ANORESSIA e CACHESSIAANORESSIA e CACHESSIA

Clelia MadedduClelia Madeddu

Oncologia MedicaOncologia Medica

Università degli Studi di CagliariUniversità degli Studi di Cagliari

Mediterranean School of OncologyCorso “Supportive and Palliative Care in the Elderly”Roma 19 Ottobre 2012

DEFINITION OF CACHEXIADEFINITION OF CACHEXIADEFINITION OF CACHEXIADEFINITION 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

UP- to- date DEFINITION OF CACHEXIAUP- 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 new definition.Lancet Oncology 2010

ETIOLOGY OF WEIGHT LOSS IN THE ELDERLYETIOLOGY OF WEIGHT LOSS IN THE ELDERLYETIOLOGY OF WEIGHT LOSS IN THE ELDERLYETIOLOGY OF WEIGHT LOSS IN THE ELDERLY

NORMAL AGINGReduced basal hunger, dysgeusia, decreased gastric emptying time, failure to adjust food

intake after a period of overfeeding or underfeeding

ENDOCRINE DISORDERS Hyperthyroidism, hyperparathyroidism and

hypoadrenalismMEDICATIONS Theophylline, lithium, digoxin, chemotherapy,

antibiotics, etc….

PSYCHIATRIC Dementia, depression, anorexia nervosa, alcoholism, and paranoia (late-life)

CHRONIC DISEASE COPD, CHF, rheumatoid arthritis, AIDS, cancer

INFECTIONS Acute and chronic infections, gastritis, cholecystitis

SYSTEM DISEASES Stroke, Parkinson’s disease, sclerodermia

From Morley J Am Geriatr Soc 1994

FACTORS INVOLVED IN AGEING WEIGHT LOSSFACTORS INVOLVED IN AGEING WEIGHT LOSSFACTORS INVOLVED IN AGEING WEIGHT LOSSFACTORS INVOLVED IN AGEING WEIGHT LOSS

CAUSES OF BODY WEIGHT LOSS IN THE CAUSES OF BODY WEIGHT LOSS IN THE ELDERLYELDERLY

CAUSES OF BODY WEIGHT LOSS IN THE CAUSES OF BODY WEIGHT LOSS IN THE ELDERLYELDERLY

Thomas DR. Clinical Nutrition 2007

Anorexia in the aging

Biological mechanisms of anorexia in the aging

MECHANISMS OF AGE-RELATED MUSCLE MECHANISMS OF AGE-RELATED MUSCLE WASTINGWASTING

MECHANISMS OF AGE-RELATED MUSCLE MECHANISMS OF AGE-RELATED MUSCLE WASTINGWASTING

Cachexia defines a distinct clinical syndrome where the

activation of proinflammatory cytokines have a direct effect

on muscle metabolism and anorexia

ETIOLOGY OF SARCOPENIAETIOLOGY OF SARCOPENIAETIOLOGY OF SARCOPENIAETIOLOGY OF SARCOPENIA

SKELETAL MUSCLE ALTERATIONS LEADING TO SKELETAL MUSCLE ALTERATIONS LEADING TO SARCOPENIASARCOPENIA

SKELETAL MUSCLE ALTERATIONS LEADING TO SKELETAL MUSCLE ALTERATIONS LEADING TO SARCOPENIASARCOPENIA

IL-6IL-6

AGINGAGING

FUNCTIONAL DISABILITYFUNCTIONAL DISABILITY

INCREASED MORBIDITY AND MORTALITYINCREASED MORBIDITY AND MORTALITY

PHYSICAL DISABILITY (ADL)PHYSICAL DISABILITY (ADL)

COGNITIVE IMPAIRMENTCOGNITIVE IMPAIRMENT

DECREASED HEMOGLOBIN LEVELSDECREASED HEMOGLOBIN LEVELS

↑ ↑ CATHECOLAMINECATHECOLAMINE ↓ ↓ SEX STEROIDSSEX STEROIDS

CACHEXIA IS BEST VIEWED AS THE CYTOKINE-ASSOCIATED WASTING CACHEXIA IS BEST VIEWED AS THE CYTOKINE-ASSOCIATED WASTING OF PROTEIN AND ENERGY STORES DUE TO EFFECTS OF DISEASE.OF PROTEIN AND ENERGY STORES DUE TO EFFECTS OF DISEASE.

