Department of Surgery Klinikum rechts der Isar Technische Universität München, Munich, Germany Surgical treatment of pancreatic cancer Helmut Friess Izmir, March 20, 2010 Department of Surgery Klinikum rechts der Isar Technische Universität München

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München New cases deaths SEER Cancer Statistics Review, Jemal et al., CA Cancer J Clin (USA) 5 year survival (in %) Pancreatic cancer: prognosis

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München Yeo et al., Ann Surg % Richter et al., World J. Surg % Wagner et al., Br J Surg % 5-year survival N0/N1 N0 Cameron et al., Ann Surg %

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München Abramson et al., J Gastrointest Surg 2009 Whipple (local vascular infiltration) versus RCTx (local advanced PDAC) Patients 709 Patients 026 Local advanced pancreatic cancer Surgery or Radiochemotherapy

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München Abramson et al., J Gastrointest Surg 2009 The more likely venous infiltration is, the lower is the 1 year survival HOWEVER resection is always better than RCTx! year survival: Whipple 55% versus RCT 39% Local advanced pancreatic cancer Surgery or Radiochemotherapy

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische 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 Y survival 62% 32% p< Y survival 20% 0% p< Y survival 10% Surgery: months

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München Resection of pancreatic cancer: significantly improves the prognosis, but…

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München What 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: , 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 Surgery Klinikum rechts der Isar Technische 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 Überleben Monate n = 2736 (29%) n = 6823 (71%)

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München National 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 patients 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 Surgery Klinikum rechts der Isar Technische Universität München … too FEW, resectable patients are finally operated on! Pancreatic cancer WHY????

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München Resections per year Mortality (in per cent) Pancreas resections High case load low mortality Particularly in pancreatic surgery Centralisation Birkmeyer et al., NEJM 2002 Pancreatic cancer – 13,560 patients Resection rate 2.6% 2.6% Mortality 45% 28% Bramhall et al., Br J Surg West Midlands - England < >

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München Fong Y, Gonen M, Rubin D, Radzyner M, Brennan MF, Ann Surg 2005 improved long-term survival 2592 resections ( 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 < High case load Days Survival Long-Term Survival Is Superior After Resection for Cancer in High-Volume Centers

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München Pancreatic surgery at the „Rechts der Isar“ Munich, July 2007 – February pancreatic operations Technische Universität München Klinikum rechts der Isar

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München Pancreatic tumors 301 Other 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 Surgery Klinikum rechts der Isar Technische Universität München head resections 183 (57%) Pylorus-preserving 147 Whipple 16 Duodenum-preserving 20 Pancreatic resections (n=322) distal resections74 total pancreatectomies43 segmental resections 6 P-preserving duodenectomy 5 others11

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München  Re-operations14 (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 Surgery Klinikum rechts der Isar Technische Universität München Curative resection Vessel infiltration, perineural infiltration, N+, Grading Prognostic factors Wagner et al., Br J Surg 2004 Pancreatic cancer What determines the outcome?

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München Pancreatic cancer (n=366) Multivariable analysis Curative resection is the single most important factor determining survival! Wagner 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 Surgery Klinikum rechts der Isar Technische 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 important 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 Surgery Klinikum rechts der Isar Technische Universität München Neoptolemos et al., Ann Surg % (ESPAC) 16.9 Wagner et al., Br J Surg % 24.2 Howard et al., J Gastrointest Surg % Raut et al., Ann Surg % 27.8 Butturino et al., Arch Surg % 15.9 Bilimoria et al., JACS % R0 Resection - Survival N R0 Survival (months)

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München Survival by Resection Margins: ESPAC Neoptolemos et al., Ann Surg 2001 R ESPAC-1: n = 541 patients ESPAC-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 Surgery Klinikum rechts der Isar Technische Universität München R0 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 Surgery Klinikum rechts der Isar Technische Universität München Redefining the R1 resection in pancreatic cancer Verbeke 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 Surgery Klinikum rechts der Isar Technische Universität München R0 resection: Standardized R0 27 (24%) R1 84 (76%) : n = 188 patients: not standardized R0 162 (86%) R1 26 (14%) Esposito et al., Ann Surg Oncol : 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 Surgery Klinikum rechts der Isar Technische Universität München tumor stomach duodenum bile duct lymph nodes splenic vein SMV portal vein splenic artery hepatic artery SMA Aorta V. cava metastasis Pancreatic cancer: Extent of radical surgery? resectable (un)resectable R2 - 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 Surgery Klinikum rechts der Isar Technische 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 Surgery Klinikum rechts der Isar Technische 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 Surgery Klinikum rechts der Isar Technische Universität München Questions answers venous resectionYes, 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 Surgery Klinikum rechts der Isar Technische 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 months gemcitabine: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 Surgery Klinikum rechts der Isar Technische Universität München randomisation (stratified according to country, resection status) Gemcitabin5FU/FAobservation X Pancreatic adenocarcinoma - resected Adjuvant treatment – ESPAC-3 July 2000 – Jan. 2007: 1088 patients

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München ESPAC-3 – final analysis, unpublished 20 vs 25 months21 vs 35 months n = 1088 patients Neoptolemos et al., unpublished data

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische 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 Surgery Klinikum rechts der Isar Technische Universität München Running 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 Surgery Klinikum rechts der Isar Technische Universität München Conclusion – 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 Surgery Klinikum rechts der Isar Technische 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 Surgery Klinikum rechts der Isar Technische 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 Surgery Klinikum rechts der Isar Technische 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 Surgery Klinikum rechts der Isar Technische 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) 14 months later (12/2007) earlier diagnosis, but this is difficult

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische 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 Surgery Klinikum rechts der Isar Technische Universität München CT: Dec. 11th 2007Diffusion-MRI: Dec 17th cm Tumor earlier diagnosis, but this is difficult

Department of Surgery, Klinikum rechts der Isar, Technische Universität München Department of Surgery Klinikum rechts der Isar Technische Universität München Case 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 Surgery Klinikum rechts der Isar Technische Universität München Conclusion – Pancreatic cancer Early diagnosis in pancreatic cancer This is the challange!!! Often R1-resection