X-FILES IN NUTRIZIONE CLINICA ED ARTIFICIALE ONCOLOGIA E NUTRIZIONE, DALLA PREVENZIONE ALLA TERAPIA

Centro Internazionale di Studi Fondazione Germana Gaslini

Genova, 7-8 Giugno 2012

Targeting: fabbisogno di amino acidi ed attività motoria nella sarcopenia cancro-correlata

Sara Mazzucco e Gianni Biolo

Dipartimento di Scienze Mediche, Chirurgiche e della Salute Clinica Medica

Università di Trieste

È una condizione caratterizzata da perdita di massa e forza muscolare

SARCOPENIA: sarx (carne) + penia (perdita)

• Perdita di funzionalità muscolare • Aumento incidenza di cadute • Aumento ospedalizzazione • Perdita di autonomia

È una condizione caratterizzata da perdita di massa e forza muscolare

SARCOPENIA: sarx (carne) + penia (perdita)

DEGRADAZIONE PROTEICA

↑ sistemi di degradazione proteici

SINTESI PROTEICA

↓ sensibilità anabolica

↑ sintesi proteine della fase acuta

Acharyya & Guttridge, Clin Cancer Res 2007; Tisdale, Physiol Rev. 2009

• Perdita di funzionalità muscolare • Aumento incidenza di cadute • Aumento ospedalizzazione • Perdita di autonomia

Weight and Body Composition Changes during and after Adjuvant Chemotherapy in Women with Breast Cancer

Freedman et al., J Clin Endocrinol Metab 2004

CHEMOTHERAPY PRE 2 wk 6 wk

MASSA MAGRA

39

40

41

42

43

21

22

23

24

kg kg

time effect P < 0.05

time effect P < 0.05

MASSA GRASSA

2115 cancer patients

15% obesity

15% sarcopenic obesity

SURVIVAL

Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Prado et al., Lancet Oncol 2008

RESISTENZA ANABOLICA

AD AMINOACIDI E PROTEINE

BILANCIO ENERGETICO

POSITIVO

INFIAMMAZIONE CRONICA

SISTEMICA

RIDOTTA ATTIVITÀ FISICA

CROSS-TALK TRA MASSA GRASSA E MASSA MAGRA NEL SOGGETTO SARCOPENICO:

IL CIRCOLO VIZIOSO

ATROFIA MUSCOLARE INSULINO-

RESISTENZA

DEPOSITO MASSA GRASSA

(addominale – periferico – epatico – muscolare)

STRESS OSSIDATIVO

RUOLO DEL BILANCIO ENERGETICO:

1. EFFETTI DEL BILANCIO ENERGETICO POSITIVO

2. EFFETTI DEL BILANCIO ENERGETICO NEGATIVO

TRATTAMENTO DELLA RESISTENZA ANABOLICA:

1. EFFETTI DI UNA DIETA IPERPROTEICA

2. EFFETTI DI UNA COSTANTE ATTIVITÀ FISICA

3. EFFETTI COMBINATI DI DIETA IPERPROTEICA E UNA COSTANTE ATTIVITÀ FISICA

RUOLO DEI NUTRIENTI FUNZIONALI

SARCOPENIA CANCRO-CORRELATA

Weight and Body Composition Changes during and after Adjuvant Chemotherapy in Women with Breast Cancer

Freedman et al., J Clin Endocrinol Metab 2004

CHEMOTHERAPY PRE 2 wk 6 wk

MASSA MAGRA

39

40

41

42

43

21

22

23

24

kg kg

time effect P < 0.05

time effect P < 0.05

MASSA GRASSA

5000

5250

5500

5750

6000 time effect P = 0.02.

RMR

REDUCED ENERGY NEEDS WITH CHEMOTHERAPY

PHYSICAL ACTIVITY

ENERGY INTAKE

(kJ/

d)

Reduced rates of metabolism and decreased physical activity in breast cancer patients receiving adjuvant chemotherapy.

