SINPE trial, Ann Surg Overall morbidity. Minor Major. Infectious Non infectious. Post-hoc analysis WL < %5 (n=379) WL between 5-10% (n=49)

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1 Chinese International Symposium on Nutritional Oncology Changchun, June IMMUNONUTRITION IN CANCER PATIENTS IMMUNONUTRITION IN SURGERY OBJECTIVE To get the patient undergoing major surgery for cancer metabolically ready Marco Braga M.D. Professor of Surgery San Raffaele University - Milan NUTRITION IN SURGERY BRAGA, Curr Opin Clin Nutr Metabol Care 2012 SINPE trial, Ann Surg 2009 Overall morbidity Ala-Glu (n=212) Control (n=216) 74 (34.9%) 71 (32.9%) RR (95% CI) 1.06 ( ) p 0.65 III MILLENNIUM NUTRITIONAL THERAPY : Specific substrates with metabolic effects Minor Major Infectious Non infectious Post-hoc analysis WL < %5 (n=379) WL between 5-10% (n=49) 58 (27.4%) 16 (7.5%) 41 (19.3%) 33 (15.6%) (34.9%) (34.6%) 54 (25.0%) 17 (7.9%) 37 (17.2%) 34 (15.7%) (32.6%) (34.8%) 1.09 ( ) 0.95 ( ) 1.12 ( ) 0.98 ( ) 1.07 ( ) 0.99 ( ) Target Major Surgery Patients, regardless of baseline nutritional status Lower GI tract (n=280) Upper GI tract (n=148) (30.4%) (42.9%) (28.3%) (42.3%) 1.07 ( ) 1.01 ( ) Patients needing postop. AN Parenteral Enteral 28 (13.2%) 22 (10.3%) 6 (2.9%) 26 (12.0%) 18 (8.3%) 8 (3.7%) 1.09 ( ) 1.24 ( ) 0.76 ( ) Length of postoperative stay Median (range) 10.2 (4.8) 9.9 (3.9) 9.0 (5-40) 8.5 (5-33) PERIOPERATIVE N-3 FATTY ACIDS ESPEN GUIDELINES Patients : 195 Esophagogastric Cancer Groups : Periop. n-3 vs. Periop. Standard vs. Postop. Standard Results : No outcome difference GI cancer patients should receive perioperative Immunonutrition ( Arg + n-3 + Nucl. ), regardless of their baseline nutritional status ( grade A) A Clin Nutr 2006 Sultan, Br J Surg 2012

2 IL-1 R II (pg/ml) IL-6 (pg/ml) Supplemented Days Control Days Gianotti, JPEN 1999 ARGININE / N-3 FATTY ACIDS INTERACTION PERIOPERATIVE IMMUNONUTRITION Postoperative acquired arginine-deficient state which leads to substantial immune dysfunction Immature myeloid-derived suppressor cells accumulation early after surgery which express Arginase 1 ( arginine depleting enzyme) N-3 fatty acids can blunt upregulation of immature cells and Arginase 1 Higher serum EPA / Arachidonic Acid Lower PGE2 serum level after surgery Higher IFN-gamma production after surgery Higher mrna expression Th1 transcription factor Arginine plus Omega-3 supplementation restores T-lymphocyte function including IL-2 production ( Th1) Popovic, J Nutrit 2007 Modulate Th1 / Th2 differentiation Suzuki, Surgery 2010 Aida, Surgery 2014 Drover, Subgroup Analysis IMMUNONUTRITION META-ANALYSES

3 IMN IN GI CANCER Systematic Review and Meta-Analysis ( 21 RCTs, 2005 Patients ) Both Perioperative and Postoperative IMN significantly reduced postoperative infections and LOS Osland, J PEN 2014 PREOPERATIVE IMMUNONUTRITION Patients : 244 Gastric Cancer Groups : Preoperative IMN vs. Regular Diet Results : Weight loss < 5% : same postop. outcome Weight loss > 5% : SSI reduction in IMN Fujitani, Br J Surg 2012 PREOPERATIVE IMMUNONUTRITION PERIOPERATIVE IMMUNONUTRITION Patients : 95 GI Surgery Groups : Preoperative IMN vs. Regular Diet Results : All patients: LOS < 1.7 days in IMN Save 1576 AUD / patient in IMN Undernourished : LOS < 3.8 days in IMN Barker, Eur J Clin Nutr 2013 Summary of Research ( ) Patients : 776 Gastric / Pancreatic Cancer 4 Groups : EN / PN, IMN / Standard Results : Enteral IMN beneficial in undernourished Morbidity 28.3% vs. 39.2% ( p = 0.04) LOS 13.1 vs ( p=0.05) Klek, World J Surg 2014 (MAL)NUTRITION IN UPPER GI CANCER Highest incidence of undernutrition, ranging between 40% and 80% at diagnosis IMMUNONUTRITION : CANDIDATES All patients undergoing major surgery at HIGH-RISK OF POSTOPERATIVE INFECTIONS Abdominal Pain Maldigestion Anorexia Biliary obstruction Most pronounced benefits in MALNOURISHED and UPPER GI CANCER ( promising data in Head & Neck Cancer) Tumour induced catabolic state protein synthesis lipogenesis skeletal muscle lean body mass Mini-invasive Surgery and ERAS protocols could change the infection risk of several procedures

4 IMMUNONUTRITION IN SURGERY FUTURE TRENDS Molecular signalling pathway Dose - Response Studies Mini-invasive Surgery / ERAS Neoadjuvant treatment DHA / EPA reduced viability of gastric cancer cells and induced apoptosis by activating CASPASE-3 DHA / EPA upregulated ADORE-1 involved in apoptosis Treatment of gastric cancer cells with antagonist of ADORE-1 reduced the effects of both DHA and EPA Cao, Front Biosci 2014 Melanoma induced in mice Myeloid derived suppressor cells are elevated by HIGH FISH OIL DIET ( mediated by IL-10 ) Omega-3 PUFA suppress intestinal polyp growth by modulating apoptotic process Barone, Carcinogenesis 2014 The consequence is downregulation of CD8 T-cells activation leading to low cancer immunosurveillance Xia, Cancer Immunol Immunother 2014 DHA modulates enterocytes Caco-2 cell expression of micrornas Gil-Zamorano, J Nutr 2014 Patients : 48 low-risk Prostate Cancer Treatment : Active surveillance Results : EPA in the prostatic tissue inversely correlated with cancer progression ( Gleason score ) Moreel, Cancer Prev Res 2014 Omega-3 PUFA intake was inversely associated with the incidence of rectal cancer. Opposite trend for colon cancer. Long-latency needed for protective effects ( yrs.) Song, Int J Cancer 2014

5 19 RCTs ( 68,954 subjects ) Treatment : Omega-3 supplementation vs. Placebo Results : Omega-3 supplementation does not affect cancer incidence ( RR 1.10) Zhang, BMC Public Health 2014

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