This document summarizes key points about the management of intrahepatic cholangiocarcinoma. It finds that surgical resection provides the best chance for long-term survival, with 5-year survival rates of 20-30% for resectable disease. For unresectable tumors, options include liver transplantation in select patients and local therapies like radiofrequency ablation, transarterial chemoembolization, and yttrium-90 microsphere treatment, which have shown some promise for improving survival. Systemic chemotherapy with gemcitabine and cisplatin is the standard first-line treatment based on improved survival seen in a phase III trial, while various targeted agents in combination with chemotherapy are under investigation in clinical trials

1. AUBHO 2014
Rachna T. Shroff, MD, MS
Assistant Professor,
Dept of GI Medical Oncology
M.D. Anderson Cancer Center
rshroff@mdanderson.org

2. None with the subject matter to be
presented
Research Funding:
Celgene
Clovis Oncology

3. >7,0000 cases annually in 2009
5-year survival is <15%
Most patients present with locally advanced or metastatic
disease
Treatment commonly administered in the community,
at low-volume centers.

4. Obesity, Metabolic Syndrome
Chronic inflammation (hepatitis, ETOH, smoking,
occupational)
Parasitic infections
Primary sclerosing cholangitis, Crohns disease
Cysts, anomalous pancreatobiliary ducts
Biliary polyps (>10 mm)

5. J Hepatol. 2004;40(3):472-7

6. 180
160
140
120
100
80
60
40
20
0
New Cases
2009
2010
2011
2012
Medical Oncology Referrals or New Cases
Causes:
Reclassification from CUP
True increase: Obesity,
Hepatitis, Better Detection
with Imaging/ Pathology

7. Adenocarcinoma
• Nodular
• Sclerosing
• Papillary
Squamous cell carcinoma
Mixed hepatocellular/cholangiocarcinoma
IHC CK7+, CK20-, CA19.9+

8. Al Jaffiry, WJG 2009

9. Extrahepatic
• Painless jaundice
• Weight loss
• Fever
Intrahepatic
• Constitutional Symptoms
• Pain
• Hepatomegaly
• Abnormal Liver Chemistries

10. Hilar Intrahepatic

11. Hilar Cholangio
Biliary Obstruction
common
Cholangitis life
threatening
Local-directed
therapies (TACE, Y90,
RFA) increased risk of
abscess/
complications
Intrahepatic
Cholangio
Course can be
relatively indolent
Local therapies for
advanced disease
feasible, particularly
radiation

12. Surgical resection is the standard of care
Post operative radiation/ chemoradiation therapy
improves recurrence-free survival in R1 disease
Role of adjuvant therapy in R0 resection is debatable
Role of liver transplantation in unresectable hilar
cholangiocarcinoma.
NCCN Guidelines

13. Surgical resection results in 20-30% long term survival
> 5 years
Klatskin tumors-junction of the hepatic ducts are
complicated by extensive perineural and lymphatic
invasion, bilateral liver involvement, and vascular
encasement
Intrahepatic cholangiocarcinoma is a contraindication
for liver transplant at most centers.

14. Unresectable CCA or resectable Cholangio with PSC
Tumor size < 3 cm
Tumor above cystic duct
No intra- or extrahepatic metastases
No intrahepatic CCA or GB involvement
Vascular encasement of the hilar vessels is not a
contraindication
CA 19-9 > 100 with mass; Biliary ploidy by FISH with bile
duct stricture

15. Neoadjuvant EBRT: 4000 to 4500 cGy + 5-FU
2000 to 3000 cGy transcatheter iridium
Capecitabine until transplantation
5-year survival with neoadjuvant therapy = 55%
5-year survival after transplantation = 71%.
Rosen HPB (Oxford). 2008

16. American Association for the Study of Liver Diseases
Heimbach J, et al: Liver Transplantation 10; 65-68, 2004

17. Disease-related factors
• Uncommon malignancies
• Unwell, elderly population, infection/obstruction
• Histological / cytological confirmation difficult
Lack of evidence
• Disease often not measurable
• Primarily small phase II and one phase III study of
gemcitabine-based combinations

18. Eligible patients (n=400*)
Arm A
Gem 1000 mg/m2 D1,8,15 q 28d
24 weeks (6 cycles)
Arm B
Cisplatin 25 mg/m2
+ Gem 1000 mg/m2
24 weeks (8 cycles)
Randomized 1:1
(stratified by centre, primary site, PS, prior
therapy and locally advanced vs. metastatic)
Upon disease progression, management will be on clinician’s
discretion (mostly best supportive care)
D1,8 q 21d
* Including 86 patients in ABC-01
+ QoL

19.  Main inclusion criteria:
 Histologically / cytologically verified disease
 Adequate biliary drainage, no uncontrolled infection
 ECOG PS 0-2
 LFTs: bilirubin  1.5 x ULN, ALT/ AST/ alk phos  3 x ULN
( 5 if liver metastases)
 Measureable disease was not mandated