Demark-Wahnefried et al., Am J Clin Nutr. 1997

Variazioni di massa GRASSA (bioimpedenza)

Bilancio energetico positivo

Bilancio energetico neutro

Variazioni dello spessore vastus lateralis

(ecografia)

*, p<0.05 statisticamente diverso da zero; §, p<0.05 versus bilancio energetico neutro

∆ (c

m)

∆ (k

g)

-5

-4

-3

-2

-1

0

*§

*

-0,5

-0,4

-0,3

-0,2

-0,1

0

*§

0

1

2

3 * §

∆ (k

g)

Variazioni di massa MAGRA (bioimpedenza)

Positive energy balance is associated with accelerated muscle atrophy and increased erythrocyte glutathione turnover during 5 wk of bed rest

Biolo et al., Am J Clin Nutr. 2008

Bilancio energetico positivo

Bilancio energetico neutro

*, p<0.05 statisticamente diverso da zero; §, p<0.05 versus bilancio energetico neutro

Δ (%

)

Δ (%

)

Proteina C reattiva Mieloperossidasi plasmatica Sintesi eritrocitaria di glutatione

Δ (%

)

-50

0

50

100

150

200§

-10

-5

0

5

10

15

20

25 §

-50

0

50

100

150

200§ *

Positive energy balance is associated with accelerated muscle atrophy and increased erythrocyte glutathione turnover during 5 wk of bed rest

Biolo et al., Am J Clin Nutr. 2008

0

5

10

15

500

550

600

650

700

750

STEPS/DAY TOTAL FAT ABDOMINAL FAT

kg ml *

*, P<0.05

Metabolic Responses to Reduced Daily Steps in Healthy Nonexercising Men

Olsen et al. JAMA 2008

2 wk PRE

Calorie restriction accelerates the catabolism of lean body mass during 2 wk of bed rest

Biolo et al., Am J Clin Nutr 2007

-1,4

-1

-0,6

-0,2

0,2

a,b,c

Deambulazione

Bed rest sperimentale

Δ m

assa

mag

ra (D

EXA

) (k

g)

Bilancio energetico NEGATIVO

Bilancio energetico NEUTRO

501 ± 39 kcal 0.8 g protein/kg ideal BW

559 ± 79 kcal 1.5 g protein/kg ideal BW

WEIGHT LOSS p = NS p < 0.01

NITROGEN BALANCE

Metabolic Effects of Very Low Calorie Weight Reduction Diets

Hoffer et al., J Clin Invest 1984

BILANCIO ENERGETICO POSITIVO ACCELERA L’ATROFIA MUSCOLARE PER AUMENTO DI STRESS OSSIDATIVO E ATTIVAZIONE DELLA FLOGOSI

BILANCIO ENERGETICO NEGATIVO ACCELERA L’ATROFIA MUSCOLARE

RESTRIZIONE CALORICA DEVE ESSERE ASSOCIATA AD

1. AUMENTO INTROITO PROTEICO

2. IDONEO PROGRAMMA DI ESERCIZIO FISICO

CONCLUSIONE (I)

Effects of amino acid infusion on skeletal muscle protein balance in severely burned patients

Biolo & Wolfe, Clinical Nutrition (abstract) 2001

-80

0

80

feni

lala

nina

(nm

ol/m

in/1

00 m

l)

Digiuno Infusione aminoacidi

*

Volontari sani

Pazienti ustionati

*, P<0.05 vs. digiuno #, P<0.05 vs. volontari sani

*#

#

BIL

AN

CIO

PR

OTE

ICO

MU

SCO

LAR

E

RESISTENZA ANABOLICA: ruolo dell’infiammazione

Short-term bed rest impairs amino acid-induced protein anabolism in humans

Biolo et al., J Physiol 2004

*

*, P<0.05 vs. ambulatory condition

*#

#

RESISTENZA ANABOLICA: ruolo dell’inattività fisica

Inactivity amplifies the catabolic response of skeletal muscle to cortisol

Ferrando et al., J Clin Endocrinol & Metab, 1999

Bed rest 14-days

Ambulatory 5-days

12-h hydrocortisone infusion (120 microg/kg/h)

-75

-50

-25

0

nmol

phe

nyla

lani

ne/

/min

/100

ml l

eg v

ol.

MUSCLE PROTEIN BALANCE

Activity Inactivity

P<0.05

RESISTENZA ANABOLICA: ruolo combinato di infiammazione ed inattività fisica

NUTRIZIONE ENTERALE NEL TRATTAMENTO DELLA SARCOPENIA CANCRO-CORRELATA:

LINEE GUIDA – FABBISOGNO PROTEICO

… …

NUTRIZIONE ENTERALE NEL TRATTAMENTO DELLA SARCOPENIA CANCRO-CORRELATA:

LINEE GUIDA

PROTEIN REQUIREMENT IN CRITICAL ILLNESS AT ADEQUATE ENERGY INTAKE

Wolfe et al., Ann Surg 1983; Ishibashi et al., Crit Care Med 1998 Hoffer Am J Clin Nutr 2003

