Daniel Kollmorgen, MD Surgical Oncology The Iowa Clinic

I have no financial conflicts

NOVEMBER Pancreatic Cancer Awareness Month WageHope.org

Pancreatic Adenocarcinoma 90% of all pancreas cancers Incidence 46,000 new cases annually Incidence increasing 4 th leading cause of cancer death Prognosis 5 year survival:7% 2030 Projection: 2 nd most common cause of cancer related death

Risk Factors Smoking: 2x Age: most over 60 Obesity: 20% increase Family History: 2-3x (first degree relative) Male > Female African American > Caucasian, Asian, Hispanic Chronic Pancreatitis Hereditary conditions

Genetics Hereditary Breast and Ovarian Cancer BRCA2 (3-6 x increase) Familial Melanoma P16 (20-47 x increase) Familial Pancreatitis PRSS1 (26-87 x increase) Neurofibromatosis NF1 Other: HNPCC, PJS, VHL,

Presentation Symptoms Painless Jaundice Back Pain Weight Loss Signs New Onset Diabetes Palpable GB New DVT Incidental Pancreas cyst noted in 1% of all Abdominal CTs

Work Up/Diagnostics Labs CA19-9 Ultrasound CT ERCP PTC MRI EUS PET

Staging T N M At Presentation / 5 year Survival I/II : 9% /26% III : 28%/10% IV : 53%/2% CT standardization Resectable vs Borderline Locally advanced Metastatic

Standard Approach Patient Issues / Co morbidities Detailed H&P, labs Imaging / Anatomy Pancreatic protocol IV and oral contrast Arterial and Venous phases Multiplanar reconstruction Borderline Resectable: tumor OR patient?

CT Interpretation Resectable: No contact with celiac, SMA, or common hepatic artery <180 degrees of contact with SMV or Portal vein Borderline 180 SMV/PV IVC contact Unresectable: Metastatic disease >180 degree artery involvement Extensive vein involvement

Resectable

Operations Pancreaticoduodenectomy (Whipple) Standard Pylorus Preserving Left Pancreatectomy (Distal) Spleen Preserving Total Pancreatectomy Celiac resection

Anatomy

Multi Disciplinary Conference Spectrum of Physicians Surgery, Med Onc, Rad Onc, Diagnostic Rad, IR, GI Anatomy/ Location Nutrition Genetics Social Support Coordinator/Navigator Clinical Trials

Social / Support Issues Coordination Literacy Issues Palliative Care Hospice Family Support Financial Issues Family History / Genetics

Whipple – Good News 3-6 hour operation 7-10 days in hospital 4-6 weeks recovery Only way to be a ‘survivor’ Triple therapy survival: 20-25% Mortality Dropping Redefining ‘Resectable’

Whipple – Bad News Mortality: <5% Morbidity: >30% Pancreatic fistula: 10% Delayed gastric emptying: 15% Endocrine and Exocrine insufficiency Delay to Adjuvant therapy

Chemotherapy Adjuvant = 5FU or Gemcitibine No standard therapy Gemzar preferred due to toxicity Combinations Albumin bound paclitaxel Erlotinib (TKI) Cisplatin

Chemotherapy II Metastatic = FOLFIRINOX Oxaliplatin, leucovorin, iriontecan, 5-FU Preferred over Gemcitabine 12 month survival: 48% v 20% High toxicity – ‘fit patients’ 32% hospitalization Gemcitabine + Nab-paclitaxel comparable Neoadjuvant FOLFIRINOX 33% went on to R0 resection

Radiation Therapy Mixed reviews in adjuvant setting NCCN guidelines one of 8 adjuvant choices Meta analysis 2012: 15 studies No change in DFS, 2 year survival, or OS Outdated delivery(?)

New (?) Concepts Blind Whipple Early Detection Neoadjuvant Approach Minimally Invasive Centralizing care

New Concepts II Radiation Techniques IMRT SBRT – TrueBeam, Cyberknife, etc IORT Molecular Concepts Biomarkers Ca 19-9 Stromal Disruption PARP Inhibitors

Early Detection Series of mutations Kras, p53, p16, SMAD4 Precursor lesions PanIN IPMN Characterization of precursors Morphology DNA: mutations, LOH Trials in high risk patients

Neoadjuvant Rationale Better Oxygenation Downstaging (?) Better Patient Selection Declare Natural History 25% advance on restaging Increase R0 resection More patients complete therapy

Neoadjuvant Outcomes No phase III trials No clear (single/best) regimen Which meds? How much? Chemo or ChemoRT? Imaging rarely changes Vascular involvement Alliance FOLFIRINOX, capcitabene/RT, OR, gemcitabine

Laparoscopic Surgery Distal Pancreatectomy Decrease: EBL, ICU, hospital stay No change in oncologic outcome Whipple Highly selected series Complication rate unchanged Morbidity 50%

Volume Counts Centralization High volume center (>5 cases/year) Mortality <5% Clear margin 76% Low volume center (<2 cases/year) Mortality 15% Clear margin 55% Surgeon vs Hospital

Stoddard and NCDB Pancreatic Adenocarcinoma cases 68 resected (~14/yr) Survival Stage I (n=15)5 year survival: 62% (26) Stage II (n=59)13% Stage III (n=23) 6%(10) Stage IV (n=59)2%(2)

TIC Experience

Advances in Chemo Modified Conventional Chemo Onivyde - liposomal irinotecan Teysuno – 5FU prodrug + enzyme inhibotors Targeted therapy PARP inhibitors Stromal Disruption Personalized Medicine Erlotinib rash Cisplatin / mitomycinin Hereditary tumors Perthera service through Pancan

New Link Genetics Hyper Acute Immunotherapy (Vaccine) Murine membrane epitopes IMPRESS 3 trial 722 patients at 70 institutions Largest American trial in resected patients PILLAR trial Borderline resectable tumors Randomized Neoadjuvant Study

More Clinical Trials? Cytotoxic combinations Banking Tumor tissue, blood, serum New Cell lines and Biomarkers Pre and post Neoadjuvant therapy Pre and post targeted therapy Primary tumor Metastatic lesion

Summary There IS progress… Complex disease Before 1990: anatomy and physiology : team building, specialization : molecular biology, genetics, early detection Clinical trials and beyond new meds and new approaches Early less invasive intervention Awareness / Social Media

Pancan.org NCCN.org/patients/guidelines Cancer.Net Riskcalculator.FACS.org Choosingwisely.org WageHope.org

Incidental Pancreas Cyst Evolving Approach History Size Simple v Complex Nodules Content CEA, amylase, genetics Growth

Other Pancreas Tumors IPMN Mucinous Cystadenoma Serous Cystadenoma