CONDITION ASSOCIATED WITH CACHEXIACONDITION ASSOCIATED WITH CACHEXIACONDITION ASSOCIATED WITH CACHEXIACONDITION ASSOCIATED WITH CACHEXIA

CHRONIC INFLAMMATIONCHRONIC INFLAMMATIONCHRONIC INFLAMMATIONCHRONIC INFLAMMATION

Thomas DR. Clinical Nutrition 2007

SYMPTOMS OF SYMPTOMS OF CANCER-RELATED CANCER-RELATED

CACHEXIACACHEXIA

anorexiaanorexia nausea/vomitingnausea/vomiting

weight loss weight loss

depletion of both fat depletion of both fat and muscle tissue and muscle tissue

resistance to antineoplastic treatments resistance to antineoplastic treatments and enhancement of their side effectsand enhancement of their side effects

anemia anemia

immunodepressionimmunodepression fatiguefatigue

CACHEXIA IS A COMPONENT OF THE HOST CACHEXIA IS A COMPONENT OF THE HOST NON SPECIFIC RESPONSE TO INFLAMMATIONNON SPECIFIC RESPONSE TO INFLAMMATIONCACHEXIA IS A COMPONENT OF THE HOST CACHEXIA IS A COMPONENT OF THE HOST

NON SPECIFIC RESPONSE TO INFLAMMATIONNON SPECIFIC RESPONSE TO INFLAMMATION

PCR Low IL-2production

INFLAMMATORYINFLAMMATORYCYTOKINESCYTOKINES

ROSROS

Low RIL-2expression

TUMORTUMORMACROPHAMACROPHAGEGE

ACTIVATIONACTIVATION

Metabolic components of cachexia are initiated by the same Metabolic components of cachexia are initiated by the same processes which drive the non specific host immune response processes which drive the non specific host immune response

to a growing tumorto a growing tumor

CANCERLYMPHOCYTESLYMPHOCYTES

MONOCYTES/MONOCYTES/

MACROPHAGESMACROPHAGES

CYTOKINES IL-1, IL-6, TNFCYTOKINES IL-1, IL-6, TNF

CENTRAL CENTRAL NERVOUS SYSTEMNERVOUS SYSTEM LIPID

METABOLISM

GLUCIDIC METABOLISM

CRH AND CRH AND SOMATOSTATINESOMATOSTATINE

GH GH ANOREXIA ANOREXIA

IGF-1IGF-1

PROTEOLYSISPROTEOLYSIS

NAUSEA AND NAUSEA AND VOMITINGVOMITING

LIPOPROTEINLIPASELIPOPROTEINLIPASE

LYPOLISIS LYPOLISIS IPERTRIGLICERIDEMIAIPERTRIGLICERIDEMIA

ADIPOCYTE SIZEADIPOCYTE SIZE

FAT TISSUEFAT TISSUE

DAMAGE ON DAMAGE ON PANCREATIC PANCREATIC

CELLS CELLS

IPOINSULINEMIAIPOINSULINEMIA

IMPAIRED GLUCOSE IMPAIRED GLUCOSE METABOLISMMETABOLISM

IPO/IPERGLICAEMIAIPO/IPERGLICAEMIA

Semin Oncol 1998; 25 (Suppl 6): 45-52.