200

130

80 45

PROTEIN REQUIREMENT IN CRITICAL ILLNESS AT ADEQUATE ENERGY INTAKE

Wolfe et al., Ann Surg 1983; Ishibashi et al., Crit Care Med 1998 Hoffer Am J Clin Nutr 2003

-2

-1.5

-1

-0.5

0

Who

le-b

ody

prot

ein

loss

(k

g / 2

wee

ks)

-2

-1.5

-1

-0.5

0

Who

le-b

ody

prot

ein

loss

(k

g / 2

wee

ks)

g protein / kg IBW per day

≈ 1.5 ≈ 2.2

200

130

80 45

≈ 0.7 ≈ 1.0

Non-protein calories – to – nitrogen ratio

Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food

Deutz et al., Clinical Nutrition 2011

*

*, compared to postabsorptive state

Design: Randomized, controlled, double-blind, parallel-group design 25 patients with cancer. Experimental group (EXP, n=13): 40 g proteins (casein + whey protein) and enriched with 10% free leucine. Control group (n=12): casein protein (24 g). Conclusions: In cancer patients, conventional nutritional supplementation is ineffective in stimulating muscle protein synthesis. This anabolic resistance can be overcome with a specially formulated nutritional supplement.

Objective: Maintenance of muscle mass is crucial to improving outcome and quality of life in cancer patients. Stimulating muscle protein synthesis is the metabolic basis for maintaining muscle mass, but in cancer patients normal dietary intake has minimal effects on muscle protein synthesis.

WISE study

(Women International Space Simulation for

Exploration)

ESA–CNES–NASA–CSA

EFFETTO DELLA SUPPLEMENTAZIONE PROTEICA SULL’ATROFIA MUSCOLARE E SULLE ALTERAZIONI METABOLICHE INDOTTE DA

INATTIVITÀ FISICA

Muscolo scheletrico

RECOVERY (20 days)

ADAPTATION (20 days)

EXPERIMENTAL BED REST (60 days)

N = 8

N = 8

Standard protein = 1 g / (kg · day) Ambulatory condition

High protein = 1.4 g protein + 0.16 g BCAA / (kg · day)

Ambulatory condition

Ambulatory condition

Ambulatory condition

EFFETTO DELLA SUPPLEMENTAZIONE PROTEICA SULL’ATROFIA MUSCOLARE E SULLE ALTERAZIONI METABOLICHE INDOTTE DA

INATTIVITÀ FISICA

Mus

colo

ca

rdia

co

WISE

WISE study

(Women International Space Simulation for

Exploration)

ESA–CNES–NASA–CSA

EFFETTO DELLA SUPPLEMENTAZIONE PROTEICA SULL’ATROFIA MUSCOLARE E SULLE ALTERAZIONI METABOLICHE INDOTTE DA

INATTIVITÀ FISICA

Sensibilità insulinica

RECOVERY (20 days)

ADAPTATION (20 days)

EXPERIMENTAL BED REST (60 days)

N = 8

N = 8

Standard protein = 1 g / (kg · day) Ambulatory condition

High protein = 1.4 g protein + 0.16 g BCAA / (kg · day)

Ambulatory condition

Ambulatory condition

Ambulatory condition

basale 60 gg bed rest

American Cancer Society Guidelines 2006

LINEE GUIDA – ATTIVITÀ FISICA

…

…

Ferrando et al., J Appl Physiol 1997

EFFETTO DELL’ATTIVITÀ FISICA ANAEROBIA COSTANTE SULLA SINTESI PROTEICA MUSCOLARE (MPS)

controllo resistance training

*, p<0.05 vs BR-1

Recreational Physical Activity and the Risk of Breast Cancer in Postmenopausal Women The Women’s Health

Initiative Cohort Study Mc Tiernan et al., JAMA 2003

Conclusions These data suggest that increased physical activity is associated with reduced risk for breast cancer in postmenopausal women, longer duration provides most benefit, and that such activity need not be strenuous.

