Embolotherapy of Cholangiocarcinoma, 2016 updates - GEST 2018

Embolotherapy of Cholangiocarcinoma, 2016 updates - GEST 2018

Embolotherapy for Cholangiocarcinoma: 2016 Update Igor Lobko,MD Chief, Division Vascular and Interventional Radiology Long Island Jewish Medical Cent...

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Embolotherapy for Cholangiocarcinoma: 2016 Update Igor Lobko,MD Chief, Division Vascular and Interventional Radiology

Long Island Jewish Medical Center

GEST 2016

Igor Lobko, M.D. • No relevant financial relationship reported

Cholangiocarcinoma Embolization • Recent Literature • Ongoing Studies • When is Embolization of Cholangiocarcinoma appropriate? Patient Selection Prognostic Factors Does Size Matter? Tumor Enhancement – What does it mean? • Cholangicarcinoma IR Therapies Algorithm

Cholangiocarcinoma • Primary malignant neoplasm of the hepatobiliary system arising from the biliary ducts epithelia • Second most common primary malignancy of the liver • 2000-3000 new cases a year in USA, 1.67/100000 • More common in South East Asia: China 0.97-7.5, Korea 7.1-8.75, Thailand 5.7-85/100000 • Usually diagnosed at advanced stage, have a poor prognosis

Literature Review

Trans arterial Therapies

Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma. • 20 articles, 657 patients • Median OS: HAI – 22.8 months TARE – 13.9 months TACE – 12.4 months DEB-TACE – 12.3 months • Toxicity: HAI - Highest

Response Rate: 56.9% 27.4% 17.3%

Boehm LM et all, J Surg Oncol. 2015 Feb

Trans-arterial embolization therapies for unresectable intrahepatic cholangiocarcinoma: a systematic review • 20 studies eligible for review between 2000-2013 ( 929 patients ) • 4 studies with more then 50 patients • 12 studies retrospective • No Randomized Controlled Trials • Radiological Response: complete – 10%, partial – 22% • MOS: TARE - 12.5 months; TACE – 13 months • 1 Year Survival TARE – 54.5% ( 40-61%); TACE – 53% ( 38-78%) • Negative Predictive Factors: TARE - Large Tumor Burden, Multiplicity, PS > 2 TACE - Hypovascularity, Extrahepatic Disease Linda Yang et all, Gastrointest Oncol. 2015 Oct

Intra-arterial therapy for advanced intrahepatic Cholangiocarcinoma: a multi-institutional analysis • Retrospective review 198 patients treated in 4 major centers • Compered cTACE, DEB, TAE, TARE Response: Complete or partial – 25.5% Stable disease – 61.5% Progression – 13% Medial OS 13.2 months and did not differ between IAT Similar Treatment Related Toxicities


Hyder O, Ann Surg Oncol. 2013 Nov

Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: A systematic review and pooled analysis • • • • •

12 Studies, 298 patients: 7 prospective and 5 retrospective studies No randomized studies Median OS 15.5 months Radiological Tumor Response: Partial – 28% Stable – 54%


7 patients down staged to surgery D.P. Al-Adra et all, Eur J Surg Oncol. 2015 Jan

Radioembolization improves survival in intrahepatic cholangiocarcinoma: a SEER-Medicare population study • Retrospective • 585 patients: Chemotherapy 513 – 88% Chemotherapy + TARE 72 - 12% • Median Overall Survival: Chemotherapy 811 days Chemotherapy + TARE 1043 days • Combination therapy of ICC with chemotherapy and radioembolization results in a median 7.6 months of greater survival than chemotherapy alone.