CRHCRH

Neuropeptide YNeuropeptide Y

REDUCED FOOD INTAKEREDUCED FOOD INTAKEREDUCED FOOD INTAKEREDUCED FOOD INTAKE

AnorexiaAnorexia

ACTIVATED IMMUNE SYSTEM

5-HT, CYTOKINES5-HT, CYTOKINES

Nausea/Nausea/vomitingvomiting

GLYCEROL +

FREE FATTY ACIDS

GLUCONEOGENESISGLUCONEOGENESIS

PROTEIN AND LIPID PROTEIN AND LIPID STORESSTORES

CHANGES OF GLUCOSE METABOLISM IN CHANGES OF GLUCOSE METABOLISM IN CACHEXIACACHEXIA

CHANGES OF GLUCOSE METABOLISM IN CHANGES OF GLUCOSE METABOLISM IN CACHEXIACACHEXIA

CORI CYCLE

a)

b)

c) IMPAIRED GLUCOSE IMPAIRED GLUCOSE TOLERANCETOLERANCEIMPAIRED GLUCOSE IMPAIRED GLUCOSE TOLERANCETOLERANCE

HYPERGLICAEMIAHYPERGLICAEMIA//HYPOGLICAEMIAHYPOGLICAEMIA

d) INSULIN RESISTANCEINSULIN RESISTANCEINSULIN RESISTANCEINSULIN RESISTANCE

CHANGES OF PROTEIN METABOLISM IN CHANGES OF PROTEIN METABOLISM IN CANCER CACHEXIACANCER CACHEXIA

muscle and liver sinthesis of albumin, etc and muscle and liver sinthesis of albumin, etc and liver synthesis of liver synthesis of acute phase proteins (APP=C Reactive Protein and Fibrinogen)acute phase proteins (APP=C Reactive Protein and Fibrinogen)

serum levels of Proteolysis Inducing Factor (PIF) serum levels of Proteolysis Inducing Factor (PIF) selective selective muscle wastingmuscle wasting

LOSS OF BODY FATLOSS OF BODY FAT

↓↓ LIPOPROTEINLIPASE ACTIVITY

↑↑ HORMONE-SENSITIVE LIPASE ACTIVITY

GLUCONEOGENESISGLUCONEOGENESIS

↓ ↓ LIPOGENESISLIPOGENESIS

TNF TNF

TNF TNF IL-1IL-1

CHANGES OF LIPID METABOLISM IN CANCER CHANGES OF LIPID METABOLISM IN CANCER CACHEXIACACHEXIA

OXIDATIVE STRESS IS THE CONSEQUENCES OXIDATIVE STRESS IS THE CONSEQUENCES OF THE INEFFICIENCY OF ENERGY OF THE INEFFICIENCY OF ENERGY

METABOLISMMETABOLISM

glycolysisglycolysis

COCO22, H, H22OO

FADH, NADH, ATPFADH, NADH, ATP

KrebsKrebs’’s cycles cycle

Penthose-phosphatePenthose-phosphatepathwaypathway

NADPHNADPH

RiboseRibose5-Phosphate5-Phosphate

GSHGSH

ENERGY SUBSTRATESENERGY SUBSTRATES(Glucose)(Glucose)

TUMORTUMOR T-LYMPHOCYTEST-LYMPHOCYTES

MACROPHAGESMACROPHAGES

AnorexiaAnorexia

Energy expenditureEnergy expenditure

Weight lossWeight loss

CytokineCytokiness IL-1,IL-6,TNF IL-1,IL-6,TNF

anorexia anorexia andandenergy energy

expenditureexpenditure

LOW LEPTIN LEVELSLOW LEPTIN LEVELS

ROSROS

Improvement ofImprovement of

ROSROSROSROS

Oxidative Oxidative stressstress

ROLE OF LEPTIN IN DISEASE ROLE OF LEPTIN IN DISEASE PROGRESSION PROGRESSION

CANCERCANCER

INFLAMMATORY RESPONSE

IL-6

LEPTINLEPTIN

WASTING

(LOSS OF FAT)