20. Primary
endpoint:
OVERALL SURVIVAL
Secondary
endpoints:
 Progression-free survival
 Toxicity
 Quality of life (EORTC QLQ C-
30)
Sample
size:
 Powered to detect increase in
MS from 8 to 11 months
Log-rank test with 80% power
and two-sided a 5% level

21. Toxicity by patient Gem Cis/Gem
n % n %
White blood cells 18 11.0% 24 15.1%
Platelets 13 8.0% 13 8.2%
Hemoglobin 6 3.7% 10 6.3%
Neutrophils 29 17.9% 36 22.6%
Infection + neutropenia 12 7.5% 16 10.2%
Infection - neutropenia 14 8.6% 10 6.4%

22. Toxicity by patient Gem (n, %) Cis/Gem (n, %)
Anorexia 4 2.5% 3 1.9%
Lethargy 27 16.6% 29 18.6%
Nausea 5 3.1% 5 3.2%
Renal function 2 1.2% 3 1.9%
Vomiting 8 3.0% 8 5.1%
Constipation 3 1.8% 2 1.3%
Diarrhea 4 2.5% 7 4.5%
Dyspnea 2 1.2% 5 3.2%
Pedal oedema 5 3.1% 4 2.6%
Pain 12 7.5% 14 9.0%
Any grade ≥3 events 108 65.5% 102 64.2%

23. Result
Gem
n (%)
Gem + Cis
n (%)
Not assessed * 74 (36%) 56 (27%)
Assessed * 132 (64%) 148 (73%)
Complete Response 1 (0.8%) 1 (0.7%)
Partial Response 20 (15.2%) 37 (25.0%)
Stable Disease 73 (55.3%) 79 (53.4%)
Progressive Disease 33 (25.0%) 28 (18.9%)
CR + PR + SD 94 (71.2%) 117 (79.1%)
p-value 0.256
* Patients not required to have measurable disease at study entry,
some patients still in follow-up

24. Treatment arm Gem Gem + Cis
Number of patients n=206 n=204
PFS events n(%) 155 (75.2) 135 (66.2)
Median PFS (mo) 6.5 8.4
Log rank p value 0.003
Hazard ratio (95% CI) 0.72 (0.57, 0.90)

25. ABC-02 - Results:
Overall Survival (ITT)
Treatment arm Gem Gem + Cis
Number of patients n=206 n=204
Deaths n(%) 141 (68.5) 122 (59.8)
Median survival (mo) 8.3 11.7
Log rank p value 0.002
Hazard ratio (95% CI) 0.70 (0.54, 0.89)

27. Cisplatin and gemcitabine significantly improves overall
survival compared with gemcitabine monotherapy (11.7
vs. 8.3 months)
Benefit gained with no clinically significant added toxicity
CisGem is recommended as a worldwide standard of
care and the backbone for further studies
Caution required in patients with PS > 2

28. Gastrointest Cancer Res. 2011;4(5-6):155-60.

29. Rogers JE, et al. J Gastrointest Oncol 2014

31. Agents Target Patients RR PFS Author
Combination Regimens First line therapy
GEMOX-cetuximab
EGFR 51 - 61% (4 mths) Malka
GEMOX-bevacizumab
VEGF 35 40
7 months
(median)
Zhu
Single Agent Regimens First or Second line
AZD6244
MEK1/2 22 14
5.4 months
(median)
Bekaii-Saab
Erlotinib
EGFR 43 7
2.6 months
(median)
Philip et al
Lapatinib
EGFR/HER2 17 0
1.8 months
(median)
Ramanathan
Sorafenib
BRAF/VEGFR 36 6
2 months
(median)
El-Khoueiry
Sorafenib
BRAF/VEGFR 46 2
2.3 months
(median)
Bengala
Zhu et al, JCO, 2009

32. Bile Acids Induce EGFR in CCA cells via TGF-α and COX-2
Hepatol. 2004;41(5):808-14

33. Wide range reported k-ras mutation in biliary
cancer (10-45%)
More likely in anomalous pancreato-biliary ducts
Less likely in the setting of pre-existing adenoma
In Wt k-ras, EGFR-directed TKIs or Monoclonal
antibodies are a consideration

35. Endpoint Estimate
Partial response 8%
Stable disease 43%
24- week progression-free 17%
Overall survival 7.5 mos
J Clin Oncol. 2006 (19):3069-3074

36. GEMOX + Cetuximab 500 mg/m2 bi-weekly
Pri-endpoint: 4 month PFS (<40%: control;
>60% study arm)
101 pts enrolled
Interim analysis: manageable toxicity
4 mth PFS 44% vs 61% (Interim Analysis)
J Clin Oncl 27:15s, 2009

37. 268 pts randomized: GEMOX +
Erlotinib
PR higher in erlotinib group (40 vs.
21, p=0.005)
Higher PFS with erlotinib (5·9
months vs 3·0 months) (p=0·049)
Median overall survival was the
same in both groups
Lancet Oncol. 2012;13(2):181-8.

