Univ. Sapienza, Rome, Italy.Domenico ALVARO, Univ.“Sapienza” Rome, Italy

Neo Gr.E.Ca.S., Cosenza, 6 Dicembre 2013.

IL COLANGIOCARCINOMA Presentazione Clinica, Diagnosi e Trattamento

Distal

INTRAHEPATIC

CHOLANGIOCARCINOMA (CCA): a heterogeneus cancer !

Hilar

UICC classification

WHO classification

Klatskin t.second-order bile ducts

INTRAHEPATIC CCA (IH-CCA)Macroscopic pattern of growth !

Mass-formingPeriductal-infiltrating

Intraductal growing (LSCGJ)

Mixed type (AJCC/UICC )

Mass-forming = 89 %Single mass = 67%HBV or HCV+ = 21%Cirrhosis = 10%Obstructive cholestasis = 10%

Anatomical location of IH-CCA

24/52 segment IV)

IH-CCA, N= 116.

Mass-forming = 94 %Single mass = 78.4%HBV or HCV+ = 30.2%Cirrhosis = 13.8%Obstructive cholestasis = 10%

50%

IH-CCA : PRESENTING SYMPTOMS (%)

4% Pruritus

4.4 % Other

IH-CCA: Algorithm for the diagnosis. Intrahepatic

massEsclude

extrahepatic malignancy !

4-phase MDCT, dynamic contrast-

enhanced MRI contrast arterial enhancement and

prompt venous washout

HCC

Cirrhosis

> 1 cmThe impact of imaging procedures in

discriminating HCC vs mixed-CCA or combined HCC-CCA

scarcely investigated !

N= 31 nodules, N 9 < 2 cm.

-Progressive homogeneous contrast uptake during the three vascular phase (42%)

N. 40 IH-CCA nodules on cirrhosis (N= 11 < 2 cm):

all nodules lacked the radiologic hallmark of HCC !

-Arterial periphereal-rim enhancement (50%);

N. 28 IH-CCA nodules on cirrhosis:

< 3 cm: 5/8 washout pattern similar to HCC !> 3 cm: 20/20 no washout, 9/20 arterial periphereal-rim enhanc.!

Biopsy

IH-CCA: Algorithm for the diagnosis. Intrahepatic

massEsclude

extrahepatic malignancy !

4-phase MDCT, dynamic contrast-

enhanced MRI contrast arterial enhancement and

prompt venous washout

HCC

Atypical appeara

nce

cirrhosisnon-cirrhotic

liver

No marker specific for CCA!

Immunohistochemistry (IHC) marker panel CK7 (+), CK20(-/+), CDX-2(-),

TTF-1 (-), PR (-), BRST-2 (-) , PSA (-)

Histology/IHC cannot differentiateCCA from metastatic gallbladder cancer,pancreas, or upper gastrointestinal tract

Histological diagnosis of IH-CCA: a diagnosis of exclusion !

(HCC ?, metastasis ? )

MembranousN-cadherin +: sensitivity 67%; specificity 88% Membranous N-cadherin +/CK7+:sensitivity 67% ; specificity 98%

Sempoux C. et al. Seminar in liver disease Vol. 31, 2011. .

CHOLANGIOCARCINOMA: Diagnosis

Novel target genes and a valid biomarker panel identified for CCA. Andresen K. et al. Epigenetics 2012; 7 (11).

CDO1, DCLK1, SFRP1 and ZSCAN18, high methylation frequencies in CCA ….unmethylated in controls.

At least one of these four biomarkers was positive in 87% of the tumor samples, with a specificity of 100% !

Nodular

Nodular

Periductal-infiltrating

Intraductal growing

(LSCGJ)Exophytic

EXTRAHEPATIC CCA (EH-CCA) Classification based on Macroscopic pattern of

growth !

