting • anorexia • weight loss • anemia • depletion of both fat and muscle tissue • fatigue • immunodepression • resistance to antineoplastic treatments and enhancement of their side effects

  15. CACHEXIA IS A COMPONENT OF THE HOST NON SPECIFIC RESPONSE TO INFLAMMATION Low IL-2 production Low RIL-2 expression PCR Immunodepression INFLAMMATORY CYTOKINES ROS TUMOR MACROPHAGE ACTIVATION Metabolic components of cachexia are initiated by the same processes which drive the non specific host immune response to a growing tumor

  16. CANCER MONOCYTES/ MACROPHAGES LYMPHOCYTES CYTOKINES IL-1, IL-6, TNFa CENTRAL NERVOUS SYSTEM GLUCIDIC METABOLISM LIPID METABOLISM  CRH AND SOMATOSTATINE  GH  ANOREXIA  IGF-1 PROTEOLYSIS NAUSEA AND VOMITING DAMAGE ON PANCREATIC b CELLS IPOINSULINEMIA IMPAIRED GLUCOSE METABOLISM IPO/IPERGLICAEMIA  LIPOPROTEINLIPASE LYPOLISIS IPERTRIGLICERIDEMIA  ADIPOCYTE SIZE  FAT TISSUE Semin Oncol 1998; 25 (Suppl 6): 45-52.

  17. ACTIVATED IMMUNE SYSTEM 5-HT, CYTOKINES CRH Neuropeptide Y Nausea/vomiting Anorexia REDUCED FOOD INTAKE

  18. CHANGES OF GLUCOSE METABOLISM IN CACHEXIA PROTEIN AND LIPID STORES GLYCEROL + FREE FATTY ACIDS a)  GLUCONEOGENESIS  CORI CYCLE b) HYPERGLICAEMIA/ c) IMPAIRED GLUCOSE TOLERANCE HYPOGLICAEMIA d) INSULIN RESISTANCE

  19. CHANGES OF PROTEIN METABOLISM IN CANCER CACHEXIA  muscle and liver sinthesis of albumin, etc and  liver synthesis of acute phase proteins (APP=C Reactive Protein and Fibrinogen)  serum levels of Proteolysis Inducing Factor (PIF)  selective muscle wasting

  20. CHANGES OF LIPID METABOLISM IN CANCER CACHEXIA GLUCONEOGENESIS TNF a TNF a IL-1 ↓ LIPOPROTEINLIPASE ACTIVITY ↑ HORMONE-SENSITIVE LIPASE ACTIVITY ↓ LIPOGENESIS LOSS OF BODY FAT

  21. OXIDATIVE STRESS IS THE CONSEQUENCES OF THE INEFFICIENCY OF ENERGY METABOLISM ENERGY SUBSTRATES (Glucose) Penthose-phosphate pathway glycolysis Ribose 5-Phosphate Krebs’s cycle NADPH CO2, H2O FADH, NADH, ATP GSH

  22. LOW LEPTIN LEVELS Oxidative stress ROS Weight loss Improvement of Anorexia anorexia and Energy expenditure energy expenditure Cytokines TUMOR T-LYMPHOCYTES IL-1,IL-6,TNF MACROPHAGES ROS

  23. ROLE OF LEPTIN IN DISEASE PROGRESSION CANCER INFLAMMATORY RESPONSE IL-6 WASTING (LOSS OF FAT) DECREASED ENERGY-INTAKE  LEPTIN  CELLULAR IMMUNITY  MORBIDITY/MORTALITY

  24. METABOLIC ABNORMALITIES INDUCED BY PROINFLAMMATORY CYTOKINES INADEQUATE ENERGY INTAKE  ENERGY EXPENDITURE WEIGHT LOSS ANEMIA ANOREXIA MUSCLE WASTING IMMUNODEPRESSION RESPONSE TO THERAPY, QoL, SURVIVAL

  25. FIRSTLY, TO ATTEMPT TO IDENTIFY AND TREAT ANY SPECIFIC UNDERLYING TREATABLE OR CONTRIBUTING CONDITIONS

  26. MAJOR CAUSES OF BODY WEIGHT LOSS IN OLDER PERSONS

  27. From QuBaiah O, Morley JE. Pathophysiology of cachexia in the elderly. In: Cachexia and wasting: an innovative approach.

