1. Sheri Ziegler 2016 Pancreatic Cancer

2. 2007 Estimated US Cancer Cases* *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2007. Men 766,860 Women 678,060 26%Breast 15%Lung & bronchus 11%Colon & rectum 6%Uterine corpus 4%Non-Hodgkin lymphoma 4%Melanoma of skin 4% Thyroid 3%Ovary 3%Kidney 3%Leukemia 21%All Other Sites Prostate29% Lung & bronchus15% Colon & rectum10% Urinary bladder7% Non-Hodgkin4% lymphoma Melanoma of skin4% Kidney4% Leukemia 3% Oral cavity3% Pancreas2% All Other Sites19% 33, 730 cases/yr

3. 2007 Estimated US Cancer Deaths* ONS=Other nervous system. Source: American Cancer Society, 2007. Men 289,550 Women 270,100 26%Lung & bronchus 15%Breast 10%Colon & rectum 6%Pancreas 6%Ovary 4%Leukemia 3%Non-Hodgkin lymphoma 3%Uterine corpus 2%Brain/ONS 2% Liver & intrahepatic bile duct 23% All other sites Lung & bronchus31% Prostate9% Colon & rectum 9% Pancreas6% Leukemia4% Liver & intrahepatic4% bile duct Esophagus4% Urinary bladder3% Non-Hodgkin 3% lymphoma Kidney3% All other sites 24%

4. Histology  Adenocarcinoma  Neuroendocrine tumors  Lymphoma

5. Pancreatic Cancer: An Imminent Threat  Incidence: 11.7 per 100,000  Rising incidence  6.7% increase 1995  2005  Lifetime risk: 1.41%  1 in 71 Americans will be diagnosed w/ PC Matrisian, Cancer Res, 2014 SEER, 2009

6. Pancreatic Cancer: Challenges  Stage for stage, pancreatic cancer is associated with the lowest survival rates of any major cancer type  The vast majority of patients are inoperable at the time of diagnosis  Pancreatic cancer is inherently resistant to most currently available therapies  Many patients suffer from rapidly declining performance scores  Compared with other cancer types, research funding for pancreatic cancer is disproportionately low given its mortality rate

7. Predisposing Factors  Age (average age 70-80s)  Smoking  Chronic pancreatitis  Obesity  Diabetes mellitus  Familial syndromes

8. Familial Syndromes  Hereditary Breast and Ovarian cancer  Peutz-Jeghers  Familial atypical multiple mole melanoma  Lynch syndrome  Hereditary pancreatitis

9. Presentation  Abdominal pain  Jaundice (often painless)  Weight loss  New onset diabetes mellitus  Pancreatic enzyme insufficiency (diarrhea, floating/fatty stools)

10. The Pancreas

11. Case  76 yr female presented with upper abdominal pain  Developed anorexia, 14 lb weight loss/2 mths  Jaundice developed  U/S- intra and extra hepatic biliary ductal dilitation  CT- 2.4cm pancreatic head mass, 18mm CBD, dilated pancreatic duct

13. Diagnosis  FNA of the primary mass or distant metastases  ERCP with stent and brushings/biopsy  FNA of the primary with EUS (endoscopic ultrasound)  EUS is also useful for staging, invasion into surrounding vessels (SMA, SMV)  Determination of resectability

14. ERCP

15. ERCP - Diagnostic CBD Stricture PD stricture Double duct sign GB Common Bile Duct Pancreatic Duct

16. EUS – Endoscopic ultrasound

18. TNM Staging (AJCC 2002) Primary Tumor (T) TXPrimary tumor cannot be assessed T0No evidence of primary tumor TisCarcinoma in situ (also PanIN 3) T1Tumor limited to pancreas, <=2cm T2Tumor limited to pancreas, >2cm T3Tumor extends beyond pancreas w/o involvement of celiac axis or SMA T4Tumor invades celiac axis or SMA Regional Lymph Nodes (N) NXRegional lymph nodes cannot be assessed N0No regional lymph node metastases N1Regional lymph node metastases Distant Metastasis (M) MXDistant metastasis cannot be assessed M0No distant metastasis M1Distant metastasis Stage Grouping Stage 0 Tis N0 M0 Stage IA T1 N0 M0 Stage IB T2 N0 M0 Stage IIA T3 N0 M0 Stage IIB T1 N1 M0 T2 N1 M0 T2 N1 M0 T3 N1 M0 T3 N1 M0 Stage III T4 Any N M0 Stage IV Any T Any N M1

