1. Pancreatic Cancer Malcolm J. Moore MD Princess Margaret Hospital

2. Pancreatic Cancer US incidence: 32,180 new cases estimated for 2005 1 – 2% of all new cancer cases Screening, early detection not on the horizon Most patients are diagnosed with advanced disease 1 CA Cancer J Clin 2005;55:10-30

3. Pancreatic Cancer – Outcome is Poor US mortality: 31,800 deaths estimated for 2005 1 – 4th and 5th leading cause of cancer-related death in males and females, respectively – 5% to 6% of all cancer deaths 5 year survival less than 5% 2. Median survival 3-4 – metastatic disease 3-6 months – locally advanced disease 9 months – Resected disease 14 months 1 CA Cancer J Clin 2005;55:10-30 2 SEER Cancer Statistics Review. http://seer.cancer.govhttp://seer.cancer.gov 3 Am J Surg 1993;165:68 4 JCO 2005; 23:4538

4. Pancreatic Cancer Epidemiology – Increases with age – No major geographical differences Genetics – P16, DPC, p53, k-ras Familial – Poorly understood

5. Pancreatic Tumors Most are ductal adenocarcinomas. – Most common site is head of pancreas – Dense fibrous reaction. – Precursor lesions – PanIN Other subtypes – Adenosquamous – Acinar cell, medullary, undifferentiated

6. Pancreatic Cancer – Ductal Adenocarcinoma most common

7. Pancreatic Tumors Serous cystadenoma/adenocarcinoma. Mucinous neoplasms Endocrine tumors – Range of differentiation-not all malignant – Functioning vs non – Well circumscribed – Vascular Tumors of the pancreas, Armed Forces Institute of Pathology, Washington 1997. p.145.

8. Well differentiated endocrine tumor - + chromogranin

9. Pathology Most are ductal adenocarcinoma – But not all, so … – Biopsy essential – Although usually can predict non-adenocarcinoma by imaging or clinical course.

10. Making the diagnosis Common symptoms Pain Gastric obstruction Biliary obstruction Diabetes Hypercoaguability Malabsorption

12. CA 19-9 Tumor associated antigen Elevated in most cases of pancreatic cancer. Also elevated in other GI cancers, pancreatitis. Slightly better specificity and sensitivity than CEA. Unknown value in clinical studies. Am J Gastroenterol 1999;94:1941-6.

13. Pain Pancreatic Cancer Pain often due to local invasion of tumor. Improved by XRT +/- chemo in 35-65% of cases Improved by palliative chemo Celiac axis blocks

14. Pancreatic Cancer Gastric/duodenal obstruction Occurs in cancers of pancreatic head. Consider in patients with refractory nausea/vomiting Remedies are – Gastrojejunostomy- open or laparoscopic – Duodenal stenting ? Role of prophylactic gastrojejunostomy

15. Pancreatic Cancer Biliary obstruction Cancers of pancreatic head. Often presenting problem. ? Surgical vs Endoscopic stenting. – Both effective. – Surgery a better long term solution. – Stent occlusion/replacement Percutaneous drainage not recommended

16. Pancreatic Cancer Diabetes ? A risk factor for disease. Can be a presenting problem. More than just loss of pancreatic function. Treat symptomatically. Not a contraindication to steroids

17. Hypercoaguability Well recognized association -Trousseau’s syndrome. Can be both central and peripheral. Generally resistant to oral agents. Long term therapy required. Association with early deaths ? Role of prophylactic anti-coagulation

18. Malabsorption Pancreatic insufficiency One reason for weight loss Use of narcotics may mask usual symptoms Trial of pancreatic enzymes

19. Surgery Only 15-20% are resectable. Whipples resection (pancreaticoduodenectomy) for tumors of the head – 3 anastamoses – Should be done in high volume centres

21. Is there a role for adjuvant therapy?

22. Original Adjuvant Trial GITSG [N=43] 1 Median survival 20 versus 11 months 5 year survival 18 vs 8% But… - 43 patients in 8 years. A larger EORTC trial (n=114 pancreatic cancer) failed to confirm the benefit of adjuvant CRT 2 5-FU + XRT with systemic 5-FU X 1 yr vs No additional treatment