Nodular+PI = 94% Obstructive jaundice = 79 % (299/376)Biliary drainage = 74.3%

BSG guidelines

EH-CCA, N= 102

Nodular-PI = 82 %HBV or HCV+ = 18.6 %Cirrhosis = 4.3%Obstructive cholestasis = 70%

EH-CCA : PRESENTING SYMPTOMS (%)

6.8% Pruritus

3,9 % abdominal pain

5.9 % No symptoms

9.9 % others

ObservationCCA

EH-CCA: Algorithm for the diagnosis Suspicion of CCA (Clinical + US)

MRI+MRCP

ERCP (citology, brushing, FISH, biopsy)Under evaluation: Endoscopic Ultrasound (EUS), Intraductal Ultrasound (IDUS), Choledochoscopy, cholangioscopy (chromoendoscopy, confocal endoscopy, narrow band imaging) Neg. citology,

brushing, FISH No dominant stricture

CCA

Biopsy (tumor

spread !!)

Positive biopsy, citology, brushing or

polysomy(Fish)

Vascular enhancement

Mass-like appearance

Biliary stricture Dominant stricture

in PSC

PET (?)Hot

spot?

yes NO

Definite diagnosis Perihilar mass with associated biliary stricture + hypertrophy–atrophy complex + vascular encasement

microscopic confirmation is needed to confirm the diagnosis

Presence and level of stricture sensitivity, specificity = 98%

Malignancy detection sensitivity 88%, specificity = 95%(Ann. Int. Med 2003)

CHOLANGIOCARCINOMADiagnosis

(Gut 2012)

CHOLANGIOCARCINOMADiagnosis

(Gut 2012)

CHOLANGIOCARCINOMADiagnosis

CHOLANGIOCARCINOMADiagnosis

Definitive diagnosis before surgery: 61%

No evidence of cancer on resected tissues 10 %

*Polisomy on bile citology or brushing *IGF1 on bile samples (ERCP)

Never reached routine clinical use !

*Surgery is the only curative treatment for CCA ! 5-year survival rates: IH-CCA 22-44 % distal EH-CCA 27-37 % hilar EH-CCA 11-41 %

*Survival depends: R0 or R1 status, vascular invasion and lymphonode metastases.

CHOLANGIOCARCINOMATREATMENT !

Open surgery 57% IH- vs 42% EH-CCA

Curative 45% IH- vs 29% EH-CCA

CHOLANGIOCARCINOMAAdjuvant therapy ?

* No evidence support postoperative adjuvant therapy !

*A phase III RCT with Mito+5FU…. no advantage (only GBC)

* UK NCRI-BILCAP study with CAPECITABINE is ongoing (final report 2014)

*France-NCT: GEMOX (final report 2015)

BSG guidelines

April 2010

*The efficacy of CisGem regimen confirmed (Furuse J. 2011)

* CisGem cost-effective vs Gem alone (Roth JA 2012)

BSG guidelines

Metanalysis of Survival, Complications, and Imaging Response following Chemotherapy-based Transarterial Therapy in Patients with Unresectable Intrahepatic Cholangiocarcinoma. Ray CE, J Vasc Int. Radiol. 2013

MESSAGE: transarterial chemotherapy-based treatments for CCA appears to confer a survival benefit of 2-7 months compared with systemic therapies !

Yttrium-90 Radioembolization for IH-CCA . Mouli S. et al. J Vasc Int. Radiol. 2013

46 pts IH-CCA unresectable.

25% partial response 73% stable disease 5 pts converted to resectable status !

A phase II trial of sorafenib (SOR) in patients (pts) with advanced cholangiocarcinoma (CCA). C. Dealis ASCO 2008.

CONCLUSIONS: Sorafenib as a single agent has a

low activity in cholangiocarcinoma !

Targeted agents in development for CCA

Cholangiocarcinoma: registered trials

Sorafenib + Gem.+ cisplatin phase IICediranib + Folfox phase IIPanitumumab + Gem.+ Irinotecan phase IIVandenatinib + Gem. phase IISunitinib phase IIPazopanib + GSK1120212 phase IIErlotinib phase II