1. Cholangiocarcinoma – An Overview AMMF Conference/Information Day
Dr Shahid A Khan
Consultant Liver Specialist St Mary's & Hammersmith Hospitals
Imperial College London
AMMF Conference/Information Day
11th May 2017

2. Cholangiocarcinoma (CCA)
What is it?
How many people are affected (epidemiology)?
What causes it?
How is it diagnosed?
What are the treatments?
What are the unmet needs?

3. Cholangiocarcinoma (CCA)
What is it?
How many people are affected (epidemiology)?
What causes it?
How is it diagnosed?
What are the treatments?
What are the unmet needs?

4. Cholangiocarcinoma (CCA)
Cancer = a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body
Cholangiocarcinoma (CCA) is a cancer of the bile ducts
Since mid 1990s, more deaths coded in UK due to CC than HCC.
Rise in CC unknown, not explained by improved diagnosis. Apparent increased intrahep CC partly explained by misclassification of Klatskin/ perihilar? But if all diagnostics – why not levelling off (CT/ MR/ ERCP been around for a few yrs), and why not more early stage tumours?
Mean estimated annual percentage change. Corrected for age.

5. CCA: Intrahepatic/ Perihilar/ Extrahepatic
50-60% “Perihilar”: arise at bifurcation of main ducts - pCCA
20-30% distal CBD - eCCA
10-20% arise in intrahepatic ducts of liver - iCCA

6. Cholangiocarcinoma (CCA)
What is it?
How many people are affected (epidemiology)?
What causes it?
How is it diagnosed?
What are the treatments?
What are the unmet needs?

7. Cholangiocarcinoma (CCA)
A cancer in a body organ can be primary or secondary
CCA is the second commonest primary liver tumour after Hepatocellular Carcinoma (HCC)
5-10% all primary liver cancers
Peak age 7th decade
Slight male preponderance
Since mid 1990s, more deaths coded in UK due to CC than HCC.
Rise in CC unknown, not explained by improved diagnosis. Apparent increased intrahep CC partly explained by misclassification of Klatskin/ perihilar? But if all diagnostics – why not levelling off (CT/ MR/ ERCP been around for a few yrs), and why not more early stage tumours?
Mean estimated annual percentage change. Corrected for age.

8. Epidemiology of CCA: Worldwide
Incidence varies, reflecting geographical risk factors & genetic differences

9. ASMR of all parenchymal tumours, HCC, unspecified tumours and intra + extrahepatic CCA in Men, Eng &Wales,
Taylor-Robinson et al., Gut 2001

10. Studies from around the world show changing trends in Incidence/Mortality of CCA:
Intrahepatic CCA↑
Extrahepatic CCA↓
CCA Overall↑
Since mid-1990’s, iCCA is commonest recorded cause of death from a primary liver tumour in England & Wales, ahead of HCC
Total deaths risen 30-fold: 36 in 1968 to > 2100 in 2013
Large rise in iCCA Age-standardised Mortality Rates (ASMR):
males 0.1 to 1.5; females 0.05 to 1.25
Largest statistical increase in any tumour over this time period
Total deaths from HCC: 472 in 1968 to approx 2000 in 2014

11. Intrahepatic CCA mortality increased 9% in M & F, , reaching rates of 1.1/100,000 men and 0.75/100,000 women
Highest rates in UK, Germany, and France (1.2–1.5/100,000 men, 0.8–1.1/100,000 women)
Joinpoint analysis for age-standardized (world population) death certification rates from intrahepatic cholangiocarcinoma (ICC) in 12 major selected European countries, the European Union (EU), the United States, Japan, and Australia, 1990–2010. Men, ; women .
Bertuccio P et al. Ann Oncol 2013

12. Trends in age-adjusted male rates for HCC and iCCA, 1978–2007
Petrick et al. Int J Ca 2016

13. Male liver cancer incidence rates per 100,000 person-years by year of birth for (a) HCC
(b) iCCA
(selected countries)
Petrick et al. Int J Ca 2016 13

14. Trends in HCC and iCCA rates are similar But:
Thailand, France, Italy: iCCA increased while HCC decreased
HCC and ICC may have some common risk factors, but geographic areas of increasing ICC rates do not entirely correspond with those of increasing HCC rates
Likely other potential differences in liver cancer aetiology 14

