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Department of SurgeryKlinikum rechts der IsarTechnische Universität München, Munich, Germany
Surgical treatment of pancreatic cancer
Helmut Friess
Izmir, March 20, 2010
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
0
5000
10000
15000
20000
25000
30000
35000
New
cas
es
deat
hs
SEER Cancer Statistics Review, 1975-2001Jemal et al., CA Cancer J Clin 2009
2008 (USA)
5 ye
ar s
urvi
val (
in %
)
1974-76
1995-00
Pancreatic cancer: prognosis
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Yeo et al., Ann Surg 1995
26%
Richter et al., World J. Surg. 2003
25%
Wagner et al., Br J Surg 2004
24%
5-year survival
N0/N1 N0/N1 N0/N1 N0
Cameron et al., Ann Surg 2006
41%
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Abramson et al., J Gastrointest Surg 2009
Whipple (local vascular infiltration) versus RCTx (local advanced PDAC)
1.324 Patients 709 Patients
026
Local advanced pancreatic cancerSurgery or Radiochemotherapy
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Abramson et al., J Gastrointest Surg 2009
The more likely venous infiltration is,the lower is the 1 year survival
HOWEVERresection is always better than RCTx!
026
1-year survival: Whipple 55% versus RCT 39%
Local advanced pancreatic cancerSurgery or Radiochemotherapy
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
A randomized multicenter trial comparing resection and radiochemotherapy for resectable locally invasive pancreatic cancer
Doi et al., Surg Today 2008
Resection vs. no resection
resection radiochemotherapy
patients 20 22 1-Y survival 62% 32% p<0.05
3-Y survival 20% 0% p<0.05
5-Y survival 10%
Surgery: + 11.8 months
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Resection of pancreatic cancer:Resection of pancreatic cancer:significantly significantly improvesimproves the the
prognosis, but…prognosis, but…
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität MünchenWhat is the reality in pancreatic cancer surgery??
Bilimoria et al., Ann Surg 2007
National Cancer Database:> 76% of ALL pancreatic cancers in the USA registered
For this study: 1995-2004, 9559 patients (T1/2N0M0)
Multivariate analysis:- How many patients were operated on/could be operated on?- How does a resection influence survival?
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
19.3 months
8.4 months
Median survival:
National failure to operate on early stage pancreatic cancer
Bilimoria et al., Ann Surg 2007
Übe
rlebe
n
Monate
n = 2736 (29%)
n = 6823 (71%)
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität MünchenNational failure to operate on early stage pancreatic cancer
Bilimoria et al., Ann Surg 2007
„Risk“factors, NOT to be operated on:
33% of the stage I patients33% of the stage I patientsWITHOUT contraindications were NOT operated!WITHOUT contraindications were NOT operated!
- age >65 years- carcinoma of the head of the pancreas- low socio-economic status- non-specialized hospitals
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
… … too FEW, resectable too FEW, resectable patients are finally patients are finally
operated on!operated on!
Pancreatic cancer
WHY????
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
02468
1012141618
<1 1 - 2 3 - 5 6 - 16 >16
Resections per yearResections per year
Mor
talit
y (in
per
cen
t)M
orta
lity
(in p
er c
ent)
Pancreas resectionsPancreas resectionsHigh case loadHigh case load
low mortalitylow mortality
Particularly in pancreatic surgeryParticularly in pancreatic surgery
CentralisationBirkmeyer et al., NEJM 2002
Pancreatic cancer – 13,560 patients
Resection rate 2.6% 2.6%Mortality 45% 28%
Bramhall et al., Br J Surg 1995
1957-1976 1977-1986
West Midlands - England
<1 1-2 3-5 6-16 >16
181614121086420
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Fong Y, Gonen M, Rubin D, Radzyner M, Brennan MF, Fong Y, Gonen M, Rubin D, Radzyner M, Brennan MF, Ann Surg 2005Ann Surg 2005
improved long-term survival
• 2592 resections (1995+1996 Medicare Data Base)
• 1101 hospitals• 10 centers with >25 cases/year, 11% (n = 291) of all cases• In-hospital mortality: 2% (high) vs 8% (low), p < 0.001
High case load
Days
Surv
ival
Long-Term Survival Is Superior After ResectionLong-Term Survival Is Superior After Resectionfor Cancer in High-Volume Centersfor Cancer in High-Volume Centers
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Pancreatic surgery
at the „Rechts der Isar“Munich, July 2007 – February 2009
417 pancreatic operations
Technische Universität München
Klinikum rechts der Isar
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Pancreatic tumors 301Other tumors 50
Chron. Pancreatitis 57 Other pathologies 9
Pancreatic operations (n=417)
Indications
84%
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
head resections 183
(57%)Pylorus-preserving 147Whipple 16Duodenum-preserving 20
Pancreatic resections (n=322)
distal resections 74 total pancreatectomies 43segmental resections 6P-preserving duodenectomy 5others 11
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Re-operations 14 (4.3%)
Fistulas 15 (4.7%)
Mortality 6 (1.9%)
Pancreatic resections (n=322)
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Curative resectionCurative resectionVessel infiltration, perineural Vessel infiltration, perineural
infiltration, N+, Gradinginfiltration, N+, Grading
Prognostic factorsWagner et al., Br J Surg 2004
Pancreatic cancerWhat determines the outcome?What determines the outcome?
