UPDATES OF IMMUNONUTRITION THERAPY IN SURGERY AND Taiwan Surgical Association Meeting Taipei - March 18, 2018 UPDATES OF IMMUNONUTRITION THERAPY IN SURGERY AND ONCOLOGY PATIENTS Marco Braga Professor of Surgery San Raffaele University , Milan

Switching philosophy Nutritional therapy ( Braga, Clin Nutr 2016 ) Switching philosophy Nutritional therapy “ the classic concept “ Nitrogen and Energy to support patients’ nutritional status Indications: Undernourished patients Pharmaconutrition or Immunonutrition Specific substrates to modulate inflammatory and immune response Indications: Patients undergoing GI cancer surgery regardless of their nutritional status

Perioperative Immunoinutrition Plasma Arginine (mmol/L) Plasma NO (mmol/L) 20 40 60 80 100 120 140 160 50 * * 40 * * 30 20 10 Days Day + 8 - 8 1 - 1 2 + 1 3 +4 4 + 8 5 6 Day - 1 Control Supplemented Braga, Arch Surg 1996

PERIOPERATIVE IMMUNONUTRITION Lower PGE2 serum level after surgery Higher IFN-gamma production after surgery Higher mRNA expression Th1 transcription factor Modulate Th1 / Th2 differentiation Suzuki, Surgery 2010 Aida, Surgery 2014

Gianotti, JPEN 1999

Perioperative Immunonutrition G-I cancer surgical patients Author Blinding IsoN Pts Infection rate p Braga ‘99 yes yes 206 13 % vs 29 % 0.02 Senkal ‘99 yes yes 154 13 % vs 24 % 0.08

reimbursement rates (€) Total costs and DRG reimbursement rates (€) Conventional Pre -op IMN Uncomplicated pts 184,725 229,208 Complicated pts 535,236 334,148 Nutrition 3,047 14,729 Total 578,085 723,368 DRG reimbursement 781,392 740,301 Difference 58,024 162,216 Braga, Nutrition 2005

Immunonutrition McClave JPEN 2013 Perioperative pharmaconutrition (formula containing arg, w-3 and nucleotides) has been shown to reduce infection, other complications, and LOS in patients undergoing major upper or lower gastrointestinal cancer surgeries, regardless of preexisting nutrition status. 9 McClave JPEN 2013

Latest Meta-analysis (83 RCTs, 7116 Pts ) IMNs reduced Infection Rate and LOS ( p< 0.001) even after exclusion of high - risk of bias RCTs RCTs Infection rate LOS GLUTAMINE 19 p = 0.003 p < 0.001 ARGININE 32 p < 0.001 p = 0.003 OMEGA- 3 52 p < 0.001 p < 0.001 RNA 25 p < 0.001 p < 0.001 Probst, Br J Surg 2017

264 well-nourished patients ( 75% laparoscopic surgery ) 7 days before surgery + 5 days after surgery Moya, Medicine 2016

Who benefit from immunonutrition? Weimann A., Braga M., Carli F. et al. Clin Nutr 2017 Who benefit from immunonutrition? Patients with high risk for postoperative infections should receive perioperative immunonutrition even if operations including those for cancer have to be delayed.

THE OXIDATIVE STRESS VICIOUS CIRCLE Ischemia/Reperfusion Tissue cells infiltration Oxygen compsuption Cytokines release ATP AMP ROS production Xantine dehidrogenase Xantine oxidase Respiratory Burst reactions Oxidative stress NF-κB Macrophages activation DNA, proteins and lipid dammage Cell death Inflammation Release of IL-1β, TNF-α, Il-6, IL-8

ANTIOXIDANTS IN CRITICALLY ILL PATIENTS MORTALITY Heyland Int Care Med 2005

POSTOPERATIVE ENTERAL ANTIOXIDANTS WELL TOLERATED AND METABOLICALLY SAFE IMPROVEMENT IN ANTIOXIDANT CONCENTRATIONS IMPROVEMENT IN ANTIOXIDANT DEFENSES Preiser CCM 2000 Nathens Ann Surg 2002 Senkal Clin Nutr 2004 Schroeder EJCN 2005

ANTIOXIDANTS (BOOSTER (300 mL) Vitamin C 750 mg Vitamin E 250 mg Selenium 150 μg Zinc 10 mg β-carotene 5 mg Green tea extract 1 g Glutamine 15 g Glucose 50 g

PLACEBO CONTROLLED TRIAL RANDOMIZED BLIND PLACEBO CONTROLLED TRIAL PANCREATIC RESECTION 1° Dose – 18 h 2° Dose - 12 h 3° Dose - 2 h Baseline D +1 D +3 D +7 D +30 T.A.C. CRP Antioxidants T.A.C. CRP Antioxidants T.A.C. CRP Antioxidants T.A.C. CRP Antioxidants Final visit Braga, Nutrition 2012

ANTIOXIDANTS BOOSTER Braga, Nutrition 2012

TOTAL ANTIOXIDANT CAPACITY * *** ** * p =0.017 ** p = 0.004 *** p = 0.001 Braga, Nutrition 2012

Quality of protein intake in cancer TPN enriched with branched-chain A.-A. improved albumin synthesis. Tayek, Cancer 1986 Hunter, BJS 1989 TPN enriched with leucin and omega-3 fatty acids increased muscle protein synthesis. Deutz, Clin Nutr 2011

Glutamine in cancer patients Glutamine is a semi-essential A.-A. in catabolic conditions, including cancer. Positive effect of Glutamine supplementation on chemotherapy toxicity Kuhn, Clin Nutr 2010

Oral Glutamine reduces CT-RT toxicity Head and Neck cancer Kaohsiung University. ClinicalTrials.gov 2017 Lopez-Vaquero Mol Clin Oncol 2017 Chattopadhyay, South Asian J Cancer 2014 Lung cancer Gul, Asian Pac J Cancer Prev 2015 Colorectal cancer Wang, The Oncologist 2007 Mixed cancer Sayles, Nutr Clin Pract 2016 Anderson, Cancer 1998

Body Composition assessed by CT Scan ( L3 ) in Pancreatic Cancer Surgical Patients Subcutaneous Fat Visceral Fat Muscle Mass Sarcopenia Rate : 64% Severe Weight Loss : 25% Pecorelli, Br J Surg 2016

Sarcopenia in Colorectal Cancer Association with preoperative CRP Association with T-stage and lymphatic invasion Increased postoperative complications Reduced overall and disease-free survival Mie University Hospital

60-day Mortality Following PD Multivariate stepwise logistic regression C-statistics index: 0.871 (95%CI: 0.800 – 0.943) Hosmer-Lemeshow test: p-value = 0.618 Pecorelli, BJS 2016

PREHABILITATION Relaxation Techniques MULTIMODAL APPROACH Relaxation Techniques Medical / Pharmacological Optimization Physical Activity ( Aerobic, Respiratory ) Specialized Nutrition

Change in %LBM from baseline Change in % body fat from baseline Prehabilitation changes body composition preop. and postop. vvv Change in %LBM from baseline Change in % body fat from baseline % of lean body mass (LBM) and fat measured using hand-to-foot bio-electrical impedance analyzer

IMMUNONUTRITION IN SURGERY FUTURE TRENDS Molecular signalling pathway Dose - Response Studies Sarcopenic patients Neoadjuvant treatment