Hyun S. Kim, Minzhi Xing, SIR 2016 Annual Meeting

Yttrium-90 radioembolization for unresectable combined hepatocellular-cholangiocarcinoma • • • •

Retrospective SIR Spheres 5 patients and Theraspheres 6 patients 11 patients Radiographic Response: Partial – 6 Stable – 4 • Median OS: From 1st TARE – 9.4 months From Initial Diagnosis – 18 months • Only Grade 1-2 toxicities observed

John D Louie, Daniel Sze, David S. Wang, SIR 2016 Annual Meeting

Summary of Published Data Good News • Embolotherapies for Cholangiocarcinoma Improve Survival • Relatively Low Toxicities with Acceptable Safety Profile • Similar results between different types of embolization Bad News • Low power studies due to small and heterogeneous samples • Most studies based on retrospective data analysis • No Randomized Trials

Current Studies Investigating Embolotherapies for Cholangiocarcinoma Treatment

• • • • •

6 - Ongoing Prospective Studies 2 – Dose Escalation Studies 2 - Safety and Feasibility 1 - International Cholangiocarcinoma Registry 2 - Randomized Trials


Yttrium Y 90 Glass Microspheres and Capecitabine in Treating Patients With Liver Cholangiocarcinoma or Liver Metastases, USA • • • • • •

Prospective Dose Escalation Study Theraspheres Started March 2009, enrollment completed Estimated Study Completion Date December 2017 30 Patients Primary Outcome Measures: Maximal tolerated dose of yttrium Y 90 Toxicity Time to tumor progression

90Y Transarterial Radioembolization (TARE) Plus Gemcitabine and Cisplatin in Unresectable Intrahepatic Cholangiocarcinoma USA • Prospective Dose Escalation Study • SIR Spheres • Start Date July 2015 • Estimated Completion Date August 2018 • 20 patients • Primary Outcome Measure: Presence or absence of a dose limiting toxicity (DLT) of 90Y TARE in combination with gemcitabine and cisplatin

International Registry on Cholangiocarcinoma Treatment (CHOLANGIO), Italy • • • • • •

Prospective Study DEB TACE with Doxorubicin Target number of patients 40 Started July 2013 Estimated Completion date August 2016 Primary Outcome Measures: Tumor response Overall Survival • Secondary Outcome Measures: Number adverse events Quality of life

Efficacy Study of Intra-hepatic Administration of Therasphere® in Association With Intravenous Chemotherapy to Treat Cholangiocarcinoma, France • Prospective Safety/Efficacy Study • Theraspheres • Started September 2013 • Estimated Completion Date April 2018 • 41 Patient • Primary Outcome Measure: Radiological response rate to the treatment with the association of chemotherapy and radioembolization 3 months after TARE.

Selective Internal Radiotherapy (SIRT) Versus Transarterial Chemoembolization (TACE) for the Treatment of Cholangiocellular Carcinoma (CCC). Germany • • • • • •

Randomized SIR Spheres Started February 2011 Estimated Completion Date October 2016 24 Patients Primary Outcome Measures: Progression-free Survival (PFS} • Secondary Outcome Measures: Overall Survival (OS) Time to Progression (TTP)

Drug-Eluting Bead, Irinotecan Therapy for Unresectable Intrahepatic Cholangiocarcinoma w/Concomitant Gemcitabine and Cisplatin (DELTIC), USA • • • • • •

Randomized DEB TACE with Irinotecan Started July 2012 Estimated Completion Date July 2016 48 Patients Primary Outcome Measures: Tumor response according to m-RECIST Criteria • Secondary Outcome Measures: Hepatic Progression Free Survival

Future Research • Prospective studies with pre-determined and standardized data assessment. • Randomized controlled trials to assess efficacy of trans-arterial therapies in comparison with available systemic chemotherapies • Randomized controlled studies comparing different embolization therapies. • Studies focused on determining the appropriateness of each specific embolization therapy • Pre treatment imaging as a tool for choosing the specific embolization therapy. • Post treatment imaging in evaluation of the efficacy of different therapies

When is cholangiocarcinoma embolization appropriate?

