Tumores Bilio-Pancreaticos Carlos Gomez-Martin Hospital Universitario 12 de Octubre. Madrid

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1 Tumores Bilio-Pancreaticos Carlos Gomez-Martin Hospital Universitario 12 de Octubre. Madrid

2 Pancreatic Cancer

3 Pancreatic Cancer Pancreatic Cancer Entity Resectable Borderline Resectable Locally advanced Metastatic Incidence 15-20% 7% 15-20% 60-70% Survival with optimal therapy dependent on resectability mo 9-11 mo 6-11 mo advanced disease Property of Prof V. Heinemann. Not for reproduction or use without express permission.

4 Pancreatic Cancer

5 Pancreatic Cancer

6 Pancreatic Cancer G.A. Gooiker et al B J Surgery 2011

7 Pancreatic Cancer G.A. Gooiker et al B J Surgery 2014

8 Pancreatic Cancer G.A. Gooiker et al B J Surgery 2014

9 Pancreatic Cancer: Adjuvant treatment Studies Investigating Adjuvant Treatments for PC Patient Factor GITSG EORTC ESPAC-1* CONKO-001 Ch/RT+ Fluorouracil Ch/RT + Gemcitabine Patients, n/n (%) Microscopically positive margins T3 of T4 disease Lymph node positive disease Local recurrence rate, % (n/n) 0 20/104 (19) 19/147 (28) 34/179 (19) 75/230 (33) 77/221 (35) NA 0 NA 154/179 (86) 162/230 (70) 178/221 (81) 6/20 (30) 23/49 (47) 73/147 (50) 127/179 (71) 148/230 (65) 151/221 (68) 47 (7/15) 51 (34/67) 63 (99/158) 37 (NA) 28 (49/173) 23 (35/155) Median survival, mos year survival, % year survival, % NA NA Regine WF, et al. JAMA. 2008;299:

10 Pancreatic Cancer: Adjuvant treatment Studies Investigating Adjuvant Treatments for GBC ESPAC-3 Gemcitabine vs 5-FU/folinic acid N= 1088 Median PFS: 14.3 (gem) vs 14.1 mos (5-FU/FA) (P =.53) Median OS: 23.6 (gem) vs 23.0 mos (5-FU/FA) (P =.39) 2-yr OS: 49.1% (gem) vs 48.1% (5-FU/FA) J Neoptolemos et al. JAMA 2010

11 Pancreatic Cancer

12 Pancreatic Cancer Pancreatic Cancer Entity Resectable Borderline Resectable Locally advanced Metastatic Incidence 15-20% 7% 15-20% 60-70% Survival with optimal therapy dependent on resectability mo 9-11 mo 6-11 mo advanced disease Property of Prof V. Heinemann. Not for reproduction or use without express permission.

13 Pancreatic Cancer: Borderline Resectable Barugola G et al. Am j Surg 2012.

14 Pancreatic Comparison Cancer among different criteria to define borderline AHPBA/SSAT/S SO MD Anderson NCCN 2012 Intergroup trial SMV-PV Abutment, encasement or occlusion Occlusion Abutment with impingement or narrowing Interface between tumor and vessel measuring 180 or greater of the circumference of the vessel wall and/or reconstructable occlusion SMA Abutment Abutment Abutment Interface between tumor and vessel measuring less than 180 of the circumference of the vessel wall CHA Celiak trunk Abutment or short segment encasement No abutment or encasement Abutment or short segment encasement Abutment Abutment or short segment encasement No abutment or encasement Property of Stefano Cascinu. Not for reproduction or use without express permission. Reconstructable shortsegment interface between tumor and vessel of any degree Interface between tumor and vessel measuring less than 180 of the circumference of the vessel wall

15 Pancreatic Cancer: Borderline Resectable Borderline resectable tumors: Neoadyuvant neo-adjuvant therapy therapy Study N of patients Staging definition Treatment Indication for surgery Patients resected Stokes, MDACC Cape/RT No progression 40% Chun, CT/RT No progression Better OS in patients receiving neo McClaine, Intergroup trial CT No progression 46% Turrini, MDACC CT/RT No progression 61% Brown, nd CT/RT No progression 80% Mehta, nd CT/RT No progression 60% Patel, nd GEM/Cape/Doc etaxel followed by 5FU/RT No progression 64% Katz, MDACC GEM/5FU/RT No progression 53% Property of Stefano Cascinu. Not for reproduction or use without express permission.

