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

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

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

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

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

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

Comparison CONKO-001 vs ESPAC-1 CONKO-001 vs ESPAC-1Comparison ESPAC-1CONKO 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%

Adjuvant Chemoradiotherapy ChemoradiotherapyAdjuvant

Adjuvant Adjuvant

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)

Comparison Adjuvant Trials Comparison

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

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

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

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

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

Moore, JCO 2007, 1960 Gemcitabine ± Erlotinib

Philip, ASCO 2007 Gemcitabine ± Cetuximab SWOG S0205 Gemcitabine ± Cetuximab SWOG S0205

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

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

Pelzer, Proc ASCO 2008, 4508

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