DECREASED ENERGY-INTAKE

CELLULAR IMMUNITY

MORBIDITY/MORTALITYMORBIDITY/MORTALITY

MUSCLE WASTINGMUSCLE WASTINGMUSCLE WASTINGMUSCLE WASTING

ANEMIAANEMIAANEMIAANEMIA

IMMUNODEPRESSIOIMMUNODEPRESSIONNIMMUNODEPRESSIOIMMUNODEPRESSIONN

METABOLIC ABNORMALITIES INDUCED BY METABOLIC ABNORMALITIES INDUCED BY PROINFLAMMATORY CYTOKINESPROINFLAMMATORY CYTOKINES

INADEQUATE ENERGY INTAKEINADEQUATE ENERGY INTAKE

ENERGY EXPENDITUREENERGY EXPENDITURE

METABOLIC ABNORMALITIES INDUCED BY METABOLIC ABNORMALITIES INDUCED BY PROINFLAMMATORY CYTOKINESPROINFLAMMATORY CYTOKINES

INADEQUATE ENERGY INTAKEINADEQUATE ENERGY INTAKE

ENERGY EXPENDITUREENERGY EXPENDITURE

WEIGHT LOSSWEIGHT LOSSWEIGHT LOSSWEIGHT LOSS

RESPONSE TO THERAPY, QoL, SURVIVALRESPONSE TO THERAPY, QoL, SURVIVALRESPONSE TO THERAPY, QoL, SURVIVALRESPONSE TO THERAPY, QoL, SURVIVAL

ANOREXIAANOREXIAANOREXIAANOREXIA

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

MAJOR CAUSES OF BODY WEIGHT LOSS IN MAJOR CAUSES OF BODY WEIGHT LOSS IN OLDER PERSONSOLDER PERSONS

MAJOR CAUSES OF BODY WEIGHT LOSS IN MAJOR CAUSES OF BODY WEIGHT LOSS IN OLDER PERSONSOLDER PERSONS

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

Lancet Oncology 2011

Lancet Oncology 2011

To date, attempts at cancer cachexia therapy with a variety ofsingle 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

COMBINED APPROACH

References: Support Care Cancer 2010;18:1–9.Oncologist 2010;15:119–21.

Strategies for intervention in cachexia

Treatment should address the fundamental issues of reduced food intake and abnormal abnormalities

Fearon KC. Clin Nutr 2012; 31:577-582

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 TNFalphaAs 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.

Basic treatmentpoliphenols (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 1Arm 1Medroxyprogesterone acetate (MPA) 500 or

Megestrol Acetate (MA) 320mg/day

rraannddoomm

Arm 2Arm 2Pharmaco-nutritional support with EPA 2-3

cartons/day

Arm 3Arm 3 L-carnitine 4 g/day

Arm 4Arm 4 Thalidomide 200 mg/day

Arm 5Arm 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

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 decreasedsignificantly in arm 1, while no significant change was observed in arm 2.

PATIENT-CENTERED OUTCOME

Fearon KC. Clin Nutr 2012; 31:577-582

IT IS EVIDENT THAT A MULTIDISCIPLINARY APPROACH IT IS EVIDENT THAT A MULTIDISCIPLINARY APPROACH IS NEEDED TO PREVENT CACHEXIA AND MANAGE THE IS NEEDED TO PREVENT CACHEXIA AND MANAGE THE

ASSOCIATED SYMPTOMS TO IMPROVE QUALITY OF LIFE ASSOCIATED SYMPTOMS TO IMPROVE QUALITY OF LIFE FOR PATIENTSFOR PATIENTS

STATO FUNZIONALECapacita’ di lavorare,

di utilizzare il tempo libero, di badare a sé stesso

BENESSERE FISICODisturbi indotti dalla malattia,

Effetti collaterali dei trattamenti

BENESSERE SOCIALEBENESSERE SOCIALERelazione con i familiari Relazione con i familiari

Relazione con i curanti, Relazione con i curanti,

ruolo sociale, ECC.ruolo sociale, ECC.

STATO PSICOLOGICOSTATO PSICOLOGICOAnsia, Ansia,

depressione, depressione,

aggressività, aggressività,

stima e sicurezza di sé, stima e sicurezza di sé,

modificazioni dello schema modificazioni dello schema corporeocorporeo

QUALITA’ DI VITA

QUALITA’ DI VITA

www.esmo2012.org

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.

A group of preschoolers were asked what A group of preschoolers were asked what happens happens

to people when they get old to people when they get old

A group of preschoolers were asked what A group of preschoolers were asked what happens happens

to people when they get old to people when they get old