38. Phase 2: GEMOX+ Bevacizumab (10 mg/kg bi-weekly)
35 pts enrolled
Median PFS 7 months (6 months was 63%)
Toxicities: neutropenia, hypertension, AST
elevation, neuropathy
Partial responses or SD associated with
significant improvement in SUV
Lancet Oncol Nov 2009 (Epub)

39. Sorafenib: 400 mg twice a day
46 patients were treated; 26 (56%) had received
chemotherapy earlier
Progression-free survival (PFS) was 2.3 months (range:
0-12 months)
Median overall survival was 4.4 months (range: 0-22
months).
El Khoureiy, ASCO 2007

40. Therapeutic
Target
Chemotherapy Agent Phase
MEK Nil ARRY-438162;
AZD6244
II
Raf kinase GemOx Sorafenib II
VEGF+
EGFR
Gemcitabine Vandetanib Randomized II
VEGFR Gemcitabine/
Cisplatin
Cediranib
(AZD2171)
Randomized
II/III
EGFR Gemcitabine + Erlotinib,
Cetuximab,
Panitumamab
II/Randomized

41. MRN Mutations
1 PTEN TP53 ARID1A IDH1
2 MCL1
3 FBXW7 KRAS TP53 SMAD4 MLL2
CREBB
4 STK11KRAS MCL1
5 <none>
6 CDKN2A KRAS SMAD4 TP53
7 KRAS SMAD4 GRIN2A TP53
8 BAP1 CDKN2A/B PBRM1
9 PIK3CA KRAS MCL1 MYC
10 ARID1A TSC2
11 BRAF PIK3R1
12 ARID1IDH1
13 KRAS ARID1A IDH2
14 <none>
15 <none>
16 KRAS FBXW7 ARID1A MSH2 TP53
17 BAP1
18 KRAS
19 KRAS FBXW7 TP53
20 PTEN KRAS MDM2
21 KRAS TP53
22 CDK4 MYC
23 <none>
24 ERBB2 FBXW7 CDKN2A SMAD4
TP53
25 ERBB2 ATM SMAD4
26 KRAS TP53
27 EGFR PIK3CA CCND1 TP53
28 IDH1
29 MCL1 MYST3
30 IDH1
31 NRAS ARID1A IDH1
32 MDM2KRAS ARID2
33 PIK3CA MCL1 ARID1A CDH1 EPHA7
EPHB1 MSH6
34 BAP1
34 BRCA1 PTCH FBXW7
35 FGFR3-TACC

43. 1.00
0.75
0.50
0.25
0.00
Proportion Surviving
p = 0.028
0 6 12 18 24 30 36 42 48 54 60
Months
KRAS-Negative
KRAS-Positive

44. 33 patients with intrahepatic cholangioca
Median tumor size - 8.8 cm
88% previously chemotherapy
Dose: 50.4 Gy (range, 35–70 Gy), most with xeloda
1-year PFS: 47%, and 1-year OS: 62%
1-year OS rate was 100% with RT dose ≥ 60 Gy
Gastrointest Cancer Res. 2010 Nov-Dec; (Suppl 1): S34

45. Intrahepatic Cholangio: 67.5 Gy in
15 fractions. No concurrent
chemotherapy
N=57
1 and 2-year OS is 69% and 58%
PFS is 41% and 28%
respectively.

46. Locoregional Therapy: Y90
48 90Y treatments were
administered to hepatic
segments or lobes.
Fatigue, abdominal pain common
Rare: grade 3 bilirubin toxicity,
gastroduodenal ulcer.
PR 6 pts (27%), SD 15 patients
(68%), and PD in 1 patient (5%).
Median OS was 14.9 months.
OS for pts without and with prior
chemo was 31.8 months and 4.4
months, respectively (P = .02).
Cancer. 2008;113(8):2119-28.

47. Vascularity is lower than HCC, thus limiting
the value of TACE
Retrospective Study 60 cases
DEB-TACE: PFS of 3.9 mos, OS 11.7 mos,
cTACE: PFS of 1.8 mos OS of 5.7 mos
Chemo (GEMOX): PFS of 6.2 mos and OS
of 11.0 mos
Eur J Gastroenterol Hepatol. 2012 (4):437-43.

48. Ann Surg Oncol. 2013 Jul 12

49. Approach to management of intrahepatic cholangiocarcinoma
Patel, T. (2011) Cholangiocarcinoma—controversies and challenges
Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2011.20

50. Localized
Induction Chemo
followed by
ChemoRT
Disseminated
Systemic
Chemotherapy
NGS
Add targeted
agents based on
molecular
phenotype
Clinical trials:
MEK + Pazopanib
FGFR Inhibitor
Proton Therapy
Select cases
with SD/PR> 6
mos on chemo,
consider OLT
(investigational)