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität MünchenPancreatic cancer Pancreatic cancer (n=3(n=36666))
Multivariable analysisMultivariable analysis
Curative resection is the single most Curative resection is the single most important factor determining survival!important factor determining survival!
Wagner et al., Br J Surg 2004Wagner et al., Br J Surg 2004
Bile duct
SMA
Celiac trunk
SMV
Portal vein
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
A margin-negative R0 resection accomplished with minimal postoperative complications is the surgeon's contribution to long-
term survival in pancreatic cancer
Curative operation (= R0) most Curative operation (= R0) most important predictor of survivalimportant predictor of survival
Howard et al., J Gastrointest Surg 2006
Multivariate analysis - prognostic parameters:
Pancreatic cancer: R0 resection
226 patients (1990 – 2002)
R0-resections: 70%
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Neoptolemos et al., Ann Surg 2001 541 81% (ESPAC) 16.9
Wagner et al., Br J Surg 2004 211 76% 24.2
Howard et al., J Gastrointest Surg 2006 226 70%
Raut et al., Ann Surg 2008 360 83% 27.8
Butturino et al., Arch Surg 2008 869 68% 15.9
Bilimoria et al., JACS 2008 12101 76%
R0 Resection - Survival
N R0 Survival (months)
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität MünchenSurvival by Resection Margins: ESPACSurvival by Resection Margins: ESPAC
Neoptolemos et al., Ann Surg 2001
R0
1994 - 2000ESPAC-1: n = 541 patients
2000 - 2007ESPAC-3: n = 1088 patients
19.9 vs 24.7 months
R1 = 19 %R0 = 81 %
R1 = 35 %R0 = 65 %
R0
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität MünchenR0 resection in pancreatic cancer
Is each R0 resection really
a R0 resection ??
Yes No
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Redefining the R1 resection in pancreatic cancerRedefining the R1 resection in pancreatic cancerVerbeke CS et al., Br J Surg 2006
Standardized histopathology (colored resection margins, multiple slicing)
22 of 26 pancreatic cancers: R+
R0-rate: 15% (new) vs 48% (old)
Pancreatic cancer: local recurrence
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität MünchenR0 resection: Standardized R0 resection: Standardized
R0 27 (24%)R1 84 (76%)
2002-2004: n = 188 patients: not standardized
R0 162 (86%)R1 26 (14%)
Esposito et al., Ann Surg Oncol 2008
2005-2006: n = 111 patients: standardized histopathology
Resektion status
Is each R0 resection really a R0 resection ??
no
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
tumor
stomachduodenumbile ductlymph nodes
splenicveinSMVportalvein
splenicarteryhepaticarterySMA
AortaV. cava metastasis
Pancreatic cancer: Extent of radical surgery?
resectable (un)resectableR2 - R1 - R0
• Individual decision - surgeon experience
• Patient benefit amount of resources survival QoL
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
• class. Whipple vs ppWhipple
• standard vs extended lymphadenectomy
Solved Questions: RCT
NO difference in regard to … morbidity, mortality and LQ.
No difference in regard to morbidity, mortality, but also survival.
