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Advances in cholangiocarcinoma
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.
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
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)
26.
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
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
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
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.
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)