Design Prospective cohort study in 74171 women aged 50 to 79 years

Effects of Aerobic and Resistance Exercise in Breast Cancer Patients Receiving Adjuvant Chemotherapy: A Multicenter

Randomized Controlled Trial Courneya et al., J Clin Oncol 2007

Purpose Breast cancer chemotherapy may cause unfavorable changes in physical functioning, body composition, psychosocial functioning, and quality of life (QOL). We evaluated the relative merits of aerobic and resistance exercise in blunting these effects. Patients and Methods Multicenter randomized controlled trial in Canada between 2003 and 2005 that randomly assigned 242 breast cancer patients initiating adjuvant chemotherapy to usual care (n 82), supervised resistance exercise (n 82), or supervised aerobic exercise (n 78) for the duration of their chemotherapy (median, 17 weeks). Results The follow-up assessment rate for our primary end point was 92.1%, and adherence to the supervised exercise was 70.2%. Aerobic exercise was superior to usual care for improving self-esteem (P= .015), aerobic fitness (P= .006), and percent body fat (adjusted P=.076). Resistance exercise was superior to usual care for improving self-esteem (P .018), muscular strength (P= .001), lean body mass (P= .015), and chemotherapy completion rate (P= .033). Exercise did not cause lymphedema or adverse events. Conclusion Neither aerobic nor resistance exercise significantly improved cancer-specific quality of life in breast cancer patients receiving chemotherapy, but they did improve self-esteem, physical fitness, body composition, and chemotherapy completion rate without causing lymphedema or significant adverse events.

Physical Activity and Survival After Breast Cancer Diagnosis

Holmes et al., JAMA 2005

Conclusions Physical activity after a breast cancer diagnosis may reduce the risk of death from this disease. The greatest benefit occurred in women who performed the equivalent of walking 3 to 5 hours per week at an average pace.

Design •Prospective observational study, •2987 female registered nurses •who were diagnosed with stage I, II, or III breast cancer.

Framework PEACE: an organizational model for examining Physical Exercise Across the Cancer Experience

University of Alberta, Edmonton, Canada. Ann Behav Med. 2001

Risk reduction Colon, breast, prostate, endometrial cancers

Improve screening

compliance Boost physical

and physiological functioning

Improve functional

capacity and quality of life Improve

Survival

Adjusting for covariates (age at inclusion, BMI at inclusion, and BMD of the femoral neck at inclusion) a significant (P < 0.05) difference was seen in the response to training of bone mineral density between the two groups.

Strength improvements from 6 to 24 wk, a significant difference was apparent between groups: nutrient group, 9±3% vs. control, 1±2% (P < 0.05).

Protein-containing nutrient supplementation following

strength training enhances the effect on muscle mass,

strength, and bone formation in postmenopausal women

Holm et al., J Appl Physiol 2008

Timing of postexercise protein intake is important for muscle hypertrophy with resistance training in elderly humans

Esmarck et al., J Physiol 2001

FATTORI CHIAVE NELLO SVILUPPO DI RESISTENZA ANABOLICA SONO:

1. ATTIVAZIONE FLOGOSI

2. DIMINUZIONE DELL’ATTIVITÀ FISICA

FABBISOGNO PROTEICO AUMENTA: MINIMO 1.2 g/kg/die

ATTIVITÀ FISICA È ANABOLICA DI PER SE E MIGLIORA L’EFFETTO ANABOLICO DELLA SUPPLEMENTAZIONE PROTEICA

CONCLUSIONI (II)

*

Inactivity-mediated insulin resistance is associated with upregulated pro-inflammatory fatty acids in human cell

membranes Mazzucco et al., Clin Nutr 2010

Fish-oil supplementation enhances the effects of strength training in elderly women

Rodacki et al., Am J Clin Nutr 2012

ST, 90-d strength training. ST90, 90-d strength training + 90 d fish oil supplementation. ST150, 90-d strength training + 150 d fish oil supplementation. N=45 (aged 64±1.4 y)

8 weeks supplementation

Dietary omega-3 fatty acid supplementation increases the rate of muscle protein synthesis in older adults: a randomized controlled trial Smith et al., Am J Clin Nutr 2011

n=7

n=8

FSR, fractional synthesis rate a, P < 0.01 in the corn oil group, clamp vs basal (ANOVA) b, P < 0.01 in the omega-3 fatty acid group, clamp vs basal (ANOVA) c, P < 0.01 in the omega-3 fatty acid group, different from the corresponding value before omega-3 fatty acid supplementation CLAMP=insulin + glucose + aminoacid infusion

GLI ACIDI GRASSI ω3

• MIGLIORANO L’AUMENTO DI FORZA MUSCOLARE INDOTTO DALL’ESERCIZIO FISICO

• MIGLIORANO LA STIMOLAZIONE ANABOLICA INDOTTA DA SOMMINISTRAZIONE DI AMINOACIDI

CONCLUSIONI (III)