23. ESPAC-1 Trial Design Neoptolemos NEJM 2004 350(12):1200-10 2x2 Factorial Design (Target 280) Observation CT CRT CRT CT Chemotherapy – 5-FU/LV [Mayo] X 6 Chemoradiation – 4000/20 [split] + bolus 5-FU. Adenocarcinoma pancreatic cancer undergoing ‘curative’ resection Randomise (stratified by centre, tumour type, resection margins)

24. Survival by Adjuvant Chemoradiotherapy Median survival No chemoRT 17.9 mo ChemoRT 15.9 mo HR 1.28 [0.99-1.66], p=0.05 N Engl J Med 2004 Mar 18;350(12):1200-10

25. Survival by Adjuvant Chemotherapy Median survival No Chemo 15.5 mo Chemo 20.1 mo HR 0.71 [0.55-0.92], p=0.009 N Engl J Med 2004 Mar 18;350(12):1200-10

26. CONKO-001 Neuhaus ASCO 2005 Resected pancreatic cancer 368 patients Stratification: R; T; N Follow up every 8 weeks Gemcitabine for 6 months Observation for 6 months J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

27. Tumor Characteristics J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

28. CONKO-001 Kaplan Meier Disease Free Survival Obs Median DFS 7.46 mo Gem Median DFS 14.21 mo Log rank p < 0.001 J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

29. CONKO-001 Kaplan Meier Overall Survival Gemcitabine 53 % patients censored (+) Observation 45 % patients censored (+) J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

30. ESPAC –3/ NCIC PA.2 Pancreatic Adenocarcinoma cancer undergoing ‘curative’ resection Randomise (stratified by centre, tumour type, resection margins) GemcitabineN=5005FU/FAN=500 5-FU/FA: FA 20 mg/m 2 iv, 5-FU 425 mg/m 2 iv X5 every 28 days, x6 cycles GEMCITABINE: 1000 mg/m 2 iv once weekly x3 wks, 1 wk rest, x6 cycles

31. Adjuvant Therapy of Pancreatic Cancer Adjuvant 5FU improves survival compared to observation Preliminary results show improved PFS (and now survival) with adjuvant gemcitabine vs. observation The optimal chemotherapy regimen (5FU/gemcitabine) not known Role of XRT still controversial.

32. Locally Advanced Pancreatic Cancer

33. Pancreatic Cancer: Unresectable Moertel 1 R adiation Alone 6.3 months Radiation and 5-FU10.4 months GITSG (randomized) 2 60 Gy Alone 5.3 months 40 Gy + 5-FU8.4 months 60 Gy + 5-FU11.4 months 1 Lancet 2:865-867, 1969 2 Cancer 48:1705-1710, 1981

34. Gemcitabine + Radiation PMH Phase I/II study  Patients with locally advanced (31), resected (32) disease-March 1999 to July 2001.  35 patients received initial gemcitabine.  8 [23%] of these did not get XRT GEMCITABINE 1000 mg/m 2 IV x7 Followed by GEMCITABINE 40 mg/m 2 IV 2X/week with XRT 3500-5250cGy over 4-6 weeks GEMCITABINE 1000 mg/m 2 IV x7 Followed by GEMCITABINE 40 mg/m 2 IV 2X/week with XRT 3500-5250cGy over 4-6 weeks Unpublished Data

35. Gemcitabine + Radiation PMH Phase I/II study  32 adjuvant patients Ü Median time to progression 14.3 months Ü Median survival 17.9 months Ü 5 year survival 19%  31 locally advanced Ü 1 complete response, 2 partial responses Ü 10 stable disease Ü Median survival 15.1 months Ü 2 year survival 19% Unpublished Data

36. Locally Advanced Pancreatic Cancer Chemoradiation in locally advanced pancreatic cancer improves: – survival 1-2 – and pain in 35-65% of patients 3-6 Outcomes are still poor and better radiation sensitizers are needed Most use up front chemo for 2 months and then chemo XRT

37. Tumor in the body and tail of pancreas with liver metastasis

38. Gemcitabine Registration Study in Pancreatic Cancer †Composite of measurements of pain (analgesic consumption and pain intensity), KPS and weight Burris HA, Moore MJ, Andersen J, et al. J Clin Oncol. 1997;15:2403-2413 Gemcitabine N = 63 5-FU N = 63p-value Clinical benefit response † 24%5%0.002 Survival Median survival, months — 5.7 — 4.4 0.002 — 1-year survival18%2%— Partial response5.4%0— Stable disease39%19%— Time to progression, months2.30.90.0002

39. Gemcitabine vs MMPI: NCIC.PA1 GEM = 6.67m (5.75-8.02) BAY = 3.74m (2.79-4.57) HR = 0.565 (0.44-0.73) P= 0.0001 BAY GEM Survival of untreated metastatic disease is short. Salvage of patients with crossover is not possible. Gemcitabine needs to be included in all treatments.

