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Cholangiocarcinoma : Can West meet East ?

Aintree University Hospital. NHS Foundation Trust. Cholangiocarcinoma : Can West meet East ?. Hassan Z Malik MD, FRCS. Consultant Hepatobiliary Surgeon. Western series. Western series. Epidemiology. 6 % of primary hepatic neoplasm. Incidence 0.67 x 100.000 (USA).

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Cholangiocarcinoma : Can West meet East ?

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

  2. Western series

  3. Western series

  4. 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

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

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

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

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

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

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

  11. Investigation algorithm PET CT ? Malhi and Gores, 2006

  12. 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

  13. 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

  14. Intrahepatic cholangiocarcinoma Nimura, Nagoya • Mass forming type14 %5 year survival • Periductal infiltrating type16 % 5 year survival • Intraductal growth type66 % 5 year survival • Rarely node positive • Multivariate analysis: • Nodal status, intrahepatic metastases, perineural infiltration • Node positve + intrahepatic metssurgery not helpful • Node negative + intrahepatic mets25 % 5 year survival • Lymphadenectomy not helpful

  15. Liver and IVC resection

  16. Hilar cholangiocarcinoma

  17. 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 Challenges

  18. Gold standard: PTC or ERCP Combined with drainage Uni / Bilobarcholangiography MRI / MRCP CT Staging laparoscopy? Locoregional assessment

  19. Contraindications for resection • Metastatic disease • Para-aortic nodes • Frail patient

  20. 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

  21. 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

  22. Defining resectability

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

  24. 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

  25. 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

  26. 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

  27. 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

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

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

  30. All patients going to laparotomy However…

  31. 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?

  32. 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

  33. 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

  34. 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 Conclusion

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

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