Standard
ppWhipple
Diener et al., Ann Surg 2007; Wenger et al., Chirurg 1999; Tran et al., Ann Surg 2004; Lin et al., Hepatogastroenterology 2005; Seiler et al., Br J Surg 2005; Bloechle et al., DGCh Forumband 1999; Paquet et al., Chir Gastroenterol 1998
Michalski et al., Br J Surg 2007; Pedrazzoli et al., Ann Surg 1998; Yeo et al., Ann Surg 2002; Farnell et al., Surgery 2005; Nimura et al., HPB 2004
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
van der Gaag et al., NEJM 2010
P<0.001
early surgery (n=94)
PreOP BD-drainage (n=102)
Drainage-associated complications
2 (2%) 47 (46%)
surgery-associated complications
35 (37%) 48 (47%)
202 patients, bilirubin 2-15 mg/dl
Solved Questions: Stent versus early surgery
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Questions answers
•venous resection Yes, R0
•arterial resection No
Open Questions
Klempnauer et al., Oncology 1996; Harrison et al., Adv Surg 1997; Bachellier et al., Am J Surg 2001; van Geenen et al., Surgery 2001; Hartel et al., Eur J Surg 2002; Keck et al., Zentralbl Chir 1995; Roder et al., Am J Surg 1996; Shibata et al., World J Surg 2001; Takahashi et al., Br J Surg 1994; Jain et al., Hepatogastroenterology 2005; Koniaris et al., J Gastrointest Surg 2005; Capussotti et al., Arch Surg 2003; Yoshimi et
al., Hepatogastroenterology 2003; Zhou et al., Hepatobiliary Pancreat Dis Int 2005; Aramaki et al., Hepatogastroenterology 2003; Tseng et al., J Gastrointest Surg 2004; Fuhrman et al., Ann Surg 1996; Harrison et al., Ann Surg 1996; Park et al., J Clin Gastroenterol 2001; Nakao et al.,
Surgery 1995; Lygidakis et al., Am J Gastroenterol 1986; Allema et al., Br J Surg 1994
Tseng et al., J Gastrointest Surg 2004; Settmacher et al., Chirurg 2004; Sasson et al., J Gastrointest Surg 2002; Nakano et al., Hepatogastroenterology 2002; Kondo et al., Langenbecks Arch Surg 2003; Wanebo et al., Arch Surg 2000; et al., Pancreas 1996
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Neoptolemos et al., NEJM 2004; Oettle et al., JAMA 2007
Adjuvant treatment
no benefit through chemoradiation significant benefit through 5-FU
observation: 6.9 monthsgemcitabine: 13.4 months
Gemcitabin
Europe: ESPAC-1 (n=541) Germany: CONKO-001 (n=354)
Chemotherapy (5-FU)
No Chemotherapy
P=0.009
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
randomisation(stratified according to country, resection status)
Gemcitabin5FU/FA observationX
Pancreatic adenocarcinoma - resected
Adjuvant treatment – ESPAC-3July 2000 – Jan. 2007: 1088 patients
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität MünchenESPAC-3 – final analysis, unpublished
20 vs 25 months 21 vs 35 months
n = 1088 patients
Neoptolemos et al., unpublished data
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
Adjuvant CTx: Gem = Standard, (5-FU/FA option)
ESPAC-3 – final analysis, unpublished
23.0 vs 23.6 months
n = 1088 patients
Grad 3-4 toxicity: 5-FU/FA 14% vs Gem 7.5%, p < 0.01
Neoptolemos et al., unpublished data
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität MünchenRunning study – ESPAC4
„curativ“ resected pancreatic cancer
adjuvant chemotherapy within 8-10 weeks postoperatively
randomisation
540 patients:6 cycles gemcitabine
540 patients:6 cycles gemcitabine/capecitabine
Primary end point: Survival
Secondary end point: Toxicity, quality of life, 2-Y survival, 5-Y survival, recurrence free survival
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität MünchenConclusion – pancreatic cancer
- resection improves prognosis! - pancreatic cancer surgery is safe!- R0 resection- extended LA: NO benefit- SMV/PV invasion: no contraindication- arterial invasion: contraindication- adjuvant chemotherapy
earlier diagnosis, but this is difficult
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
• 76 year old patient• routine check up (09/2006): slightly increased CA 19-9 (59U/ml)
• CT pancreas: no pathology
• Gastroscopy/Colonoscopy: no pathology
• 4 months later: CA 19-9 control
earlier diagnosis, but this is difficult
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
• CA 19-9: 202 U/ml• CT pancreas: no pathology
• endosonography: no pathology
• 2 months later CA 19-9 control
4 months later (01/2007)
earlier diagnosis, but this is difficult
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
• CA 19-9: 285 U/ml• MRI pancreas: no pathology• PET-CT pancreas: no pathology• endosonography: no pathology• capsule-endoscopy: no pathology 2 months later CA 19-9 control, etc, etc, ..
6 months later (03/2007)
earlier diagnosis, but this is difficult
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
• CA 19-9: 777 U/ml• CT/MRI pancreas: no pathology• endosonography: normal, small cystic lesion in the pancreatic head
Referral to Munich (Surgery)Referral to Munich (Surgery)
14 months later (12/2007)
earlier diagnosis, but this is difficult
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
CA19-9: 1149 U/ml (<37)
Diffusion-MRI, MRCP
15 months later (01/2008)
earlier diagnosis, but this is difficult
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität München
CT: Dec. 11th 2007 Diffusion-MRI: Dec 17th 2007
1.5 cm Tumor
earlier diagnosis, but this is difficult
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität MünchenCase presentation – pancreatic cancer
• distal pancreatectomy with splenectomy• histology: T1, N+ (!) adenocarcinoma perineural invasion
Diagnosis: difficult + too late !!
Department of Surgery, Klinikum rechts der Isar, Technische Universität München
Department of SurgeryKlinikum rechts der IsarTechnische Universität MünchenConclusion – Pancreatic cancerConclusion – Pancreatic cancer
Early diagnosis in
pancreatic cancer
This is the challange!!!
Often R1-resection
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