40. Negative Combination Chemotherapy Trials 2004-2006 Gemcitabine vs gemcitabine FDR + oxaliplatin [N=313] –Louvet C et al. ASCO 2004;22:14S (Abs. 4008) Gemcitabine vs gem FDR + gem FDR + oxaliplatin [N= 835] –Poplin et al. ASCO 2006;24:14S (Abs. 4003) Gemcitabine vs gemcitabine + pemetrexed [N=565] –Richards DA et al. ASCO 2004;22:14S (Abs. 4007) Gemcitabine vs gemcitabine + irinotecan [N=360] –Roche Lima, J Clin Oncol 2004 Gemcitabine vs gemcitabine + exatecan [N=349] –O’Reilly EM et al. ASCO 2004;22:14S (Abs. 4006) Gemcitabine vs gemcitabine + capecitabine [N=319] –Hermann et al. ASCO 2005;23:14S (Abs. 4508) Gemcitabine vs gemcitabine + 5FU/LV [N= 473] –Reiss et al. ASCO 2005;23:14S (Abs. 4509)

41. Gemcitabine and Fluoropyrimidines Phase III trials Trial Treatment armsn Overall survival p Median1-year Berlin et alGemcitabine1625.4 months18 %0.09 (2002) Gem/bolus 5-FU1606.7 months 19 % Riess et alGemcitabine2366.2 months~18%0.683 (2005)Gem/FU/LV2305.85 months ~18% Herrmann et al Gemcitabine1597.3 months31%0.314 (2005)Gem/capecitabine 1 1608.4 months31% Cunningham Gemcitabine2666.0 months19%0.026 (2005)Gem/capecitabine 2 2677.4 months26% 1 Gemcitabine 1000mg/m 2 wkly ×2 q3 weeks Capecitabine 1300mg/m 2 /day X 14 q3 weeks 2 Gemcitabine 1000mg/m 2 weekly ×3 q4 weeks Capecitabine 1660mg/m 2 /day for 21days q4 weeks

42. 5FU/LV +/- Oxaliplatin Second Line therapy  168 patients randomized  Mostly good PS status  PFS also better by 4 wks  Effect most pronounced in non- responders to gem in first line  Kubica et al ASCO 2008

43. Gemcitabine + Drug Vs Gemcitabine? Heinemann, et al. ASCO 2007 HR Survival P-ValueN Gem + platinum0.850.01623, 5 trials Gem + 5-FU0.900.03901, 6 trials Good PS 90%+ Poor PS 60- 80% 0.76 1.08 <0.0001 0.04 1,108, 5 trials 574

44. Combination Chemotherapy in Pancreatic Cancer One positive study in first line ? – Gemcitabine + Capecitabine. One positive study in second line. – 5FU + oxaliplatin. Many negative studies Incremental benefit of combination chemotherapy. – Restricted to patients with (very) good PS Is it worth doing any more studies?

45. OncogeneRelevance K-ras Noted in 75% to 90% of cases ‘Signature’ defect of pancreatic cancer Sonic Hedgehog Crucial role in embryological signaling Evolving role in pancreas cancer AURKA Encodes Aurora-A kinase Overamplification - chromosomal instability SuppressorRelevance CDKN2A/p16 Normal function induces cell cycle arrest Early event –enhances effect of K-ras SMAD4 Encodes transcription factor; lost in 50% cases May also potentiate K-ras phenotype p53 Role in cell cycle arrest and apoptosis Loss contributes to chromosomal instability Some key molecular abnormalities in Pancreatic Cancer

46. YYYYYY YYYYYY ras FAK Src raf ERK MEK ECM Integrin Homodimer PI3K Akt Nucleus Regulation of Gene Transcription Pro-MMP Growth Factor Ligand (EGF, VEGF) EGF Receptor Pancreatic Cancer: Other Molecular Targets

