Locally advanced and bordeline forms of pancreatic cancer

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1 19 May 2011 Locally advanced and bordeline forms of pancreatic cancer P r Pascal Hammel Pôle des Maladies de l Appareil Digestif Hôpital Beaujon, Clichy Université Paris VII, Denis Diderot [email protected]

2 Locally advanced cancer (LA) of the pancreas 1- How to define it? 2- What treatment to propose? 3- Evaluation of tumour response? 4- Is it possible to return to surgery?

4 Locally advanced (LA) pancreatic cancer How to assess a LA cancer? Not easy! Multidisciplinary meeting

5 TNM (AJCC 2002, 6thversion) T4 : Tumour involving mesenteric artery or coeliac trunk But what arterial involvement : abutment? > 90 > 180?. Difficulty : unresectable tumour due to another locoregional feature: - major venous involvement - posterior involvement, neighboring organ - suspicious lymph nodes Not stricto sensu «locally avanced» cancers.

6 LA cancer : definition

7 LA cancer : definition SMV Maire, Pancreatology 2004 SMA Resectable 1st intent No metastases No arterial involvement SMV and portal vein ok Doubtful resectability «Borderline» SMV or portal vein > 180 Venous thrombosis (short) SMA < 180 HA (reconstructible) Non resectable Arterial involvement SMA > 180 Coeliac trunk involved Thrombosis of SMV or portal vein Cava or aorte involvement Irresectability : 13 % 25 % 100 % (coelioscopy) True neoadjuvant False neoadjuvant = (attempt to) salvage

8 Pancreatic infiltration : non univocal? Mazzeo, Abdom Imaging 2009

9 MACROinfiltration Microinfiltration Mazzeo, Abdom Imaging 2009

11 LA Cancer : What say the French Guidelines?

12 LA Cancer : What say the French Guidelines? PS : FOLFIRINOX not validated in that situation!

13 Visible part of LA cancer? Chemotherapy Radiotherapy?? Back to surgery?

14 LA cancer : chemo? Radiotherapy? What order? CRT d emblée CRT Gem CRT Gem Chauffert B, Ann Oncol 2008

15 LA cancer : chemo? Radiotherapy? What order? CRT first CRT after 3 months chemo (selection) CRT Gem Chemo then CRT Chimiothérapie seule CRT Gem Chimiothérapie seule Chemo then CRT Huguet F, J Clin Oncol 2007 Chauffert B, Ann Oncol 2008 CRT is not excluded, but a «selection chemo» seems suitable

16 LA cancer : role of radiochemotherapy

17 LAP07 19 May Patients included (/902) 198 randomization R2 (/600) France Belgique Australie Nouvelle-Zélande Suède Canada (in preparation)

19 LA cancer : evaluation of tumour response? Very difficult! CT scan White et al. Ann Surg Oncol 1999 Sa Cunha et al.j Am Coll Surg 2005 Endoscopic ultrasonography Bettini et al. Gastroenterol Clin Biol Petscan 18-FDG Heinrich et al. Ann Surg 2008

21 Should we hope that surgical resection will finally be possible? D2 P Do not give false hope to the patients : 10% of patients will be eligible for tumour resection but do not exclude this possibility!

22 Should we hope that surgical resection will finally be possible in LA cancer? Sa Cunha et al.j Am Coll Surg 2005

23

24 Resection margins Graisse AMS Marge résection (encrée) Mazzeo, Abdom Imaging 2009

25 LA cancer : role of CA 19.9 after CRT? CT scan n Mean CA 19-9 (UI/mL) Tumour response 4 72 Stable disease Progression Surgical exploration : 27 patients Sa Cunha et al.ihpba 2008

26 LA cancer : role of CA 19.9 after CRT? CA 19-9 (UI/ml) n Resectability n (%) p > (22%) < (77%) Sa Cunha et al. IHPBA 2008

27 LA cancer : role of CA 19.9 after CRT? Keep in mind the limits of level CA 19.9 measurement! -False positive :. Cholestasis. Diabetes. Other cancer Frequent in pancreatic cancer! -False negative - Lewis (-) blood phenotype (~ 5% of population)

28 LA cancer : role of CA 19.9 after CRT? Young patient Good status Induction chemo/rt CA 19-9 > 200 U/mL Clinical improvement CT scan : disease controlled Laparoscopy Metastases? no PD

29 Cancer LA : sélection pour la chirurgie Young patient Good status Induction chemo/rt CA 19-9 > 200 U/mL Clinical improvement CT scan : disease controlled CA 19-9 < 200 U/mL Laparoscopy Metastases? no Laparotomy Arterial tissues + Biopsies - PD

30 Cancer borderline

31 LA cancer : definition SMV Maire, Pancreatology 2004 SMA Resectable 1st intent No metastases No arterial involvement SMV and portal vein ok Doubtful resectability «Borderline» SMV or portal vein > 180 Venous thrombosis (short) SMA < 180 HA (reconstructible) Non resectable Arterial involvement SMA > 180 Coeliac trunk involved Thrombosis of SMV or portal vein Cava or aorte involvement Irresectability : 13 % 25 % 100 % (coelioscopy) True neoadjuvant False neoadjuvant = (attempt to) salvage

