Aintree University Hospital Consultant Hepatobiliary Surgeon NHS Foundation Trust Cholangiocarcinoma: Can West meet East ? Hassan Z Malik MD, FRCS Consultant Hepatobiliary Surgeon

Western series Authors Year Resection (n) Lenght of study (years) 5-year survival Cherqui 1995 14 5 - Casavilla 1997 34 31 Lieser 1998 28 Harrison 32 23 42 Roayaie 16 7 21 Madariaga 35 Weber 2001 33 19 Lang 2005 27 22 Puhalla 9 Nuzzo Young 2006 2010 87 10 15 36 20

Western series Authors Year Resection (n) Lenght of study (years) 5-year survival Cherqui 1995 14 5 - Casavilla 1997 34 31 Lieser 1998 28 Harrison 32 23 42 Roayaie 16 7 21 Madariaga 35 Weber 2001 33 19 Lang 2005 27 22 Puhalla 9 Nuzzo Young 2006 2010 87 10 15 36 20

Epidemiology 6 % of primary hepatic neoplasm Incidence 0.67 x 100.000 (USA) Male / Female 1 : 1 Age 60 - 80 years Gallstones 25 - 60 % Autopsy 0.01 - 0.46 % Patel, 2001. Cherqui et al: 1995

Classification Intrahepatic Peripheral 5 % Extrahepatic Gerald Klatskin Peripheral 5 % Extrahepatic Hilar ( Klatskin tumour ) 65 % Distal 30 % Nakeeb, 1996. Reding, 1991. National Library of Medicine

Age-adjusted incidence Age-adjusted mortality On the rise & deadly Age-adjusted incidence Age-adjusted mortality Median age at diagnosis : 71 yr / 76 yr at death : 71 yr / 74 yr Patel, 2001. Khan, 2002

Aetiological factors Primary sclerosing cholangitis ( PSC ) Caroli’s disease Choledochal cysts Hepatolithiasis Liver fluke Unknown Gores, 2000

Aetiological factors Primary sclerosing cholangitis ( PSC ) Caroli’s disease Choledochal cysts Hepatolithiasis Liver fluke Unknown – 80% : genetic and environmental factors Gores, 2000

Diagnostic tools Tumour markers CEA, CA 19-9 Cytology ( increased sensitivity with DIA, FISH ) ERCP / Spyglass CT MRI / MRCP PET / CT ?

Spyglass Liverpool experience 96 strictures were sampled using dual modality Overall accuracy in characterisation nature of stricture 81% Noorullh O et al. Gut 2013

Investigation algorithm PET CT ? Malhi and Gores, 2006

Intrahepatic cholangiocarcinoma Mass forming type Margin pushes rather than infiltrates Periductal infiltrating type Involves Glissonian capsule, PV, HA Intraductal growth type Polypoid tumour inside ducts, often without obstruction Often associated with dysplasia and hyperplasia Subtype: Biliary cystadenocarcinoma Combined type Liver Cancer Study Group of Japan; 1997

Intrahepatic cholangiocarcinoma Nimura, Nagoya Reported IHPBA September 6, 2006 1977 - 2005 244 cases 75 inoperable 169 resected ( 69% ) 92 Mass forming type 54 Periductal infiltrating type 23 Intraductal growth type 116 R0 resections

Intrahepatic cholangiocarcinoma Nimura, Nagoya Mass forming type 14 % 5 year survival Periductal infiltrating type 16 % 5 year survival Intraductal growth type 66 % 5 year survival Rarely node positive Multivariate analysis: Nodal status, intrahepatic metastases, perineural infiltration Node positve + intrahepatic mets surgery not helpful Node negative + intrahepatic mets 25 % 5 year survival Lymphadenectomy not helpful

Liver and IVC resection

Hilar cholangiocarcinoma

Challenges Complexity of Hilar anatomy Assessment of tumour extent Pathophysiology of jaundice and functional assessment Technical demands of surgery Ro resections Extended Liver resection Vascular resections PSC Neoadjuvant and adjuvant therapies Nihilism in West

Locoregional assessment Gold standard: PTC or ERCP Combined with drainage Uni / Bilobar cholangiography MRI / MRCP CT Staging laparoscopy?

