Pancreatic Cancer Updatesin Management2017 Estimated Deaths fromCancer in the United States2020 Pancreas cancer will be the 2nd leading cause of death in the USMary Dillhoff, MD, MSAssociate Professor-ClinicalDepartment of SurgeryDivision of Surgical OncologyThe Ohio State University Wexner Medical CenterGeneticsAims Discuss management and surveillance ofpremalignant lesions of the pancreas Work-up of newly diagnosed pancreascancer Define resectable, borderline and locallyadvanced unresectable pancreas cancer Surgical updates and safety Outline neoadjuvant treatment options Clinical trialsSyndromeEstimated Cumulative EstimatedRisk PancreaticIncreasedCancerRiskCompared toGeneralPopulation11-36% by age 65-70132 foldyears45-53% by age 70-7526-87 foldyearsPeutz-Jegherssyndrome (STK11)Familial pancreatitis(PRSS1, SPINK,CFTR)Melanoma Pancreatic 14-17% by age 70-75Cancer Syndromeyears(CDKN2A)Lynch Syndrome4% by age 70 years(MLH1, MSH2, MSH6)20-47 fold9-11 fold1

GeneticsSyndromeEstimatedCumulative RiskPancreatic CancerHereditary breast andovarian syndrome(BRCA1, BRAC2)Familial pancreaticcancer1.4-1.5% (women),2.1-4.1% (men) byage 70 3 first degreerelatives, 7-16% byage 702 first degree relatives3% by age 70EstimatedIncreased RiskCompared toGeneralPopulation2.4-6 fold 3 first degreerelatives - 32 fold 2 first degreerelatives - 6.4 fold1 first degreerelative - 4.6 foldBackground-Premalignantlesions of pancreas Pancreatic cysts are identified in 2.4-19% ofpatients undergoing CT or MRI Most common Intraductal papillary mucinous neoplasm(IPMN) Mucinous cystic neoplasm (MCN) Solid pseudopapillary neoplasm (SPN) Serous cystadenoma (SCA) PseudocystLaffan et al. AJR Am J Roentgenol 2008;191:802-807Lee et al. Am J Gastroenterol 2010;105:2079-2084Premalignant lesions ofpancreasPancreatic Cystic LesionsNeoplasticMain Duct y(SPN)SurgerySide BranchIPMNSerous CysticNeoplasm (SCN)Non-neoplasticPseudocystRetention CystLymphoepithelialcystDuplication cystSurveillanceor Surgery2

IPMNMain duct IPMN Main Duct IPMN Branch Duct IPMN Mixed type IPMNBranch duct IPMNMixed type IPMN3

IPMN-Incidence ofmalignancyAll (Mean) Main Duct Branch Duct Mixed Type(Mean)(Mean)(Mean)Malignant 8.2-66.7%(40.4)35.7-100% .8% IPMN Symptoms Most are asymptomatic Vague abdominal pain Nausea/vomiting Pancreatitis Jaundice Weight loss Diabetes Most common in males in their 50’sTanaka et al. Pancreatology 2012Diagnosis and Work-up Referral to pancreatic expert History of pancreatitis? YES-Pseudocyst likely Symptoms? Imaging Detect cystic lesions Determine main vs. branch duct Determine risk of malignancy and ability toresect EUS Cyst fluid analysis FNA Presence of mural nodule or other high riskfeaturesTreatmentGuidelines4

Updated Fukuoka CriteriaFukuoka Criteria 2012“Worrisome” features1. Pancreatitis2. Cyst 3cm3. Thickened/enhancing cyst wall4. MD 5-9mm5. Non enhancing mural nodule6. Change in caliber of PD with distalatrophy7. Elevated Ca 19-98. Cyst growth 5mm 2 yearsHigh Risk Stigmata1. Obstructive jaundice2. Enhancing nodule3. MD 1cmEUSConsiderSurgeryConfirm muralnodule, MDinvolvement orsuspicious or positivecytologyTanaka et al. Pancreatology 2017ConsiderSurgeryTanaka et al. Pancreatology 2017Updated Fukuoka CriteriaInterpreting Cyst FluidHow big isit? 1cmImaging2-3 years1-2cmImaging yearlyx 2 years thenlenghtenTanaka et al. Pancreatology 20172-3cmEUS in 3-6monthsalternatingwith MRIConsidersurgery inyoungpatients 3cmClosesurveillance, MRIand EUS every 36 monthsStronglyconsider surgeryBrugge WR et al. Gastroenterology 2004;126:1330-65

Interpreting Cyst Fluid CEA Distinguish mucinousfrom non-mucinouslesions 192 Sensitivity 73% Specificity 84%Molecular Analysis of Cyst Fluid Interpace Diagnostics Formerly RedPath Provide mutational analysis Proprietary test which they donot reveal Mutational Profile LOH markers Oncogenes DNA quantity and quality Clinical informationBrugge WR et al. Gastroenterology 2004;126:1330-6.FluidAnalysisIPMNPathology: BD-IPMN with highgrade dysplasia6