16 Pancreatic Cancer: Borderline Resectable Extending Surgery VENOUS RESECTION 28 studies (retrospective) 1 1,458 patients median mortality rate 4% median average lenght stay: 17 days 75% chance of a clear margin 18 studies (non randomised) 2 2,247 patients No difference in perioperative morbidity, mortality and 5- year OS 1 Chua et al. J Gastrointest Surg Zhou et al. World J Surg 2012

17 Pancreatic Cancer: Borderline Resectable Extending Surgery 26 studies (retrospective) 2243 patients no AR 336 patients AR ARTERIAL RESECTION in perioperative mortality OR 5.04 (95% CI: ) Poor survival: 1 year OR 0.49 (95% CI: ) 3 year OR 0.38 (95% CI: ). Mollberg et al, Ann Surg 2011

18 Pancreatic Cancer The Intergroup definiton of Borderline resectable Pancreatic Cancer NCT : Alliance A trial Chemotherapy and Radiation Therapy Before Surgery Followed by Gemcitabine in Treating Patients With Pancreatic Cancer Estimated Enrollment: 20 Study Start Date: May 2013 Estimated Primary Completion Date: July 2015

19 Pancreatic Cancer

20 Pancreatic Cancer: Locally advanced disease P Hammel et al. ASCO 2013

21 Pancreatic Cancer: Locally advanced disease S. Mukherjee et al. Lancet Oncology 2013

22 Pancreatic Cancer: Locally advanced disease S. Mukherjee et al. Lancet Oncology 2013

23 Pancreatic Cancer: Locally advanced disease S. Mukherjee et al. Lancet Oncology 2013

24 Pancreatic Cancer

25 Pancreatic Cancer: Metastatic Disease

26 Pancreatic Cancer: Metastatic Disease FOLFIRINOX vs Gemcitabine Phase III study in metastatic pancreatic cancer R FOLFIRINOX Gemcitabine n=342 MPACT: Summary of Efficacy R Gem/nabPac Gemcitabine n=861 Gemcitabine FOLFIRINOX p ORR (%) DCR (%) PFS (mo) < OS (mo) < year survival (%) Inclusion criteria: - Age < 75 years - ECOG Bilirubin < 1.5 ULN - No coronary heart disease Property of Prof V. Heinemann. Not for reproduction or use without express permission. Applicable in 26% of patients Single institution chart review by Gill, et al. ASCO 2012 Conroy T, et al. NEJM 2011 Gemcitabine Gem/nabPac HR P ORR (%) x DCR (%) x PFS (Mo) OS (Mo) year-survival (%) Inclusion criteria: - Age 1 8 years - KPS 70 - Bi irubi. 1 0 ULN Inclusion of selected patients! Central review of response rate Von Hoff et al. ASCO 2013 Property of Prof V. Heinemann. Not for reproduction or use without express permission.

27 Pancreatic Cancer: Metastatic Disease Modified from M.H.G.Katz ASCO2014

28 Pancreatic Cancer: Metastatic Disease Defining eligibility of FOLFIRINOX for first-line metastatic pancreatic adenocarcinoma (MPC) in the province of British Columbia: A population-based retrospective study. J Clin Oncol 30, 2012 (suppl; abstr e14588) Only 26 out of 100 patients fulfilled the ACCORD study eligibility criteria The most common reasons for FOLIFIRINOX exclusion were: poor ECOG score of 2 or greater (64%), age of 76y or greater (22%), elevated bilirubin (22%), inadequate renal function (6%). S.Gill et al. ASCO 2012.

29 Relevance of Treatment Duration? DCR (%) 33 Pancreatic Cancer: Metastatic Disease MPACT Trial PFS (Mo) 3.7 OS (Mo) 6.7 Phase-II Study Phase-III Study n ORR (%) 48 23* DCR (%) 68 48* PFS (mo) year-survival (%) 22 Inclusion criteria: - Age 1 8 years - KPS 70 - Bi irubi. 1 0 ULN Property of Prof V. Heinemann. Not for rep OS (mo) Treatment duration ca 6 months (6 cycles) 3.9 months *independent review von Hoff et al. J Clin Oncol 2011 Property of Prof V. Heinemann. Not for reproduction or use without express permission. Von Hoff et al. ASCO 2013 D. Von Hoff et al JCO 2011 D. Von Hoff et al ASCO 2013

30 FOLFIRINOX vs Gemcitabine Pancreatic Cancer: Metastatic Disease R n=342 2nd-Line Therapy FOLFIRINOX- Arm Gemcitabin- Arm Patient number nd-line chemotherapy 47% 50% Gemcitabine 82.5% Gemcitabine-based combination 12.5% FOLFIRINOX Gemcitabine ACCORD and MPACT Trials: Subsequent Therapies FOLFOX 49.4% Gemcitabine + oxaliplatin 17.6% 5-FU/FA + cisplatin 16.5% FOLFIRINOX 4.7% Median survival after start of 2nd-line therapy: 4.4 MedOS months in both after treatment start arms of 2nd line: Conroy T. et al. ASCO months Property of Prof V. Heinemann. in boths Not for reproduction arms or use without express permission. Conroy et al ASCO 2010 D.Von Hoff et al ASCO GI 2013 LBA 148

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32 Gallbladder Cancer

33 Gallbladder Cancer

34 Gallbladder Cancer RADICAL CHOLECYSTECTOMY Colecistectomia + 2 cm de parénquima hepático subyacente+linfadenectomia del lig hepatoduodenal, 2ª porcion duodenal, peripancreaticos y tronco celiaco V. Rajagopalan y cols. Oncology 2005.

