Pancreas Cancer and Neoadjuganoff

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1 Pancreas & Liver Tumors Boris W. Kuvshinoff, MD MBA Associate Professor of Surgery Director, Liver and Pancreas Tumor Center April 22, 2014

2 Liver & Pancreas Tumor Center HPB (Hepatopancreaticobiliary) Primary liver tumors Bile duct and gallbladder cancers Pancreatic tumors (solid & cystic) Selected metastatic tumors to liver Neuroendocrine tumors (Carcinoid, Islet) GI Endoscopy (diagnostic and therapeutic) Endoscopic Ultrasound, FNA ERCP, Spyglass cholangioscopy

3 Site Lifetime Probability of Developing Cancer By Site, Men: USA Risk All sites 1 in 2 Prostate 1 in 6 Lung and bronchus 1 in 13 Colon and rectum 1 in 17 Urinary bladder 1 in 28 Non-Hodgkin lymphoma 1 in 46 Melanoma 1 in 53 Kidney 1 in 67 Leukemia 1 in 68 Pancreas 1 in 71 Stomach 1 in 81 Liver 1 in 94 Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 5.2 Statistical Research and Applications Branch, NCI,

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5 Pancreas-directed therapies Common Indications Pancreas cancer Mucinous cystic neoplasm IPMN Islet-cell tumors Biliary obstruction Therapies at RPCI Whipple procedure Open and laparoscopic partial pancreatectomy Neoadjuvant CRT Clinical trials for advanced disease Systemic therapy Palliative care

6 Pancreatic Cancer (Adenocarcinoma) Estimated 45,000 cases diagnosed and 38,460 deaths (US) 2500 deaths in New York (est.) 85-90% present with non-resectable disease (local or metastatic) Siegel Ca Statistics 2013

7 Clinical Staging Stage Description Presentation Median Survival I - IIB Resectable 10-20% mos. Borderline Mesenteric Vessel abutment/impingement 10-15%? III Locally Advanced 30-40% 8-18 mos. IV Metastatic 40-50% 6-9 mos.

8 Endoscopic Ultrasound (EUS)

9 Whipple Procedure A B C D

10 National Failure to Operate on Early Stage Pancreatic Cancer Nihilistic Attitude, Mortality from PD in 1960 was 25% 35.7% 21.8% Cited risk factors: 1. Advanced age 2. Black race 3. Lower income 4. Institution bias (non-nccn/nci) Bilimoria Ann Surg 2007

11 Hospital Volume and Operative Mortality Pancreatectomy for Malignancy ( ) Evenly Distributed Volume Tertiles Volume Group Hospitals Procedures Op Mortality 95% CI OR Mortality Low (1-8/yr) % Medium (9-32/yr) % 2.64 ( ) 1.68 ( ) High (>32/yr) % 1.0 Cox D, et. al. SSO Presentation 2011.

12 Borderline Resectable SMV & PV abutment Not a contraindication to surgical resection but higher than acceptable risk of R1 resection

13 Uncinate or Body/Tail Location and Node Ratio Predict Margin Positivity and Poor Outcome in Resected Pancreas Cancer B Kuvshinoff, S Ashraf, C Andrews, J Gibbs, and M Javle Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York Overall Survival vs Margin Positivity Probability of Survival Negative margin HR 1.9 Margin Positivity Negative Positive p<0.002 Positive margin Time (Months)

14 Use of Neoadjuvant CRT for Borderline Resectable Pancreas Cancer! Gemcitabine cgy in 25 fractions of 180 cgy to primary/regional lymphatics Additional 900 cgy in 5 fractions of 180 cgy to primary! Pancreaticoduodenctomy with partial SMV resection! Path T3N1aM0 Poorly Differentiated AdenoCA (1/35 LN, neg margins)

15 Preoperative (Neoadjuvant) Therapy: Putative Benefits Higher proportion of patients will receive adjuvant therapy Potential downsizing tumors to increase liklihood of a margin-negative resection Patient selection to exclude those with progressive, metastatic disease who will not benefit from surgery Treatment of micrometastatic disease earlier

16 PRODIGE 4/ ACCORD 11 FOLFIRINOX n = 171 Gem n = 171 Hazard ratio p-value Median PFS 6.4 months 3.3 months 0.47 < Median OS 11.1 months 6.8 months 0.57 < year survival rate 48.4% 20.6% 18-month survival rate 18.6% 6%

