Transcript Cachexia - Mediterranean School Of Oncology

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
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 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 ELDERLY
Reduced basal hunger, dysgeusia, decreased gastric
emptying time, failure to adjust food intake after a
period of overfeeding or underfeeding
NORMAL AGING
ENDOCRINE DISORDERS
MEDICATIONS
PSYCHIATRIC
CHRONIC DISEASE
INFECTIONS
SYSTEM DISEASES
Hyperthyroidism, hyperparathyroidism
and hypoadrenalism
Theophylline, lithium, digoxin, chemotherapy,
antibiotics, etc….
Dementia, depression, anorexia nervosa,
alcoholism, and paranoia (late-life)
COPD, CHF, rheumatoid arthritis, AIDS, cancer
Acute and chronic infections, gastritis, cholecystitis
Stroke, Parkinson’s disease, sclerodermia
From Morley J Am Geriatr Soc 1994
FACTORS INVOLVED IN AGEING WEIGHT LOSS
CAUSES OF BODY WEIGHT LOSS IN THE ELDERLY
Thomas DR. Clinical Nutrition 2007
Anorexia in the aging
Biological mechanisms of anorexia in the aging
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
ETIOLOGY OF SARCOPENIA
SKELETAL MUSCLE ALTERATIONS LEADING TO
SARCOPENIA
AGING
↓ SEX STEROIDS
↑ CATHECOLAMINE
IL-6
FUNCTIONAL DISABILITY
INCREASED MORBIDITY AND MORTALITY
PHYSICAL DISABILITY (ADL)
COGNITIVE IMPAIRMENT
DECREASED HEMOGLOBIN LEVELS
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
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
CACHEXIA IS A COMPONENT OF THE HOST
NON SPECIFIC RESPONSE TO INFLAMMATION
PCR
Low RIL-2
expression
Low IL-2
production
INFLAMMATORY
CYTOKINES
ROS
MACROPHAGE
ACTIVATION
TUMOR
Metabolic components of cachexia are initiated by the same processes
which drive the non specific host immune response to a growing tumor
LYMPHOCYTES
CANCER
MONOCYTES/
MACROPHAGES
CYTOKINES IL-1, IL-6, TNFa
CENTRAL NERVOUS
SYSTEM
 CRH AND
SOMATOSTATINE
 GH  ANOREXIA
LIPID
METABOLISM
 LIPOPROTEINLIPASE
GLUCIDIC
METABOLISM
DAMAGE ON
PANCREATIC b CELLS
IPOINSULINEMIA
 IGF-1
LYPOLISIS
IPERTRIGLICERIDEMIA
PROTEOLYSIS
 ADIPOCYTE SIZE
IMPAIRED GLUCOSE
METABOLISM
NAUSEA AND
VOMITING
 FAT TISSUE
IPO/IPERGLICAEMIA
Semin Oncol 1998; 25 (Suppl 6): 45-52.
ACTIVATED
IMMUNE SYSTEM
5-HT, CYTOKINES
CRH
Neuropeptide Y
Anorexia
Nausea/vomiting
REDUCED FOOD INTAKE
CHANGES OF GLUCOSE METABOLISM IN
CACHEXIA
 PROTEIN AND LIPID
STORES
GLYCEROL +
FREE FATTY
ACIDS
b)
 GLUCONEOGENESIS
a)
 CORI CYCLE
c) IMPAIRED GLUCOSE TOLERANCE
d) INSULIN RESISTANCE
HYPERGLICAEMIA/
HYPOGLICAEMIA
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
CHANGES OF LIPID METABOLISM IN CANCER CACHEXIA
GLUCONEOGENESIS
TNF a
↓ LIPOPROTEINLIPASE
ACTIVITY
TNF a
IL-1
↑ HORMONE-SENSITIVE
LIPASE ACTIVITY
↓ LIPOGENESIS
LOSS OF BODY FAT
OXIDATIVE STRESS IS THE CONSEQUENCES OF
THE INEFFICIENCY OF ENERGY METABOLISM
ENERGY SUBSTRATES
(Glucose)
Penthose-phosphate
pathway
glycolysis
NADPH
Ribose
5-Phosphate
Krebs’s cycle
CO2, H2O
FADH, NADH, ATP
GSH
LOW LEPTIN LEVELS
Oxidative stress
ROS
Weight loss Anorexia
Improvement of
anorexia and
Energy expenditure
energy expenditure
TUMOR
T-LYMPHOCYTES
MACROPHAGES
Cytokines
IL-1,IL-6,TNF
ROS
ROLE OF LEPTIN IN DISEASE PROGRESSION
CANCER
INFLAMMATORY
RESPONSE
IL-6
WASTING
DECREASED
ENERGY-INTAKE
(LOSS OF FAT)
 LEPTIN
 CELLULAR IMMUNITY
 MORBIDITY/MORTALITY
METABOLIC ABNORMALITIES INDUCED BY
PROINFLAMMATORY CYTOKINES
INADEQUATE ENERGY INTAKE
 ENERGY EXPENDITURE
WEIGHT LOSS
ANEMIA
ANOREXIA
MUSCLE WASTING
IMMUNODEPRESSION
RESPONSE TO THERAPY, QoL, SURVIVAL
FIRSTLY, TO ATTEMPT TO IDENTIFY AND TREAT ANY SPECIFIC
UNDERLYING TREATABLE OR CONTRIBUTING CONDITIONS
MAJOR CAUSES OF BODY WEIGHT LOSS IN
OLDER 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
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 cancerrelated symptoms that affect patient Quality of Life
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 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.
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
+
r
a
n
d
o
m
Arm 1
Medroxyprogesterone acetate (MPA) 500 or
Megestrol Acetate (MA) 320mg/day
Arm 2
Pharmaco-nutritional support with EPA 2-3
cartons/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
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.
PATIENT-CENTERED OUTCOME
Fearon KC. Clin Nutr 2012; 31:577-582
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
STATO FUNZIONALE
Capacita’ di lavorare,
di utilizzare il tempo libero,
di badare a sé stesso
Disturbi indotti dalla malattia,
Effetti collaterali dei trattamenti
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.
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.
www.esmo2012.org
A group of preschoolers were asked what happens
to people when they get old