department of surgery klinikum rechts der isar technische universität münchen, munich, germany...

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


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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



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%



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



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



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



Resection of pancreatic cancer:Resection of pancreatic cancer:significantly significantly improvesimproves the the

prognosis, but…prognosis, but…


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?



19.3 months

8.4 months

Median survival:

National failure to operate on early stage pancreatic cancer


Übe

rlebe

n

Monate

n = 2736 (29%)

n = 6823 (71%)


Department of SurgeryKlinikum rechts der IsarTechnische Universität MünchenNational failure to operate on early stage pancreatic cancer


„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



… … too FEW, resectable too FEW, resectable patients are finally patients are finally

operated on!operated on!

Pancreatic cancer

WHY????



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



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



Pancreatic surgery

at the „Rechts der Isar“Munich, July 2007 – February 2009

417 pancreatic operations

Technische Universität München

Klinikum rechts der Isar



Pancreatic tumors 301Other tumors 50

Chron. Pancreatitis 57 Other pathologies 9

Pancreatic operations (n=417)

Indications

84%



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



Re-operations 14 (4.3%)

Fistulas 15 (4.7%)

Mortality 6 (1.9%)

Pancreatic resections (n=322)



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 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



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%



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 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 SurgeryKlinikum rechts der IsarTechnische Universität MünchenR0 resection in pancreatic cancer

Is each R0 resection really

a R0 resection ??

Yes No



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 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



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



• 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



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



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



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



randomisation(stratified according to country, resection status)

Gemcitabin5FU/FA observationX

Pancreatic adenocarcinoma - resected

Adjuvant treatment – ESPAC-3July 2000 – Jan. 2007: 1088 patients


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



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 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 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



• 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




• 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)




• 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, ..





• 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)





CA19-9: 1149 U/ml (<37)

Diffusion-MRI, MRCP





CT: Dec. 11th 2007 Diffusion-MRI: Dec 17th 2007

1.5 cm Tumor



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 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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