Surveillance No high quality data to baserecommendations Great variation in literature MCN’s are almost always solitaryand require no surveillance imagingBasic algorithm for all cancers NAME ITSTAGE ITTREAT ITPresentation: Painless jaundice, weight loss,abdominal pain, diabetesWork-up: Cross sectional imaging, labs,EUS/ERCP as necessaryPreoperative assessment: medical clearance,assess resectability, need for neoadjuvant therapyProceed to OR or chemotherapyPatients with distant metastatic diseasechemotherapy is the mainstay of treatmentDefining ctableNo arterial contact(celiac, SMA, CHA) 180 degreeswithout vein contourirregularityBorderlineTumor contact withCHA, 180 degreesSMA 180 degreesSMV/PV,reconstructionpossible, contactwith IVCLocally Advanced- Tumor 180 degreesUnresectableSMA, celiac, firstjejunal SMA branchUnreconstructibleSMV/PV,SurgerySurgeryNot yetBorderline or locallyadvanced diseaseNoSurgeryMetastaticdisease7

ResectablePancreas CancerBorderline Resectable andLocally Advanced UnresectablePancreas CancerBorderline resectable:Abutment SMAPancreaticoduodenectomy(Whipple)Locally advanced:Encasement SMAImproving surgical outcomes Perioperative mortality 2% Complication rates remain high40-50% Average length of stay 8 days Pancreatic fistula 20% Diabetes 20% Adoption of minimally invasiveand robotic surgery may furtherreduce length of stayAuthor: Cancer Research UK / Wikimedia CommonsCC BY-SA 4.08

Surgeon volume and outcomesQuantity matters! High volume improves perioperative andlong-term outcomes Included 14 different procedure types Pancreas surgery HV 5 vs. LV 5 In hospital mortality 2.4 vs. 6.4% 51% reduction in hospital mortalityBirkmeyer et al : N Engl J Med. 2002 Apr 11;346(15):1128-37Birkmeyer et al : N Engl J Med 2003; 349:2117-2127Whipple with or without drains Multicenter randomized controlled trial 68 drains 69 no-drain Increase in complications in no-drain group 52% vs. 68% p 0.047 Higher average complication severity Higher gastroparesis, intra-abdominal fluid collection,intra-abdominal abscess (10% vs. 25%), severediarrhea, need for postoperative percutaneous drain,prolonged length of stay Data safety monitoring board stopped the study earlybecause of an increase in mortality from 3% to 12% inpatients undergoing whipple without drainVan Buren et. al Ann Surg 2014Pasireotide for postoperativepancreatic fistulas Pasireotide Somatostatin analogue with longer half lifethan octreotide and broader binding profile tooctreotide receptors Decreases pancreatic exocrine secretions Single center randomized trial 152 subcutaneous pasireotide 14 doses, first dose pre-surgery 148 patients placebo Results Pancreatic fistula 9% vs. 21% p 0.006 Consistent for both whipple and distalpancreatectomyAllen et al. NEJM 2014Distal pancreatectomywith and without drains Multicenter randomized controlled trial Closed suction drain vs. no drain distalpancreatectomy Baylor Ohio State Indiana University No difference in complications or fistularateVanBuren Ann Surg 20179

Robotic Whipple Surgeon sits in roomcontrolling robotic armsto perform surgerythrough small incisions Decrease length of stay,less post operative pain,quicker recoveryOpenWhippleRoboticWhippleThe role ofNeoadjuvantChemotherapy10

Preoperative/Neoadjuvant therapy inpancreatic cancer:Meta-analysisGillen et al. PLoS Med 7(4): e100267 2010ResultsBlazer Ann Surg Onc 2015 Apr; 22(4):1153-9Neoadjuvant therapyThe Ohio State Experience Borderline resectable (BRPC) and locallyadvanced unresectable (LAPC) 43 patients 18 BRPC 25 LAPC Modified FOLFIRINOX No bolus 5-FU, no LV, decreasedirinotecan Radiation based on response and intendedsurgeryBlazer Ann Surg Onc 2015 Apr; 22(4):1153-9ResultsBlazer Ann Surg Onc 2015 Apr; 22(4):1153-911

ResultsBlazer Ann Surg Onc 2015 Apr; 22(4):1153-9Neoadjuvant therapyfor patients withresectable disease Common in some major cancer centers NCCN guidelines now acceptable to offerneoadjuvant therapy NEOPAC Trial Accruing in Europe Resectable pancreas cancer Randomized to Surgery vs. preoperativegemcitabine and oxaliplatin followed bysurgery All patients adjuvant gemcitabineBlazer Ann Surg Onc 2015 Apr; 22(4):1153-9ESPAC-4 Multi-center randomized controlled trial 732 patients gemcitabine alone vs.gemcitabine and Capecitabine Median OS 28 months vs. 25.5 months (HR0.82) 29% 5 year survival vs.16% No increased toxicity compared withgemcitabine alone 60% R1 resection12

Making the unresectable,resectable Locally advanced and borderlineresectable Considered as “potentially” or “never”resectable mFOLFIRINOX x 2 months then reassess Gemcitabine radiation (36Gy or 50Gy) ifstable or progressive disease Surgery after maximum response withplanned vascular resectionPre-treatmentAfter chemo andchemo/XRTConclusions Premalignant lesions are common and diagnosisand management best by multidisciplinary teams Modest improvement in pancreatic cancersurvival with newer chemotherapy options Surgery for pancreatic cancer is safe Hospital volume and surgeon volume areimportant for outcomes Management by multidisciplinary teams andenrollment in clinical trials is most important forimproving outcomes in the future13