Contraindications for resection Metastatic disease Para-aortic nodes Frail patient

Hilar cholangiocarcinoma Surgical technique Division of the bile duct within the pancreas Extensive neurectomy and lymphadenectomy Resection of affected liver or to gain greater duct clearance Resection of the caudate lobe ( segment 1 ) Bilateral resection and reconstruction of portal vein and hepatic artery when necessary Hepaticojejunostomy to individual segmental or subsegmental ducts within the hepatic remnant

Defining resectability Number of different staging systems have now combined into proposed new staging system by “International study group” incorporating – Tumour type Biliary involvement Arterial involvement Venous involvement Nodal disease Underlying liver disease DeOlivera et al Hepatology 2011

Defining resectability

Hilar cholangiocarcinoma Impact of resectional surgery Kosuge et al (Makuuchi),1999.

Hilar cholangiocarcinoma Prognostic factors 306 resections from MSKCC & AMC Concordance Index 0.72 for validation dataset, compared to 0.60 for the 7th edition of the AJCC system Koerkamp et al, Ann Oncol 2015

Hilar cholangiocarcinoma Transplantation Mayo clinic protocol External beam radiation therapy (45 Gy in 30 fractions, 1.5 Gy twice daily) and continuous infusion 5-FU – administered over 3 weeks Brachytherapy (20 Gy at 1 cm in approximately 20–25 hours) – administered 2 weeks following completion of external beam radiation therapy Capecitabine – administered until the time of transplantation, held during perioperative period for staging Abdominal exploration for staging – as time nears for deceased donor transplantation or day prior to living donor transplantation Liver transplantation - Review of data from 12 US centres: 287 patients; drop out rate 11.5% Murad et al Gastroenterology 2012

Hilar cholangiocarcinoma Transplantation - Intention to treat 5-yr survival 53% - 30% patients never had confirmation of malignancy on pre-tissue acquisition - Results from RCT: Liver Resection Versus Radio- chemotherapy-Transplantation for Hilar Cholangiocarcinoma (TRANSPHIL) awaited Murad et al Gastroenterology 2012

What factors to consider Prognostic factors Size of tumour Vascular invasion Nodal status Patient co-morbidity/unit outcomes What factors to consider when planning surgery „Medical risk of resection in YOUR unit Resectability Remaining functional liver tissue Invaded structures/segments

Prognostic factors Resectability Size of tumour Vascular invasion Nodal status Resectability Remaining functional liver tissue Invaded structures/segments

Long term outcomes Gomez at al EJSO 2013 Nagoya (2000-2008) Liverpool (2000-2011) Gomez at al EJSO 2013

All patients going to laparotomy However… All patients going to laparotomy

Clinical Problem Curative resection – median survival 40 months Post resection only 50% fit enough for adjuvant chemotherapy However only 10-20% patients are resectable Up to one third of those taken to laparotomy are in-operable Median survival of all patients going to laparotomy is thus 17 months Role for neo-adjuvant chemotherapy?

Current evidence Adjuvant chemotherapy - results of BILCAP and PRODIGE-12 awaited - ACTICCA-1 trial Neo-adjuvant chemotherapy – possible active agents Gem/Ox with Cetuximab RR 60% & secondary resection rate 30% (Grunberger et al Lancet Oncol 2010) BINGO: Gem/Ox with Cetuximab RR 23% (oral presentation ASCO 2012) ABC-02 Cis/Gem RR 30.1% (NEJM 2010) Problems: What chemo regimen ? Safety

The Future Need for next generation trials Combination of peri-operative Cisplatin and Gemcitabine backbone and novel agents AIM to downsize disease, bring more patients to resection thus improving overall survival

Conclusion Aggressive disease Radical resection in select patients can achieve 5-year survival Importance of lymphadenectomy and caudate lobe resection as well as negative margin Role of transplantation unproven Expanding role of multi-modal treatment

Can West meet East? Surgery (298) Drainage (130) Surgery (57) Nagoya (2000-2008) Surgery (298) Liverpool (2000-2011) Drainage (130) Surgery (57) Drainage (288)