Pancreatic cancer Pancreatic cancer perspectives perspectives

Is there any improvement ?Is there any improvement ?

Pancreatic cancer Pancreatic cancer perspectives perspectives

Is there any improvement ?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 2009March 2009March 2009March 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 2009March 2009March 2009March 2009

• Chemotherapy– Which drugs?

• Role of radiotherapy – Standard?– R1 disease?

• Neoadjuvant treatment– Chemotherapy / radiotherapy– Downstaging

• Definitive chemoradiotherapy

Adjuvant TreatmentAdjuvant TreatmentAdjuvant TreatmentAdjuvant Treatment

Oettle, JAMA 2007, 267

Gemcitabine vs ObservationGemcitabine vs Observation CONKO-001CONKO-001

Gemcitabine vs ObservationGemcitabine vs Observation CONKO-001CONKO-001

RGemcitabine1000 mg/m2 3/4 Wo

Observation

Neoptolemos, NEJM 2004, 1200

European Study Group for Pancreatic CancerEuropean Study Group for Pancreatic Cancer ESPAC-1 ESPAC-1

European Study Group for Pancreatic CancerEuropean Study Group for Pancreatic Cancer ESPAC-1 ESPAC-1

2xFU 500x3 6xFU+LV Beides

Protocol Violations• 30% Chemoradiation

• 9% nil• 50% Chemotherapy

• 17% nil

ComparisonComparison CONKO-001 vs ESPAC-1CONKO-001 vs ESPAC-1

ComparisonComparison CONKO-001 vs ESPAC-1CONKO-001 vs ESPAC-1

ESPAC-1 CONKO-001

2-J-Survival

5-J-Survival

40% v 21%

21% v 9%

47% v 42%

22% v 11%

1-J-DFS 58% v 43% 58% v 31%

Adjuvant Adjuvant ChemoradiotherapyChemoradiotherapy

Adjuvant Adjuvant ChemoradiotherapyChemoradiotherapy

Adjuvant Adjuvant ChemoradiotherapyChemoradiotherapy

Adjuvant Adjuvant ChemoradiotherapyChemoradiotherapy

442 patientswith resected pancreatic cancer

Radiotherapy 50.4 Gy+ FU 250 mg/m2 CI

3 weeksFU 250 mg/m2 CI

Regine, JAMA 2008, 1019

Adjuvante ChemoradiotherapyAdjuvante ChemoradiotherapyGemcitabine vs FluorouracilGemcitabine vs FluorouracilAdjuvante ChemoradiotherapyAdjuvante ChemoradiotherapyGemcitabine vs FluorouracilGemcitabine vs Fluorouracil

12 weeksFU 250 mg/m2 CI

3 weeksGEM1000 mg/m2

12 weeksGEM1000 mg/m2

RTOG 9704

• Median Survival 20.9 Mo (G) vs 16.9 Mo (FU)• 3-J-Survival 31% vs 22% (p=0.09)

ComparisonComparisonAdjuvant TrialsAdjuvant Trials

ComparisonComparisonAdjuvant TrialsAdjuvant Trials

119 patients with locally advanced pancreatic cancer

Radiotherapy 60 Gy+ FU 300 mg/m2 CI+ Cisplatin 20 mg/m2 d1-5

Chauffert, Ann Oncol 2008, 1592

Gemcitabine1000 mg/m2 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)

Gemcitabine1000 mg/m2 3/4 Wo

Definitive ChemoradiotherapyDefinitive ChemoradiotherapyDefinitive ChemoradiotherapyDefinitive Chemoradiotherapy

Loehrer, ASCO 2008

Definitive ChemoradiotherapyDefinitive ChemoradiotherapyECOG 4201ECOG 4201

Definitive ChemoradiotherapyDefinitive ChemoradiotherapyECOG 4201ECOG 4201

9.2 v 11 Mo (.034)

6 mos 12 mos 18 mos 24 mos

GEM alone 76% 32% 11% 4%

GEM plus XRT 74% 50% 29% 12%

Huguet, JCO 2007, 326

Test chemotherapy before definitive Test chemotherapy before definitive ChemoradiotherapyChemoradiotherapy

Test chemotherapy before definitive Test chemotherapy before definitive ChemoradiotherapyChemoradiotherapy

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 TreatmentAdjuvant TreatmentAdjuvant TreatmentAdjuvant Treatment

Gem ± Marimasmat (Bramhall, 2002) NA 5.5

Gem ± Pemetrexed (Richards, 2004) 3.3 6.2Gem ± CPT-11 (Rocha-Lima, 2004) 3.4 6.3

Gem ± Tifarbinib (Van Cutsem, 2004) 3.7 6.4Gem ± Exatecan (O’Reilly, 2004) 3.7 6.7

Gem ± Cisplatin (Heinemann, 2003) 5.3 7.5Gem ± Oxaliplatin (Louvet, 2004) 5.8 9.0Gem ± Oxaliplatin (Poplin, 2006) - 5.9Gem ± Bevacizumab (Kindler, 2007) - 6.1Gem ± Cetuximab (Philip, 2007) - 6.4Gem ± Erlotinib (Moore, 2005) 3.7 6.4

Gem ± 5FU bolus (Berlin, 2002) 3.4 6.7

Gem ± Capecitabine (Cunningham, 2005) - 7.4

Gem ± Capecitabine (Herrmann, 2005) 4.8 8.4Gem ± 5FU/LV (Riess, 2005) 4.9 5.9

Best chemotherapy option in metastatic Best chemotherapy option in metastatic pancreatic cancerpancreatic cancer

Best chemotherapy option in metastatic Best chemotherapy option in metastatic pancreatic cancerpancreatic cancer

Sultana, JCO 2007, 2607

Moore, JCO 2007, 1960

Gemcitabine Gemcitabine ± ± ErlotinibErlotinibGemcitabine Gemcitabine ± ± ErlotinibErlotinib

Overall Survival by Treatment Arm

0%

20%

40%

60%

80%

100%

0 12 24 36Months After Registration

GemcitabineGemcitabine and Cetuximab

N369366

Events338331

Medianin Months

66

P = 0.14

5.96.4

Philip, ASCO 2007

Gemcitabine Gemcitabine ± ± CetuximabCetuximabSWOG S0205SWOG S0205

Gemcitabine Gemcitabine ± ± CetuximabCetuximabSWOG S0205SWOG S0205

Moore, ASCO 2007

Possible predictive factors for EGFR drugsPossible predictive factors for EGFR drugsKRAS StatusKRAS Status

Possible predictive factors for EGFR drugsPossible predictive factors for EGFR drugsKRAS StatusKRAS Status

Pelzer, Proc ASCO 2008, 4508

Second-line chemotherapy in metastatic Second-line chemotherapy in metastatic pancreatic cancerpancreatic cancer

Second-line chemotherapy in metastatic Second-line chemotherapy in metastatic pancreatic cancerpancreatic cancer

Second-line chemotherapy in metastatic Second-line chemotherapy in metastatic pancreatic cancerpancreatic cancer

Second-line chemotherapy in metastatic Second-line chemotherapy in metastatic pancreatic cancerpancreatic 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 Improvements in the treatment of pancreatic cancerpancreatic cancer

Improvements in the treatment of Improvements in the treatment of pancreatic cancerpancreatic cancer