47. The Epidermal Growth Factor Signaling Pathway

48. 5.9 6.4 SWOG: Gemcitabine +/- Cetuximab Overall Survival HR = 1.09 (95% CI: 0.93, 1.27) PFS

49. Patient Population  Adenocarcinoma of pancreas  No prior chemotherapy  Measurable or non- measurable disease  EGFR status not an eligibility criterion Stratification  Center  PS (0/1 vs 2)  Stage of disease (Loc Adv / Metastatic) RANDOMIZERANDOMIZE Gemcitabine + Erlotinib 100/150 mg Gemcitabine + Placebo NCIC. PA.3 Study Schema

50. Overall Survival for All Patients HR = 0.81* 95% CI (0.67, 0.97) P = 0.025 Gemcitabine + Erlotinib Median = 6.4 months 1 Year Survival = 24% Gemcitabine + Placebo Median = 5.9 months 1 Year Survival = 17%

51. Progression-Free Survival * Adjusted for PS, pain and disease extent at randomization HR = 0.76* 95% CI (0.63, 0.91) P = 0.003 Gemcitabine + Erlotinib Median = 3.75 months Gemcitabine + Placebo Median = 3.55 months

52. PA.3 Rash vs Survival Grade 2 Grade 0 Hazard Ratio =0.71 p<0.0001 Grade 1 Grade 0 N= 79 Grade 1 N= 108 Grade >2 N= 103 Median Survival5.295.7510.51 1 year Survival16%11%43%

53. NCIC PA.3: K-ras, EGFR & Survival N= 569; 146 adequate specimens (26%) Gem + ErlotinibGem + PlaceboHRP K-ras WT (21%)6.1 mths4.5 mths0.660.34 K-ras Mut (79%)6.0 mths7.4 mths1.070.78 EGFR Pos (47%)5.2 mths 0.900.32 EGFR Neg (53%)8.4 mths6.7 mths0.600.08

54. PA3 : Impact of venous thromboembolism on survival Gemcitabine alone Gemcitabine + erlotinib Incidence 14% in both arms Associated with poor outcome HR 2.1

55. VEGF and Angiogenesis

56. CALGB 80303 Gemcitabine +/- Bevacizumab GEM + BEVACIZUMAB (n=302) GEM ALONE (n=300) HRp Median survival (mos) 5.86.11.030.78 PFS (months)4.94.71.00.99 Response (%) CR + PR1110 SD3631 Kindler HL et al. J Clin Oncol Phase II : 8.7 mos median survival; 5.8 mos PFS 67% tumor control rate (PR+SD)

57. Why were phase II and III data different? Phase III Gem + B Phase III Gem Phase II Gem + B Median age646563 PS 036%39%60% PS 1 PS 2 53% 11% 52% 9% 38% 2% Thrombosis-----------Permitted-----------Excluded Kindler HL et al. J Clin Oncol 2007;25(Suppl. 18 Pt I):420s (Abstract 4508)

58. Primary endpoint: overall survival (6.9 - 9.0 months) Trial closed October 2006. Presented at ASCO 2008. Previously untreated metastatic pancreatic cancer (n=600) Gemcitabine + Erlotinib 100 mg + placebo Gemcitabine + Erlotinib 100 mg + Bevacizumab 5mg/kg q 2 weeks Phase III trial of first-line Gemcitabine + Erlotinib +/- Bevacizumab in (AVITA)

59. Results Tumor Control (CR + PR + SD): G + E = 54% G + B + E = 63%

60. Treating the individual patient One size (gemcitabine) fits all? Probably not… (with an admitted lack of level 1 evidence) Good performance status - KPS 90 + – Consider combination chemotherapy – I would use gemcitabine + cisplatin. K-ras wild type – Gemcitabine + erlotinib.

61. Treating the individual patient Locally advanced disease should be approached differently than metastatic disease. Prophylactic anticoagulation – No phase III studies – VTE is common - associated with bad outcome – I do it (low molecular wt heparin) routinely.

62. The way forward in Clinical Research Test novel targets and combinations in the phase II setting. No phase III studies without a clear signal from phase II. Separate studies for locally advanced and metastatic disease. Translational research is critical!! – Routine tissue collection in trials – We need to understand a lot more about biology