19. Staging: Patients Often Staged Clinically, Not by TNM Classification  Resectable  Absence of extrapancreatic disease, no evidence of direct tumor extension to the SMA or celiac axis (presence of fat plane between the tumor and these vessels), patent PV  (Borderline resectable)  Absence of extrapancreatic disease, SMA encasement < 180 o SMV/portal impingement, short segment SMV occlusion, celiac encasement < 180 o, abutment/encasement of hepatic artery  Locally advanced/unresectable  Absence of extrapancreatic disease, SMA encasement > 180 o, unreconstructable SMV/portal vein occlusion; any celiac abutment or celiac encasement > 180 o, aortic invasion or encasement, lymph node metastases beyond field of resection  Metastatic  Liver being the most common site for distant disease

20. Stage Classification% at Diagnosis5-Yr Survival, % Localized822 Locally advanced/ unresectable 279 Metastatic532 Pancreatic Cancer by Stage

21. Five-year Relative Survival (%) during Three Time Periods By Cancer Site  All sites505366  Breast (female)757989  Colon 515965  Leukemia354249  Lung and bronchus131316  Melanoma828692  Non-Hodgkin lymphoma485363  Ovary3740 45  Pancreas23 5  Rectum495766  Urinary bladder737882 Surveillance, Epidemiology, and End Results Program, 2006. Site1975-1977 1984-1986 1996-2002

22. Why is pancreatic cancer so hard to treat?

23. Factors to Overcome  No adequate screening test  High incidence of metastatic disease at presentation  Fulminant clinical course  Lack of adequate systemic therapies  Chemotherapy resistant  Radiation resistant  Lack of understanding of the biology

24. Resectable Disease

25. Resectable Borderline Resectable Locally Advanced PV SMV SMA

26. Kitts 527268 Resectable tumor, RRHA SMV SMA T Resectable adenocarcinoma of the pancreatic head

27. Resectable : likely to require venous resection SMV SMA

28. Surgery (tumors of head or neck)  Pancreaticoduodenectomy (Whipple)  Operative mortality <2-3% in major surgical centers

29. Surgery (tumors of body or tail)  Often present late with larger tumors and frequent metastases  Distal pancreatectomy +/- splenectomy

30. Poor survival even after surgery  Even without clinical evidence of metastasis, 5y survival after resection is poor  Mostly due to metastatic disease Agarwal et al., Pancreas 2008

31. Adjuvant Therapy

32. Adjuvant therapy  Rationale: High risk of local and systemic recurrence Overall poor prognosis  5-yr survival after resection: 25% node-neg vs. 10% node-pos  Current standard: No universally accepted standard approach

33. Adjuvant therapy  5 major randomized trials  Over 1200 patients studied  Significant methodological differences  Chemoradiotherapy in N. America (GITSG, RTOG)  Chemotherapy alone in Europe (EORTC,ESPAC-1, CONKO)

34. Adjuvant 5-FU–Based ChemoXRT in Pancreatic Cancer  Median survival: 20 vs 11 months (P =.03) 2-year survival 43% vs 18% (4000 cGy XRT in split- course with concurrent 5-FU, followed by weekly 5-FU x 2 years) Kalser MH, et al. Arch Surg. 1985;120:899-903. 100 90 80 70 60 50 40 30 20 10 0 06121824303642485460 Months Survival (%) Control Chemotherapy + radiotherapy

35. Gemcitabine-based adjuvant therapy  RTOG 9704 (ASCO 2006) 442 subjects All received chemoradiation (50.4 Gy) + CI 5-fu 2 Arms:Additional 5-fu Additional Gemcitabine No overall difference in aggregate survival Head lesions only  Gemcitabine arm superior MS 20 vs. 17 mos 3-yr OS 32 vs. 21 % (p=0.047)

37. Neoadjuvant Therapy

38. Rationale for Neoadjuvant therapy  Intact vasculature permits maintenance of oxygenation in tissue necessary for radiation-induced necrosis  Improved delivery of chemotherapy to tumor  May downstage tumor  20-30% of resected patients are unable to receive adjuvant therapy  Saves patients with occult metastases from morbidity of unnecessary surgery

39. Neoadjuvant therapy  No randomized studies comparing to adjuvant  Small, Phase II, mostly single instituiton  5-fu and Gemcitabine chemoradiation have been studied  Neoadjuvant chemoradiation can be given safely without excess surgical morbidity

40. Preoperative Therapy R1 Resection YES13% NO19% The Importance of Neoadjuvant Therapy Pancreaticoduodenectomy: Ductal Adenocarcinoma M D Anderson (N = 360) Raut, Ann Surg 2007;246:52-60