17 Objective Response Rate FOLFIRINOX n = 171 Gem n = 171 p-value Complete response (CR) 0.6% 0% Partial response (PR) 31% 9.4% Stable disease (SD) 38.6% 41.5% Disease control (CR + PR + SD) 70.2% 50.9% Progression 15.2% 34.5% Not assessed 14.6% 14.6% Median duration of response 5.9 months 4 months NS

18 Overall Survival Proportion of Survival Pts at risk Months nab-p + Gem: 431 Gem: nab-p + Gem Gem Events/n (%) OS, months Median (95% CI) th Percentile 333/431 (77) 8.5 ( ) /430 (83) 6.7 ( ) 11.4 HR = % CI ( ) P = Subsequent therapy: 38% for nab-p + Gem and 42% for Gem OS censored at time of secondary therapy: 9.4 vs 6.8 months; HR 0.68; P = Trial conclusions not impacted by secondary therapies Von Hoff et al. ASCO

19 Response Rates Variable nab-p + Gem (n = 431) Overall response rate Independent review, % (95% CI) Investigator assessment, % (95% CI)! 23 ( ) 29 ( ) Gem (n = 430)! 7 ( ) 8 ( ) P Value! 1.1 x 10! 3.3 x 10 Disease control rate by independent review, (95% CI) 48 ( ) 33 ( ) 7.2 x 10 a Includes CR + PR + SD 16 weeks. Von Hoff et al. ASCO

20 Neoadjuvant FOLFIRINOX, Gemcitabine/Abraxane, Xel/RT

21 Neoadjuvant FOLFIRINOX, Gemcitabine Abraxane, Xel/RT Xeloda + XRT 4500 cgy in 25 fractions using 4-field technique to primary/regional lymphatics Additional 540 cgy in 3 fractions 4-field technique to primary Pancreaticoduodenctomy: final path showed only fibrosis, no residual carcinoma identified

22 Survival based on tumor location and node ratio Overall Survival vs Tumor Location Overall Survival vs Node Ratio Probability of Survival Uncinate Location Head Only Tail/Body Uncinate p=0.004 Tail/body Head only Probability of Survival p=0.005 Node Ratio Time (Months) Time (Months)

23 Locally Advanced Stage III Celiac trunk Involvment Contraindication to surgical resection

24 RPCI Experience Stage III Locally advanced, unresectable Progression Free Survival Overall Survival Matched groups with exception that Chemo group had more ECOG 2 patients and CRT group had less grade 3/4 toxicity. KS May, 2011

25 Candidates for Liver-directed Therapies Primary Liver Tumors HCC (Hepatoma) IHC (Intrahepatic cholangiocarcinoma) Metastatic Disease Colorectal cancer Neuroendocrine tumors Selected patients with breast, germ cell, renal cell, melanoma

26 Liver Tumor Program Open and Laparoscopic liver resection RFA and Microwave Tumor Ablation Neoadjuvant chemotherapy for resectable colorectal liver metastases Radioembolization (Sir-Spheres) TACE, drug-eluting beads NanoKnife (Electroporation, non-thermal tumor destruction using electrical current)

27 Hepatocellular Cancer (HCC) Stage Description Presentation 5-yr Survival I Single Tumor, no vascular invasion 41% 28% II Multiple or single <5 cm, vascular invasion 22% 19% III Multiple > 5 cm, major vessels, nodes or organs involved 35% 6.2% IV Metastatic 1.4% 1.3%

28 Hepatitis, Cirrhosis and HCC 80% of HCC develops in cirrhotic livers Chronic infection Hepatitis B 90% (vertical) 10% (adults) Cirrhosis 15-40% HCC (annual risk) 0.4% (chronic) 2-6.6% (cirrhosis) Hepatitis C 70-80% 20-30% (10-20 yrs) 3-5%/yr HCC: New York = 998/yr Erie Co. = 45/y

29 Hepatocellular Cancer (HCC)

30 Colon & Rectum Cancer SEER Stage at Diagnosis Stage Distribution 5-yr Survival Localized (I-II) 39% 90% Nodal Metastases (III) 37% 70% Distant Metastases (IV) 20% 12% Unknown Stage 5% 33%

31 Contemporary Outcomes for Resection of Colorectal Liver Metastases Study Years 5-yr survival Choti (2002) % Abdalla (2004) % Fernandez (2004) % Pawlik (2005) %