• Patient Selection

• “To Be or Not to Be” OR

Failure vs Success - Does Size Matter? - Can preprocedure imaging predict the outcome? - Can favorable IR therapy be chosen prospectively?

Prognostic Factors for ICC Survival • R0 Resection: Achieved – 63% 5 Year Survival – 40-63% Local Recurrence – 62% • Lympho-Vascular Invasion • Intrahepatic Invasion • Metastases: 50-75% • Lymph Nodes Metastases: 30-50% of all patient, 25% tumor < 3cm • Multifocal Tumors

Patient Selection • No Other Local Therapies Possible: Poor Surgical Candidates Multiple Bilobar Masses Gross Vascular Invasion Unfavorable Location for Ablation Large Size: Too Big for Ablation or when Surgical Resection would live insufficient amount of functioning liver • Metastatic disease

Correlation between Tumor Size and Aggressive Futures • 443 Patients Surgical Resections for ICC • Perineural Invasion and Regional Lymph Node Metastases are independent risks for microvascular invasion in tumors > 5cm < 3cm




> 15cm

Microscopic Vascular Invasion






High Tumor Grade






Spolverato G, Tumor size predicts vascular invasion and histologic grade among patients undergoing resection of intrahepatic cholangiocarcinoma. J Gastrointest Surg. 2014 Jul

Correlation between Tumor Size and Aggressive Futures

The incidence of multiple tumors, vascular invasion, and poorly undifferentiated tumors increased with tumor size (all P < .005)

Dario Ribero, MD, Surgical Approach for Long-term Survival of Patients With Intrahepatic Cholangiocarcinoma. A Multi-institutional Analysis of 434 Patients. Arch Surg. 2012

Tumor Size and Possibility of Curative Resection 1

• Curative Resection/5 year Survival – 10% • The 5-year survival rate of 15 patients who had ICC measuring ≤2 cm in greatest dimension without lymph node metastasis or vascular invasion was 100% 2


Spolverato G Can hepatic resection provide a long-term cure for patients with intrahepatic cholangiocarcinoma? Cancer. 2015 Nov 15


Sakamoto Y, Proposal of a new staging system for intrahepatic cholangiocarcinoma: Analysis of surgical patients from a nationwide survey of the Liver Cancer Study Group of Japan. Cancer. 2015 Oct 2

Ablation vs Embolization for Treatment of Cholangiocarcinoma Using Size Criteria • Ablations should be reserved for favorably located tumors < 3 cm, may be even < 2 cm. • Tumors > 3 cm should be treated with Embolotherapies. • Even for small tumors, 2-3cm, ablations combined with embolization may improve outcomes.

Tumor Enhancement as Prognostic Factor in Therapy Selection • 42 patients undergone hepatectomy • Microvascular Density (MVD) compared with tumor enhancement on CT: 24 < 16HU > 18. Low Attenuation Hypo-group-24

Higher Attenuation Hyper-group-18

Size <5/>5cm



Histologic Differentiation Well/Moderately/Poorly



2 years tumor recurrence



Survival: 1-3-5 year

49 – 17 – 17%


Nanashima A, Intrahepatic cholangiocarcinoma: relationship between tumor imaging enhancement by measuring attenuation and clinicopathologic characteristics. Abdom Imaging. 2013 Aug,

Metastatic Disease Multiple Tumors High Grade Gross Vascular Invasion

Cholangiocarcinoma < 2cm

2-3 cm

> 3cm


Ablation +/- Embolization


Hypervascular TAE


Hypovascular TARE

Embolotherapy for Cholangiocarcinoma: 2016 Update Summary • Embolotherapy for Cholangiocarcinoma works and improves survival • Low Toxicities • High rate of aggressive futures make embolotherapy a preferable modality for treatment of unresectable cholangiocarcinomas • Mass size correlates with presence of lymphovascular invasion and tumor differentiation • Cholangiocarcinoma enhancement correlates with tumor grade and patients survival • More and better quality research needed.