41. Surgery Summary Local tumor resectability is best determined by EUS and high quality CT Resectable tumors may be treated with upfront surgery or a neoadjuvant approach Locally advanced tumors, as defined by arterial encasement, are not resectable and surgery is not a realistic treatment option

42. Locally Advanced, Unresectable Disease

43. Locally Advanced (Stage III) SMV SMA

44. Locally advanced, unresectable  30% of newly diagnosed patients  Most with adherence to adjacent structures (celiac or SM vessels)  Median survival 8-12 mos  Optimal treatment is controversial  Treatment options: RT alone Chemotherapy alone Concurrent chemoradiation

45. Chemoradiation > RT alone  1696 patients treated between 1991-96  Adjusted mean survival duration (weeks): Chemoradiation47 RT alone29 Chemo alone27 No therapy15  Supports the use of chemoradiation over either modality alone Krzyzanowska, JCO 2003

46. Treatment of Metastatic Disease

47. Efficacy endpoints  Traditional tumor measurements to assess RR are often inadequate in the primary tumor site.  Characteristic desmoplastic reaction and inflammatory response  Recent trials have included QOL endpoints  “Clinical benefit” and survival may be more accurate determinants of efficacy.

48. Fluorouracil (5-FU)  Extensively studied since 1950’s  5-fu (infusional and bolus) RR 0- 9%OS 10-24 wks  Capecitabine  Phase II study, 42 patients  Chemotherapy-naive  24% achieved clinical benefit (pain intensity, analgesic use, KPS)  7% RR  Well tolerated, 17% Gr 3 Side effects Cartwright, JCO 2002

49. Gemcitabine  Nucleoside analog  Pivotal Trial  126 patients randomized: Gem 1000mg/m2 IV qwk 7/8, then 3/4 5-fu 600mg/m2 IV qwk  Primary efficacy measure= Clinical benefit response  Composite of pain, KPS and weight  Clinical benefit required improvement >= 4 weeks  RR, TTP, OS Burris, JCO 1997

50. Metastatic Pancreatic Cancer: The Basis of Gemcitabine as the Mainstay of Treatment  Pivotal study defining role for gemcitabine as first-line treatment for patients with advanced pancreatic cancer  Median survival (vs bolus 5-FU): 5.65 vs 4.41 mos. (P =.0025)  1-year survival: 18% vs 2%  Clinical benefit*: 23.8% vs 4.8% (P =.0022)  Response rate: 5.4% vs 0% (P = NS) Burris HA, et al. J Clin Oncol. 1997;15:2403-2413. Gemcitabine 5-FU 100 80 60 40 20 0 02468101214161820 Survival Time (Mos) Patients Surviving (%) *A composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight.

51. Phase I/II Trial: Gemcitabine Plus Nab- Paclitaxel in Advanced Pancreatic Cancer  Gemcitabine 1000 mg/m 2 + nab-paclitaxel at 3 dose levels: 100, 125, 150 mg/m 2 (both agents administered weekly x 3 of 4)  N = 67  Toxicities  Common grade 3/4 toxicities: fatigue, neutropenia/ thrombocytopenia, sensory neuropathy Von Hoff DD, et al. J Clin Oncol. 2011;29:4548-4554.

52. ORR: 48% 100 75 50 25 0 036912151821242730 Months Probability of Survival (%) 12.2 mos Nab-paclitaxel 125 mg/m 2 (n = 44) 300 200 100 0 -100 0101 Patient Maximum Percent Change From Baseline in CA19-9 PR (n = 21)SD (n = 16) -20 -40 -60 -80 20 40 60 80 120 140 160 180 220 240 260 280 0202 0303 0404 0505 0606 0707 0808 0909 10101 1212 1313 1414 1515 1616 1717 1818 1919 2020 21212 2323 2424 2525 2626 2727 2828 2929 3030 3131 32323 3434 3535 3636 3737 Von Hoff DD, et al. J Clin Oncol. 2011;29:4548-4554. Efficacy Results of Gemcitabine/Nab-Paclitaxel

53. CA 19-9  Tumor marker  Amongst markers found to have the greatest sensitivity (70%) and tumor specificity (87%)  Cutoff value of 70 U/ml  Can be elevated with biliary tract obstruction by a noncancerous lesion

54. International Phase III Trial Pancreatic cancer (locally advanced or metastatic) Gemcitabine 1000 mg/m 2 weekly x 3 of 4 Gemcitabine 1000 mg/m 2 + Nab-Paclitaxel 125 mg/m 2 weekly x 3 of 4

55. Phase III trial:Gemcitabine and Abraxane GemcitabineGemcitabine and Abraxane Overall Survival6.7 mths8.5 mths 1 Year Survival22 %33 % N= 861 Pts

56. Phase III Trial of Gemcitabine vs FOLFIRINOX Metastatic Pancreatic Cancer Gemcitabine 1000 mg/m 2 weekly x 7 of 8, then weekly x 3 of 4 (n = 171) FOLFIRINOX Oxaliplatin 85 mg/m 2 LV 400 mg/m 2 Irinotecan 180 mg/m 2 5-FU bolus 400 mg/m 2, then 2400 mg/m 2 infusional over 46 hrs (n = 171) Conroy T, et al. N Eng J Med. 2011;364:1817-1825.

