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

2. 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

3. 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

4. Epidemiology 6 % of primary hepatic neoplasm
Incidence x (USA)
Male / Female 1 : 1
Age years
Gallstones %
Autopsy %
Patel, Cherqui et al: 1995

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

6. 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, 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

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

15. Intrahepatic cholangiocarcinoma
Nimura, Nagoya
Mass forming type % 5 year survival
Periductal infiltrating type 16 % 5 year survival
Intraductal growth type % 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 % 5 year survival
Lymphadenectomy not helpful

16. Liver and IVC resection

17. Hilar cholangiocarcinoma

18. 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

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

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

21. 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

22. 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

23. Defining resectability

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

25. 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

26. 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

27. 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

28. 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

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

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

31. All patients going to laparotomy
However…
All patients going to laparotomy

32. 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?

33. 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

34. 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

35. 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

36. Can West meet East? Surgery (298) Drainage (130) Surgery (57)
Nagoya ( )
Surgery (298)
Liverpool ( )
Drainage (130)
Surgery (57)
Drainage (288)