35 Gallbladder Cancer T.M. Pawlik et al. J Gastrointest Surg 2007.

36 Gallbladder Cancer There are no randomized phase III clinical trial data to support a standard adjuvant regimen. Clinical trial participation is encouraged!!

37 Gallbladder Cancer Horgan AM, Amir E, Walter T, Knox JJ. J Clin Oncol. 2012;30(16):1934.

38 Gallbladder Cancer N+ R1 Horgan AM, Amir E, Walter T, Knox JJ. J Clin Oncol. 2012;30(16):1934.

39 Gallbladder Cancer Studies Investigating Adjuvant Treatments for GBC B. G. Müller et al. ASCO 2014

40 Gallbladder Cancer Studies Investigating Adjuvant Treatments for GBC NCT : Phase III Capecitabine or Observation After Surgery in Treating Patients With Biliary Tract Cancer stimated Enrollment: 360 Study Start Date: March 2006 Primary Completion Date: August 2013 NCT : Phase III Gemcitabine Hydrochloride and Oxaliplatin or Observation in Treating Patients With Biliary Tract Cancer That Has Been Removed by Surgery Estimated Enrollment: 190 Study Start Date: July 2009 Estimated Primary Completion Date: July 2016

41 Gallbladder Cancer Hezel AF and Zhu AX. Systemic therapy for biliary tract cancers. The Oncologist 2008;13: gemcitabine/oxaliplatin, gemcitabine/capecitabine capecitabine/cisplatin capecitabine/oxaliplatin 5-fluorouracil/oxaliplatin 5-fluorouracil/cisplatin Gemcitabine Capecitabine, 5-fluorouracil.

42 Gallbladder Cancer J. Valle et al NEJM 2010

43 Gallbladder Cancer Gem, n (%) Gem/Ci s n(%) p value Any grade 3/4 Toxic effect 137 (68.8) 140 (70.7) 0.69 Treatment was discontinued at 24 weeks or because of disease progression, patient or clinician choice, or unacceptable toxic effects. J. Valle et al NEJM 2010

44 Gallbladder Cancer for a maximum of six cycles or unacceptable toxicity whichever was earlier. Sharma A, Dwary AD, Palmer DH et al. J Clin Oncol. 2010;28:4581.

45 Cholangiocarcinoma

46 Cholangiocarcinoma

47 Cholangiocarcinoma TNM Staging

48 Hiliar Cholangiocarcinoma Parikh AA et al. HBP 2005

49 Hiliar Cholangiocarcinoma M.L DeOliveira et al. Hepatology 2011

50 Hiliar Cholangiocarcinoma M.L DeOliveira et al. Hepatology 2011

51 Intrahepatic Cholangiocarcinoma

52 Intrahepatic Cholangiocarcinoma

53 Cholangiocarcinoma

54 Cholangiocarcinoma. PostResection Therapy Horgan AM, Amir E, Walter T, Knox JJ. J Clin Oncol. 2012;30(16):1934.

55 Cholangiocarcinoma. PostResection Therapy N+ R1 Horgan AM, Amir E, Walter T, Knox JJ. J Clin Oncol. 2012;30(16):1934.

56 Cholangiocarcinoma. Advanced Disease

57 Cholangiocarcinoma. Advanced Disease J. Valle et al NEJM 2010

58 Cholangiocarcinoma. To stent or not to stent Preoperative Biliary Drainage in Resectable disease? K.N. Shah et al. Surg Oncol Clin N Am 2014

59 Cholangiocarcinoma. To stent or not to stent Indications for Preoperative Biliary Drainage in Resectable disease K.N. Shah et al. Surg Oncol Clin N Am 2014

60 Cholangiocarcinoma. Photodinamic Therapy Tumoricidal effects most pronounced within 4 9 mm depth

61 d be considered in patients with unresectable disease. asis should be placed on treatment goals and expected mes. Data regarding cost effectiveness, operator expee, availability of endoscopic expertise, and patient rence would certainly play a role in treatment choice. e present body of evidence is limited by scarcity of hed randomized controlled trials. The available data of survival and biliary drainage. Ortner et al. were the to report the results of a randomized controlled trial of duct stenting with and without PDT for CCA [9]. Impr ment of bilirubin obstruction was only achieved after application and not after stenting alone. Selection bias have contributed to these favorable results as patients successfully underwent biliary stenting a month prio Cholangiocarcinoma. Photodinamic Therapy Leggett CL et al. 2012

62 Cholangiocarcinoma. Some molecular insights Sia D et al. Gastroenterology 2013

63 Cholangiocarcinoma. Some molecular insights SIA et al. Pag Figure 4. Summary of characteristics of ICC classes. Specific molecular and clinical characteristics differ between ICC classes. Molecular characteristics such as signatures of poor prognosis Sia D et al. Gastroenterology 2013 NIH-PA Author Manuscript NIH-PA Author Manuscript N Page 17 Figure 3.

64 Cholangiocarcinoma. Some molecular insights N.Razumilava. The Lancet 21 June (9935) Pgs

65 Cholangiocarcinoma. Some molecular insights Rohle D. Et al. Science 2013

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