  28. Lancet Oncology 2011

  29. Lancet Oncology 2011

  30. COMBINED APPROACH To date, attempts at cancer cachexia therapy with a variety of single interventions have had limited success. The main features of cachexia (progressive loss of muscle mass and function) have been shown to be only minimally influenced by the nutritional or pharmacological tools currently available. However, a combination of dietary, nutritional, and pharmacological approaches to normalize the metabolic milieu may be capable of reversing advanced cancer-related symptoms that affect patient Quality of Life References: Support Care Cancer 2010;18:1–9. Oncologist 2010;15:119–21.

  31. Strategies for intervention in cachexia Treatment should address the fundamental issues of reduced food intake and abnormal abnormalities Fearon KC. ClinNutr 2012; 31:577-582

  32. From July2002 to January 2005, 44 patients were enrolled. Of these, 39 completed the treatment and were assessable. Body weight, LBM and appetite increased significantly from baseline. There was an important decrease of proinflammatory cytokines IL-6 and TNFalpha As for quality of life evaluation, there was a marked improvement in the European Organization for Research and Treatment of Cancer QLQ-C30, Euro QL-5DVAS, and multidimensional fatigue symptom inventory-short form scores. At the end of the study, 22 of the 39 patients were ‘‘responders’’ or ‘‘high responders.’’ The minimum required was 21; therefore, the treatment was effective and more importantly was shown to be safe.

  33. Medroxyprogesterone acetate (MPA) 500 or Megestrol Acetate (MA) 320mg/day Arm 1 Pharmaco-nutritional support with EPA 2-3 cartons/day Arm 2 random Basic treatment poliphenols (300 mg/day) + antioxidant agents alpha lipoic acid 300 mg/day, carbocysteine 2.7 g/day (Fluifort, Dompè), Vitamin E 400 mg /day (Sursum, Abiogen), Vitamin A 30000 IU and Vitamin C 500 mg/day + Arm 3 L-carnitine 4 g/day Arm 4 Thalidomide 200 mg/day Arm 5 Combination of the above agents The most effective treatment in terms of all three primary efficacy endpoints, i.e. LBM, REE and fatigue, and the secondary endpoints appetite, IL-6, GPS, and ECOG PS score was the combination regimen that included all selected agents. The Oncologist 2010;15:200–211

  34. A total of 104 advanced-stage gynecological cancer patients were enrolled and randomly assigned to receive either: megestrol acetate (MA) plus L-carnitine, celecoxib, and antioxidants (arm 1) or MA alone (arm 2). The treatment duration was 4 months. The combination arm was more effective than arm 2 as regards: 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 and oxidative stress parameters IL-6, TNF-α, CRP, and ROS decreased significantly in arm 1, while no significant change was observed in arm 2.

  35. PATIENT-CENTERED OUTCOME Fearon KC. ClinNutr 2012; 31:577-582

  36. IT IS EVIDENT THAT A MULTIDISCIPLINARY APPROACH IS NEEDED TO PREVENT CACHEXIA AND MANAGE THE ASSOCIATED SYMPTOMS TO IMPROVE QUALITY OF LIFE FOR PATIENTS BENESSERE FISICO Disturbi indotti dalla malattia, Effetti collaterali dei trattamenti STATO FUNZIONALE Capacita’ di lavorare, di utilizzare il tempo libero, di badare a sé stesso QUALITA’ DI VITA STATO PSICOLOGICO Ansia, depressione, aggressività, stima e sicurezza di sé, modificazioni dello schema corporeo BENESSERE SOCIALE Relazione con i familiari Relazione con i curanti, ruolo sociale, ECC.

  37. Eur J Cancer 2008; 4 4: 1 1 2 4 –1 1 3 2 We are aware that multimodal therapies for cancer cachexia should ideally be introduced within a context of the “best supportive care”, which includes optimal symptom management and careful psychosocial counseling.

  38. A group of preschoolers were asked what happens to people when they get old

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