57. FOLFIRINOX vs Gemcitabine: Overall Survival Overall Survival 100 75 50 0 036912151821242742 Months Patients Alive (%) 25 39363330 Gemcitabine FOLFIRINOX HR: 0.57 (95% CI: 0.45-0.73; P <.001 Gemcitabine FOLFIRINOX Pts at Risk, n 17113489482814763312222 17114611681623420139522223 OutcomeFOLFIRINOXGEMCITABINE Response Rate31.6%9.4% Medium Survival 11.16.8 1 Year Survival48.4%20.6% Conroy T, et al. N Eng J Med. 2011;364:1817-1825

58. Is FOLFIRINOX Tolerable? Safety and Toxicity Event, n/N (%)FOLFIRINOX (n = 171) Gemcitabine (n = 171) P Value Hematologic  Neutropenia75/164 (45.7)35/167 (21.0)<.001  Febrile neutropenia9/166 (5.4)2/169 (1.2).03  Thrombocytopenia15/165 (9.1)6/168 (3.6).04  Anemia13/166 (7.8)10/168 (6.0)NS Nonhematologic  Fatigue39/165 (23.6)30/169 (17.8)NS  Vomiting24/166 (14.5)14/169 (8.3)NS  Diarrhea21/165 (12.7)3/169 (1.8)<.001  Sensory neuropathy15/166 (9.0)0/169<.001  Elevated ALT12/165 (7.3)35/168 (20.8)<.001  Thromboembolism11/166 (6.6)7/169 (4.1)NS Conroy T, et al. N Eng J Med. 2011;364:1817-1825.

59. FOLFIRINOX: Take-Home Messages  Markedly positive survival results; exceed those seen in any previous randomized phase III trial in advanced PDAC—close to 1 year!  New gold standard for first-line metastatic pancreatic cancer (for patients with good performance score)

60. Targeted Therapy

61. Erlotinib - Targeted Agent Approved for Pancreatic Cancer

62. Gemcitabine + Erlotinib  Expression of EGFR is common, poor prognosis  Phase III study  569 patients randomized to: Gemcitabine 1000mg/m2 weekly +/- Erlotinib 100mg po daily  Few objective responses (8.6 vs. 7.9%)  Overall survival 6.2 vs. 5.9 mos favoring combination  1-yr survival 23 vs. 17% (p=.023)  FDA approved in 2005 in combination with gemcitabine Moore, JCO 2007

64. Metastatic Pancreatic Cancer  Pancreatic cancer remains a clinical challenge  Current therapies offer only modest benefits  FOLFIRINOX  Gemcitabine and Abraxane  Gemcitabine  Numerous studies incorporating new, targeted agents have offered little/no benefit over Gemcitabine alone.

65. Conclusions  Localized disease -> Surgery  Most adjuvant therapy -> ChemoXRT  Combination chemotherapy and multimodality therapy for earlier stages of disease (locally advanced, resectable) need to be clarified  Locally advanced (non-resectable)-> Chemotherapy vs Radiation vs ChemoXRt  Chemotherapy options: evolving and improving in advanced pancreatic cancer (eg, FOLFIRINOX)  “Targeted” therapeutic agents have been disappointing

66. Conclusions  Pancreatic cancer is a horrible disease  Median survival less than one year for most  Majority found with metastatic disease  Surgery is the only treatment that may lead to durable cure at this point in time

67. Pancreatic Neuroendocrine tumors

68. Case  62 yo male presented with L flank  Presented to urgent care, palpated an abdominal mass  CT done- 11 x 8 cm mass in the body of the pancreas, no mets, obliteraion of portal, splenic, SMV  Patient has no symptoms, no weight loss, no pain

69. Case

70. Histology  Nonfunctional  Functional  Insulinomas -> Hypoglycemia  Gastrinomas -> Peptic Ulcer Disease  Glucagonomas -> Diabetes

71.  EUS/FNA- low grade neuroendocrine neoplasm  Resect if possible  Prognosis is good, even in metastatic disease -> median survival >5yrs  Options: Observation Somatostin analog Chemotherapy Biologic therapy