1. Dr Marco Matos Medical Oncologist Gold Coast Cancer Care, Gold Coast University Hospital and, Pacific Private Oncology Group

2. Pancreatic cancer is a highly lethal malignancy. The 5 year survival rate is less than 5%. The tumour microenvironment (fibroblasts, immune cells, etc) occupies the majority of the tumour mass and one of the contributing factors to the failure of systemic therapies.

4. The progression from normal to intraepithelial neoplasia to invasive pancreatic cancer is associated with architectural and cytological changes

7. PRECISE PRE-TREATMENT STAGING IS VITAL IN LOCALLY ADVANCED PANCREATIC CANCER RADIOGRAPHIC STAGE Ro RESECTION PRE- OPERATIVE THERAPY THERAPEUTIC OBJECTIVE ResectableProbableOptionalCure Borderline resectable PossibleRecommendedCure Un-resectableImprobableNoPalliative Resectable, borderline resectable and unresectable locally advanced disease have different management approach

8. StudyNChemoCXRTResOSOS res Heinrich 2008 28Gem/cis-89%19m Evans 200886-Gem 3074%23 m34m Varadhachary 2008 90Gem/cisGem 3059%17 m31m Palmer 200750Gem vs Gem/cis -54%14m28m Telamonti 2006 20GemGem 3685%26m

12. CONKO 03 Gemcitabine refractory OFFBSC CONKO 07 Neoadjuvant gemza x3 or FOLFIRINOX x6 CRT with GemzaChemotherapy CONKO 001 adjuvant GemzaObservation CONKO 002 Phase 2 Advanced pancreatic ca GFFObservation CONKO 004 adjuvant Chemotherapy + LMWH Chemotherapy (Gem or GFFP) CONKO 005 adjuvant R0 resection Gemza plus erlotinib Gemza) CONKO TRIALS

13. CONKO 006 R1 pancreatic cancer Arm B Gemcitabine 1000 mg D1,8,15 q 4/52 plus sorafenib 200 mg bd x12 mo Arm A Gemcitabine1000 mg D1, 8,15 q 4/52 plus BSC x 12 mo

14. CONKO 006 Randomized, double-blinded placebo-controlled multi-center design the study was planned based on the relapse rate to detect an improvement of disease-free-survival (DFS) from 42% to 60% after 18 mo. Secondary objectives were DFS at 12 and 24 mo, overall survival (OS) and treatment safety

15. CONKO 006 Arm AArm B Median age63 T3-497 N pos8685 127 patients between Feb2008 and Sept Arm A Gem 65 ptes Arm B Gem Sor 57 ptes

16. CONKO 006 Arm AArm B Diarrhoea6%0% Fatigue2%0% Neutropenia7%16% Thrombocytopenia4%1% Elev. GGT8%5% hypertension2%0% HFS3%0% Grade 3 -4 Toxicities Arm AArm B DFS9.6 mo10.7 mo OS17.6 mo15.6 mo Treatment duration27 weeks (1-51)27 weeks (2- 62) Results

18. milestones Pre 1996“Nothing works” 1996 – 2005Gemcitabine improves survival compared with 5FU 2005Gemcitabine and erlotinib modestly improves survival compared with gemcitabine 2010FOLFIRINOX improves survival compared with gemcitabine 2012NAB paclitaxel and gemcitabine improves survival compared with gemcitabine

19. We have options!!!! …many options Pancreatic cancer Gemcitabine Gemcitabine and Abraxane FOLFOX / FOLFIRI FOLFIRINOX5FU Gemcitabine and Tarceva

20. Which one? Pancreatic cancer Gemcitabine Gemcitabine and Abraxane FOLFOX / FOLFIRI FOLFIRINOX5FU Gemcitabine and Tarceva

21. What regimen? Response rate Overall survival PFS QOL Ability to close monitor the patient Expertise on toxicity Complexity and cost Tumour biomarkers Extend of disease Tolerance Age Performance status Comorbidities /organ function Compliance Patient Tumour And treatment Data Physician and the regimen

22. Presented By Hedy Kindler at 2014 ASCO Annual Meeting Gemcitabine The cornerstone of mPC treatment Minimal response rate Statistically but modest improvement in overall survival Minimal toxicity Improves pain, QOL and weight No predictive biomarker: hENT1 data does not apply For the elderly patient with poor PS

26. Gemcitabine and erlotinib

28. PA 3 demonstrate that any drug added to gemcitabine improves OS Statistically significant but very modest improvement in OS (HR0.82) Modest toxicity No improvement in QOL Very expensive (~ 4000 AUS/ mo) No biomarker identified Which patient?

29. FOLFIRINOX

32. The YALE FOLFIRINOX experience Community and academic oncologists were reluctant to use full dose FOLFIRINOX due to its toxicity profile Impact of dose- attenuation on toxicity and efficacy OxaliplatinIrinotecanBolus 5FU CIV 5FU Yale 90%64%66%100% Phase III 78%81%82% Despite routine dose modifications: RR/PFS/OS not significant different than controls YALE patients had less toxicity than in ACCORD 11: Grade 3-4 fatigue: 5.7 vs 23.6% Grade 3-4 neutropenia: 11.4 vs 43.6% Ongoing prospective Phase II trial of m FOLFIRINOX: bolus 5FU 300 mg/m2; irinotecan 130 mg/m2.

33. FOLFIRINOX Significantly improves mOS (6.8 vs 11.1 mo, HR 0.57, p < 0.0001) and PFS (3.3 vs 6.4 mo, HR 0.47, p<0.0001 Is more toxic: 46% grade 3-4 neutropenia FOLFIRINOX is more expensive than gemcitabine but is more cost effective, increasing QALY. Cost per QALY: 60 K Impact of routine dose modifications is unclear No biomarkers identified yet

34. NAB paclitaxel and gemcitabine

37. First randomised trial that demonstrate that a cytotoxic added to gemcitabine improves OS (6.7 vs 8.5 mo) and PFS (3.7 vs 5.6 mo) More toxic: 38% grade 3-4 neutropenia, 17% grade 3-4 neuropathy No QOL data No cost effective Await biomarker data : SPARC

38. Comparing: FOLFIRINOX vs MPACT

39. Summary Pancreatic cancer is a highly aggressive malignancy with poor prognosis We have effective systemic therapy options. Sufficient data to support multiple lines of therapy Choice of regimen needs to be tailored to the patient