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PROTEIN ANABOLIC RESISTANCE IN CANCER
Dr. Barbara van der Meij
CRICOS CODE 00017B
CONTENTS
• Obesity and body composition
• Metabolic alterations in cancer
• Protein anabolic resistance
• Implications for clinical practice
The obesity epidemic in cancer
1 9 9 0 1 9 9 2 1 9 9 4 1 9 9 6 1 9 9 8 2 0 0 0 2 0 0 2 2 0 0 4 2 0 0 6 2 0 0 8 2 0 1 0 2 0 1 2
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O b e s i t y t r e n d s i n t h e U S , 1 9 9 0 - 2 0 1 2
Y e a r
% O
be
sity
G e n e r a l P o p u l a t io n
C a n c e r S u r v i v o r s
N S C L C
Engelen et al. Curr Opin Clin Nutr Metab Care. 2015
Correlation BMI and FFMi
Correlation between BMI and FFMI in 186,975 healthy white individuals
R = 0.62, P <0.001.
Franssen et al. J Am Med Dir Assoc. 2014;15(6):448 e1-6
Metabolic alterations in cancer
Argiles, Nat Rev Cancer 2014
Muscle and fat loss in cancer
Prado, AJCN 2013
n=368 lung, colorectal, pancreatic and cholangiocarcinoma
Studies in different types of cancer:
• Changes in plasma amino acids (e.g. decreased arginine, glutamine, citrulline)
• Increased protein turnover
• Increased muscle protein breakdown
Protein metabolism in cancer
Lai Sem Cancer Biol 2005, Miyagi et al. PLoS One. 2011, Fukutake et al. PLoS ONE. 2015, van Dijk, J Cach Muscle Wasting 2015, van der Meij, unpublished data
Associated with…
• Fatigue and apathy
• Hospital length of stay ↑
• Increased susceptibility to infection
• Postoperative complications and mortality ↑
• Delay in return to work
• Poor quality of life
• Response to chemo/radiotherapy ↓
• Treatment toxicity ↑Komurcu, SO, 2000, Rosenbaum, JPEN, 2000,
Curt, Oncol, 2000; Grossmann, Surg, 2002; Spelten, EJC, 2003, Argiles, Eur J Oncol Nurs, 2005, Gordon,
QJM, 2005, Prado, Appl Physiol Nutr Metab, 2014, Barret, Nutr Cancer, 2014
Weight loss / muscle wasting in cancer:
Sarcopenia and toxicity
• Breast cancer, n=55
• Sarcopenia: n=14 (25.5%)
• Sarcopenic patients:
more dose limiting toxicity
Prado, Clin Cancer Res 2009
Can cancer patients have an anabolic response to food?
Primed and constant continuous stable isotope infusion: 2H5-Phe, 13C915N-Tyr, D5-Trp
Stable isotope pulse: 2H3-Leu, [2H3]-3-MetHis, 2H2-Gly, 2-D-OHPro,
1-13C-KIC, 15N2-ARG, 2H2-CIT, 13C-Urea,
1,2-13C2 Taurine
X
XX
DXA (wb, hip and spine) & BIA
X
X
Blood sampling
Intake of complete high protein meal and 13C-Phe, 13C3-Tripalmitin, 2H2-Palmitic acid, 15N-Spirulina
Respiratory and handgrip muscle function
Questionnaires (wellbeing, diet, and cognition)
Kin Com one leg exercise X
T=-1h T=0h T=2hT=1h T=3h T=4h T=5h T=6h T=7hT=7.5h
• n=16 cancer patients and n=16 healthy subjects
Maximum Inspiratory Pressure (MIP)Maximum Expiratory Pressure (MEP)
Hand grip strength
Leg extension (KinCom)
Body composition
Cancer(n=16)
Healthy (n=16)
P-value
Gender n (%) M / F 9 / 7 9 / 7 1.00
Age y 60.1 (16.6) 59.8 (15.9) 0.97
Weight kg 72.7 (16.1) 77.3 (12.9) 0.38
BMI Overweight n (%)Obesity n (%)
kg/m² 26.8 (5.4)4 (25)4 (25)
26.7 (3.2)7 (43.8)4 (25)
0.95
0.47
FFM-i kg/m² 17.7 (2.2) 18.1 (2.4) 0.56
Arms FFM kg 5.2 (1.8) 5.8 (1.7) 0.30
Legs FFM kg 15.0 (3.2) 16.7 (3.5) 0.14
van der Meij, unpublished data
Myofibrillar protein breakdown -fasted
MEAL:BOOST High Protein drink (237 mL)15g protein, 6g fat, 33 g carbohydrates
van der Meij, unpublished data
Mean (SD) Unit Healthy controls
(n=16)
Cancer patients
(n=16)
P-value
Muscle function
Maximal inspiratory pressure cmH2O 102.8 (40.2) 72.2 (30.6) 0.17
Maximal expiratory pressure cmH2O 112.8 (41.7) 96.2 (33.9) 0.45
Handgrip strength N 292 (66) 236 (96) 0.06
/FFM 5.5 (1.0) 4.8 (1.3) 0.08
Handgrip endurance % lost 25.4 (6.8) 23.5 (13) 0.61
Leg extension strength N 374 (140) 253 (118) 0.01
N/FFM 42.6 (10.2) 32.6 (10.8) 0.01
Leg extension endurance % lost 25.4 (13.3) 29.3 (11.4) 0.42
Muscle function
High-protein supplement → anabolism
• n=8 pancreatic cancer and n=7 healthy controls
FORTISIP High Protein drink (200 mL)12g protein, 6g fat, 37 g carbohydrates
van Dijk, J Cach Muscle Wasting 2015
Essential Amino Acids (EAA) → anabolism
Engelen, Ann Oncol 2015
EAA intake (umol/kg FFM)
Net
pro
tein
an
abo
lism
14 g EAA/leucine mixture
Conclusion:Not enough solid evidence for protein supplements in cancer
• HMB, arginine and glutamine: – Increase in lean body mass after 4 weeks in advanced solid tumour
patients– No benefits in lung cancer after 8 weeks
• L-carnitine in pancreatic caner: increase of BMI and survival
Mochamat, J Cachexia Sarcopenia Muscle 2016
Summary
• Body composition in cancer is relevant: – Obesity and aging epidemic– High body fat and low muscle mass: associated with toxicity,
muscle weakness, impaired quality of life and mortality
• Cancer patients have a higher protein turnover than healthy subjects– Higher muscle protein breakdown– Similar anabolic potential– Protein supplementation works (short-term)– Limitation: small sample sizes
• Where to go from here?
Recommendations
ESPEN guidelines on Nutrition in Cancer Patients:
• Aim: 1.2 – 1.5 g protein/kg body weight
• Higher quality protein is recommended
• Promote physical exercise throughout cancer treatment
• Future research:
– Effects of long-term protein supplementation (>1.2 g/kg)
– Effects on muscle mass, muscle function, quality of life
– Additional effect of physical exercise and pharmaceutics (multimodal interventions)
Arends, Clin Nutr 2017
Dr. Mick Deutz
Dr. Marielle Engelen
Department of Health and KinesiologyCenter for Translation Research on Aging and Longevity
Texas A&MCollege Station, TX, USA
ACKNOWLEDGEMENT