32 NCCN Guidelines Surgical Principles Colorectal Cancer Liver 1. Hepatic resection treatment of choice Complete resection with maintenance of normal hepatic function No unresectable extrahepatic disease 2. Re-evaluate for resection after neoadjuvant chemotherapy 3. Ablation acceptable for unresectable or high risk patients

33 EORTC 40983: Effect of Perioperative Chemotherapy PeriOpCT Surgery

34 Chemotherapy-associated hepatotoxicity Blue liver : Sinusoidal vasodilatation and congestion (VOD) Yellow liver : Steatosis, steatohepatitis

35 Laparoscopic Liver Resection Extraction or hand-assist

36 Laparoscopic Liver Resection

37 Radiofrequency Ablation

38 Methods of Ablation Percutaneous Laparoscopy Open Surgery

39 Laparoscopic RFA Multifocal Colorectal Cancer

40 Radiofrequency Ablation for HCC Case History 78 yo gentleman with hepatitis C cirrhosis (Child s B) Single lesion 4.5 x 3 cm Not candidate for resection or transplant

41 Radiofrequency Ablation for HCC Pre-treatment Post-ablation

42 Microwave Ablation

43 Microwave Tissue heated from friction of spinning water molecules! Faster than RFA No grounding pads Multiple tumors can be ablated simultaneously Less heat sink Microwave ablation of liver tumors

44 Microwave Ablation: Colorectal Liver Metastases Pre-treatment: S/P left hepatectomy, chemotherapy Post-treatment: Laparoscopic MW ablation

45 Non-thermal Ablation of Liver and Pancreatic Tumors: NanoKnife IRE

46 NanoKnife IRE System High Voltage (2-3 kv) pulses open pores in tumor cell membranes, cells swell and die Can ablate tumors near critical structures such as bile ducts, blood vessels, even nerves Mimics natural cell death so ablated tissue resorbed within weeks Less inflammation and pain No heat sink Has been used for locally advanced pancreatic cancers

47 NanoKnife for Pancreatic Neoplasms Metastatic Renal Cell CA Radiation therapy NanoKnife IRE

48 Pancreas & Liver Tumor Center Neuroendocrine Clinic Carcinoid Clinic Team Surgical Oncology Medical Oncology Interventional Radiology Pathology Nuclear Medicine Gastroenterology Dietician Cytoreduction therapies Surgery liver resection primary tumor resection including lymph nodes Chemoembolization Radioembolization RFA and Microwave Systemic therapy

49 Pancreatic Neuro Endocrine Tumors Islet Cell Tumors (PNET)

50 Islet Cell Tumors (PNET) Glucagonoma Pancreatic tail lesion arterial phase CT Pancreatic tail lesion octreoscan

51 77 yo with symptomatic (pain) liver mass Liver bx WD NET Serotinin, CgA elevated Occult primary Midgut Carcinoid

52 48 yo with crampy abdominal pain CT evidence of partial SBO Serotinin, CgA elevated Bilobar liver metastases No prior abdominal surgery Midgut Carcinoid

53 Carcinoid: Patterns of Spread

54 Well-Differentiated NET s 35,825 Cases (SEER ) Yao JC et. Al. J Clin Oncol 2008; 26:

55 Questions

56 TransArterial ChemoEmbolization (TACE) Tumor Blush

57 Transarterial Chemoembolization Pre-treatment 3 mos. Post-treatment

58 Transarterial chemoembolisation (TACE) Pretreatment 4 months TACE 10 months post-tace

59 32µ diameter Yttrium 90 Beta 0.93MeV 64.1hrs half life Penetration 2.5mm mean 11mm max Liver-Directed Therapy with Resin 90Y-Microspheres (SIRT)

60 Ileal Carcinoid with Liver Metastases 59 yo Dentist with symptoms for 8 years diagnosed with ileal carcinoid 2005, referred to us in Summer of Sir-Spheres (Y90 Resin Microspheres) 18 months post Radioembolization

61 Aggressive liver-directed therapy for GI carcinoid Resect/ablate TACE +/- resect/ablate Non-aggressive Touzious JG et al. Ann Surg 2005: 241,

62 SIRT vs. TACE in NET s Wu Y, Tomaszewski G, Groman A, Iyer RV and Kuvshinoff BW. Submitted to SSO, 2011.