15. Average total hospital charges per hospitalization due to CCA (USA)
Average total hospital charges per hospitalization due to cholangiocarcinoma
Wadhwa et al. Gastroenterol. Rep. 2016

16. USA: Sex & race/ethnicity disparities in CCA incidence: 2000–2011 SEER
Increasing age associated with increasing incidence of CCA
Highest incidence of CCA among men and among Asians
Sex‐specific cancer incidence by increasing age among patients with (a) intrahepatic cholangiocarcinoma and (b) extrahepatic cholangiocarcinoma.
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Mosadeghi et al., Hep Res 2016

17. Taiwan:
iCCA incidence increased 3-fold: 0.72 to 2.19
eCCA incidence increased 1.5-fold: 0.48 to 0.73
Rising incidence of CCA seen across all ages/genders, esp in > 65 years

18. Cholangiocarcinoma (CCA)
What is it?
How many people are affected (epidemiology)?
What causes it?
How is it diagnosed?
What are the treatments?
What are the unmet needs?

19. CCA: Causes (Aetiology) & Known Risk Factors
Primary sclerosing cholangitis
Parasitic Infection (Opisthorcis viverrini, Clonorchis sinensis)
Fibropolycystic Liver Disease
Intrahepatic Biliary Stones
Chemical Carcinogen Exposure/Nitrosamines? Thorotrast?
Chronic Liver Disease
Viral Hepatitis
Obesity
Type 2 Diabetes
>70% of CCA cases in West have NO known risk factors

20. CCA: Causes (Aetiology) & Known Risk Factors
Bergquist et al Best Pract Res Clin Gastro

21. Cholangiocarcinoma (CCA)
What is it?
How many people are affected (epidemiology)?
What causes it?
How is it diagnosed?
What are the treatments?
What are the unmet needs?

22. Hence most CCA cases are diagnosed very late
CCA: How is diagnosed?
Symptoms not specific and occur late in the disease process
Discomfort, weight loss, jaundice, itching, sometimes dark urine, pale stool
Imaging
Ultrasound, CT, MRI scans
but the appearances are non-specific
Biopsies (various routes)
Can be difficult due to location
Tumour markers in blood
None are very accurate
Hence most CCA cases are diagnosed very late

23. Cholangiocarcinoma (CCA)
What is it?
How many people are affected (epidemiology)?
What causes it?
How is it diagnosed?
What are the treatments?
What are the unmet needs?

24. International Liver Cancer Association CCA Guidelines on, 2014

25. Surgical Resection for CC
Mainstay of treatment, only chance for cure
Goal: R0 resection with adequate remnant liver volume
Perioperative mortality < 5% in specialized centres
OUTCOMES:
Recurrence rates %
Median disease free survival 26 months
5-year survival 15 – 40%

26. Molecular Targeted Therapy for CCA – studies so far
Sadeghi & Finn, Clin Liv Dis 2014
Currently no targeted therapy validated for CCA
Little or no improvement in survival
MEK inhib trials included some pts who progressed on 1st line 26

27. Other Options for Targeted Therapy in Advanced CCA
Rizvi et al, Sem Liver Dis 2014
Biomarker adaptive design in future CCA clinical trials? 27

28. Cholangiocarcinoma (CCA)
What is it?
How many people are affected (epidemiology)?
What causes it?
How is it diagnosed?
What are the treatments?
What are the unmet needs?

29. Unmet Needs and Future (hope) in CCA
Greater awareness and research funding
More accurate, early diagnostic tools to enable more patients to have potentially curative surgery
Equitable and rapid access for specialist centre opinion
Need for better second and third-line treatments
Ongoing trials in advanced CCA – chemotherapy; local techniques e.g. ablation
Oncological treatment for CCA will be more individualized, when the genetic profile of a tumour can predict response to any given agent 29

30. Acknowledgments NIHR Biomedical Research Centre
Biomedical Research Council (BMRC)
Imperial College Healthcare Trustees
(donations from Mr. and Mrs. Barry Winter)

31. Cholangiocarcinoma – An Overview AMMF Conference/Information Day
Dr Shahid A Khan
Consultant Liver Specialist St Mary's Hospital
Imperial College London
AMMF Conference/Information Day
11th May 2017