32 Patterns of recurrence Smeenk et al Ann Surg 2007; 246: Pancreatic cancer patients Metastases are direct cause of death in 80% Hishinuma S J Gastroenterol Surg 2006

33 Neoadjuvant «true»: rational Oxygenation of tumour : better good radiosensitivity Better tolerance (patients OMS 0) 25% of patients do not receive adjuvant treatment (complications post-op) Decrease the rate of R1 (margins) 25-30% of «resectable» tumours become metastatic : processus of selection for «useful» surgery

34 Neoadjuvant therapy: borderline resectable pancreatic cancer Borderline resectable Definition? Pre-operative chemo/ chemoradiotherapy In pts w/borderline resectable disease Downstaging/sizing Higher rate of resectability Decrease R1 margin rate Effect on survival?? which regimen? duration? biliary stenting staging/response? Pathology RM?

35 Neoadjuvant treatment : ARCC Deberne M et al. Bull Cancer 2007.

36 Neoadjuvant treatment Crane C. Cancer/Radiotherapie, 2009

37 Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages 111 studies 4,394 patients Gillen et al PLoS Med ;7:e

38 Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages Gillen et al PLoS Med ;7:e

41 Neoadjuvant «true»: ARCC 1 prospective non randomized study of M.D. Anderson (Spitz F et al, JCO 1997) : 142 patients ARCC pre-op versus ARCC post-op no difference in survival

42 Trial of FFCD SFRO Biliary drainage Neoadjuvant «true» RT: 50 Gy 5 w (w1 to w5) CT: 5FU 300 mg/m 2 /j, 5j/7, 5 s + cisplatin 20 mg/m 2 D1-5 (w1 and w5) Evaluation after CRT - Surgery (w 9-11) 41 pts (NO : n = 33, N1 : n = 3) Feasability of treatment : 67 % Resection curative intent : 63 % Mortality post-op (D30) : 2 % Progression : 12 % Irresectability : 25 % Mornex, ASCO GI 2006 #

43 Neoadjuvant «true» Essai FFCD 9704 SFRO : pathology results. Complete response : 4 %. Major response : 50 % 80% SDCC*,. Minor response : 12 % < 50% SDCC, *SDCC : severely degenerative cancer cells Mornex, ASCO GI 2006

44 Neoadjuvant «true» Institut Paoli Calmettes, Marseille , 61 patients head cancer : n = 49 patients, body : n=12 CRT resection : 65 % No resection : 35 % (progression) Survival 2 yrs : 52 % Median survival : 26 m Réponse histologique majeure : n = 9 Réponse complète : n = 3 Moutardier & Delpero, Int J Radiat Oncol Biol Phys 2004 et J Gastrointest Surg 2004

45 Neoadjuvant «true» Varadhachary et al., ASCO GI 2006 Phase II Cancers (head) stade I - II Chemo first intent (4 cycles) Gemcitabine + cisplatin Radiotherapy 30 Gy + Gemcitabine weekly (400 mg/m 2 ) Inclusion RT RT Réévaluation G/C G/C G/C G/C G G G G Sem Assessement before treatment Evaluation after w

46 Neoadjuvant «true» Varadhachary et al., ASCO GI patients CRT completed: 91 % Laparotomy : 73 % Tumour resection : 60 % RO : 54 %

47 Neoadjuvant «true» Varadhachary et al., ASCO GI 2006 Toxicity : grade 3 neutropenia = 25 % Survie 1.0 OS Overall 15 m Résection Tumour resection 21 m 0.0 Absence de résection No resection 10 m mois < 50% of viable tumour cells : 61 % of resected specimen

48 Recruitment problems? Randomized Phase II: Gem+RT vs Gemcitabine+5FU+Cis followed by RT+5FU Locally advanced, potentially resectable pancreatic adenocarcinoma Sample size per treatment arm Resection rate 20-30% 10 centres: 22 patients; terminated early, poor accrual Landry et al, J Surg Oncol ;101:587-92

49 Competing Trials: randomized phase II-III trial of peri- or post-operative chemotherapy in resectable pancreatic adenocarcinoma Patients stage I/II pancreatic cancer 370 patients Surgery Gemcitabine days 1, 8, and 15 6 months Surgery R Cisplatin days 1-5 Epirubicin days 1 and 8 Gemcitabine days 1 and 8 Capecitabine on days 1-14 for 6 months Neoadjuvant Cisplatin days 1-5 Epirubicin days 1 and 8 Gemcitabine days 1 and 8 Capecitabine days 1-14 for up to 3 months Surgery Primary outcome: Proportion of patients who are event-free at 1 year Adjuvant (within 2 months of surgery) PEXG every 14 days for 3 months M Reni, World J Gastroenterol 2010; 16:

50 Take home messages Assessement of tumour : difficult Multidisciplinary meeting (do not forget thoracic CT scan!) First traitement LAP 07 Chemotherapy gem-based (followed by CRT?) Evaluation CT scan : difficult again no metastases? Secondary resection - Possible but unfrequent (10 %?), centers with high volume pancreatic surgery - Specific strategy (CRT, CA 19.9, laparoscopy, arterial biopsies before to envisage pancreatictoduodenectomy)