1. Pancreatic cancer perspectives Is there any improvement ? Pancreatic cancer perspectives Is there any improvement ?

2. 10-15% resectable –DFI 8-13 months –Most recurrences within 2 years Recurrences –Retroperitoneum (34-87%) –Liver (38-73%) –Peritoneum (19-53%) –Extraabdominal sites (8-29%) March 2009

3. Predictors for recurrence –Grade, size, nodes, resection margin, vascular/lymphatic/perineural invasion 5-year survival –Node negative disease 25-30% –Node positive disease 10% Distant Metastases >> isolated local recurrence March 2009

4. Chemotherapy –Which drugs? Role of radiotherapy –Standard? –R1 disease? Neoadjuvant treatment –Chemotherapy / radiotherapy –Downstaging Definitive chemoradiotherapy Adjuvant Treatment

5. Oettle, JAMA 2007, 267 Gemcitabine vs Observation CONKO-001 CONKO-001 Gemcitabine vs Observation CONKO-001 CONKO-001 R Gemcitabine 1000 mg/m 2 3/4 Wo Observation

6. Neoptolemos, NEJM 2004, 1200 European Study Group for Pancreatic Cancer ESPAC-1 2xFU 500x36xFU+LVBeides Protocol Violations 30% Chemoradiation 9% nil 50% Chemotherapy 17% nil

7. Comparison CONKO-001 vs ESPAC-1 CONKO-001 vs ESPAC-1Comparison ESPAC-1CONKO-001 2-J-Survival 5-J-Survival 40% v 21% 21% v 9% 47% v 42% 22% v 11% 1-J-DFS58% v 43%58% v 31%

8. Adjuvant Chemoradiotherapy ChemoradiotherapyAdjuvant

9. Adjuvant Adjuvant

10. 442 patients with resected pancreatic cancer Radiotherapy 50.4 Gy + FU 250 mg/m 2 CI 3 weeks FU 250 mg/m2 CI Regine, JAMA 2008, 1019 Adjuvante Chemoradiotherapy Gemcitabine vs Fluorouracil Adjuvante Chemoradiotherapy Gemcitabine vs Fluorouracil 12 weeks FU 250 mg/m2 CI 3 weeks GEM1000 mg/m2 12 weeks GEM1000 mg/m2 RTOG 9704 Median Survival 20.9 Mo (G) vs 16.9 Mo (FU) 3-J-Survival 31% vs 22% (p=0.09)

11. Comparison Adjuvant Trials Comparison

12. 119 patients with locally advanced pancreatic cancer Radiotherapy 60 Gy + FU 300 mg/m 2 CI + Cisplatin 20 mg/m 2 d 1-5 Chauffert, Ann Oncol 2008, 1592 Gemcitabine 1000 mg/m 2 7/8 Wo Median Survival 14.3 Mo (G) vs 8.4 Mo (p=0.014) 1-J-Survival 51% vs 24% (p=0.03) Gemcitabine 1000 mg/m 2 3/4 Wo Definitive Chemoradiotherapy

13. Loehrer, ASCO 2008 Definitive Chemoradiotherapy ECOG 4201 Definitive Chemoradiotherapy ECOG 4201 9.2 v 11 Mo (.034) 6 mos12 mos18 mos24 mos GEM alone76%32%11%4% GEM plus XRT74%50%29%12%

14. Huguet, JCO 2007, 326 Test chemotherapy before definitive Chemoradiotherapy 15 v 11.7 Mo (.0009) 10.8 v 7.4 Mo (.005)

15. Chemotherapy –Which drugs? Gemcitabine, ESPAC-3 Role of radiotherapy –Standard? Probably not –R1 disease? Maybe Neoadjuvant treatment –Chemotherapy/Chemoradiotherapy? Efficacy –Increase resectability? Worth a try Definitive chemoradiotherapy? Sequential Adjuvant Treatment

16. Gem ± Marimasmat (Bramhall, 2002)NA5.5 Gem ± Pemetrexed (Richards, 2004)3.36.2 Gem ± CPT-11 (Rocha-Lima, 2004)3.46.3 Gem ± Tifarbinib (Van Cutsem, 2004)3.76.4 Gem ± Exatecan (OReilly, 2004)3.76.7 Gem ± Cisplatin (Heinemann, 2003)5.37.5 Gem ± Oxaliplatin (Louvet, 2004)5.89.0 Gem ± Oxaliplatin (Poplin, 2006)-5.9 Gem ± Bevacizumab (Kindler, 2007)-6.1 Gem ± Cetuximab (Philip, 2007)-6.4 Gem ± Erlotinib (Moore, 2005)3.76.4 Gem ± 5FU bolus (Berlin, 2002)3.46.7 Gem ± Capecitabine (Cunningham, 2005)-7.4 Gem ± Capecitabine (Herrmann, 2005)4.88.4 Gem ± 5FU/LV (Riess, 2005)4.95.9 Best chemotherapy option in metastatic pancreatic cancer Sultana, JCO 2007, 2607

17. Moore, JCO 2007, 1960 Gemcitabine ± Erlotinib

18. 5.9 6.4 Philip, ASCO 2007 Gemcitabine ± Cetuximab SWOG S0205 Gemcitabine ± Cetuximab SWOG S0205

19. Moore, ASCO 2007 Possible predictive factors for EGFR drugs KRAS Status Possible predictive factors for EGFR drugs KRAS Status

20. Pelzer, Proc ASCO 2008, 4508 Second-line chemotherapy in metastatic pancreatic cancer

21. Pelzer, Proc ASCO 2008, 4508

22. Adjuvant chemotherapy Maybe chemoradiotherapy in R1 disease Hint of additive effect of EGFR drugs in metastatic disease Effective second-line chemotherapy in metastatic disease –May have impact on choice of first-line chemotherapy Only translational research will lead to real progress Improvements in the treatment of pancreatic cancer