State of the art

treatment options for primary liver malignancies

and metastatic disease

Peter Huppert

Prof. of Radiology and Neuroradiology

Klinikum Darmstadt

Certified Vascular and Oncologic Center

Disclosure

Speaker name:

Peter Huppert, M.D.

I have the following potential conflicts of interest to report:

Consulting

Employment in industr

Stockholder of a healthcare company

Owner of a healthcare company

Other(s)

x I do not have any potential conflict of interest

Interventional Trx. Options in Liver Tumors

transhepatic

• Tumor ablation

• Portal vein embolization

• Biliary drainage

transarterial

• Conventional TACE

• Drug-eluting TACE

• Radioembolization

Liver Tumor Ablation

Basic Principle

• Thermocoagulation by heating • Energy delivery by RF, MW,

laser light, FUS...

Approach/Method

• perc. transhepatic access • monopolar-multipolar probes • various probe designs

Liver Tumor Ablation

Indication

• HCC: n </=3; size </= 5 cm • Mts.: n </=3; size </= 3 cm • Resection not preferred

Outcome/Limitations

• Local control >85% (<3 cm size) • New lesions 50-70%/1-3a • Limitations:

- critical sturctures < 1cm - heat sink effect of vessels > 3mm

+17 mo.

Liver Tumor Ablation

Indication

• HCC: n </=3; size </= 5 cm • Mts.: n </=3; size </= 3 cm • Resection not preferred

Outcome/Limitations

• Local control >85% (<3 cm size) • New lesions 50-70%/1-3a • Limitations:

- critical sturctures < 1cm - heat sink effect of vessels > 3mm

+17 mo.

+7 mo.

Liver Tumor Ablation

Indication

• HCC: n </=3; size </= 5 cm • Mts.: n </=3; size </= 3 cm • Resection not preferred

Outcome/Limitations

• Local control >85% (<3 cm size) • New lesions 50-70%/1-3a • Limitations:

- critical sturctures < 1cm - heat sink effect of vessels > 3mm

+17 mo.

+7 mo.

Portal Vein Embolization

Basic Principle

• flow redistribution into FRL • induction of hyperplasia

Approach/Method

• percut. transhep. PV catheter. • selectiv segmental PV embx. • Particles, glue, coils

Portal Vein Embolization

Indication

• Prior to liver resection • Insufficient FRLV

Outcome/Limitations

• + 20-30% of FRLV • Limited in cirrhosis

+ 4 weeks

Transhepatic Biliary Drainage

Basic Principle

• recanalization of biliary obstruction

• reconstitution of internal biliary flow

Approach/Method

• percutaneous transhepatic access

• unilateral/bilateral drainage • stenting, silicon-prosthesis

Transhepatic Biliary Drainage

Indication

• failed ERCP • Hilar and extrahepatic biliary

obstruction • cholangitis

Outcome/Limitations

• effective in hilar and distal obstructions

• limited in multiple intrahepatic obstructions by mts.

Conventional TACE

Basic Principle

• local intraarterial chemotherapy • embolization of tumor feeding

arteries • accumulation of drugs and

embolics within tumor vessels

Approach/Method

• transfemoral selective catheter. • microcatheter if needed • various drugs and embolics

combined

Conventional TACE

Indication

• HCC: non-resectable, intermediate stage – multinodular, PS 0, Child A/B

• CCC: non-resectable, PD after systemic treatment

• Mts.: palliative for various types

Outcome/Limitations

• HCC: survival benefit 6-12 mo. in selected cases

• limited effects in all others with no proven survival benefit

Conventional TACE

Indication

• HCC: non-resectable, intermediate stage – multinodular, PS 0, Child A/B

• CCC: non-resectable, PD after systemic treatment

• Mts.: palliative for various types

Outcome/Limitations

• HCC: survival benefit 6-12 mo. in selected cases

• limited effects in all others with no proven survival benefit

Radioembolization

Basic Principle

• internal radiation/brachytherapy • catheter-directed application of

microparticles emitting ß-radiation

• minor embolic effects

Approach/Method

• bland embx. of non-target arteries in advance

• evaluation of av shunting • appropriate dose application

Radioembolization

Indication

• HCC, Liver-Mts. • advanced disease • portal vein thrombosis

Outcome/Limitations

• tendency of better local response compared to TACE

• no proven survival benefit • RILD, costs

+ 11 mo

Mts. CRC

Drug-eluting TACE

Basic Principle

• cytotoxic drug loaded into microspheres

• drug release after catheter-directed application and embx.

• sustained drug delivery and exposure

Approach/Method

• technique similar to conv. TACE • today available for Doxorubicin,

Epirubicin and Irinotecan • today 3 types of microspheres

SO3-

SO3-

SO3-

SO3-

SO3-

SO3-

SO3-

SO3-

SO3-

SO3-

SO3-

SO3-

SO3-

Irt+ Irt+

Irt+ Irt+

Irt+

Irt+

Irt+

Irt+

Irt+

Irt+

Irt+

Irt+

Irt+

Interaction of irinotecan (Irt+) with SO3-

groups by an ion-exchange process

displaces water from the hydration shells

Drug-loaded Beads

adapted from Biocompatibles

Drug-Eluting Microspheres DC-BEADSTM TandemTM

Images: Biocompatibles, Biosphere, Celonova

HepaSphereTM

material polyvinyl alcohol sodium acrylate polyvinyl alcohol

sizes 70-150μm..500-700μm 30-200 (x 4) ) μm 40μm, 75μm, 100μm

loading 200 mg Irinotecan/4cc 200 mg Irinotecan/50mg 200 mg Irinotecan/4ml

150 mg Doxorubicin/4cc 50 mg Doxorubicin/50 mg 200 mg Doxorubicin/4cc

Drug-eluting TACE

Indication

• HCC (similar to conv. TACE) • colorectal cancer liver mts.

(salvage, downstaging)

Outcome/Limitations

• HCC: improved local efficacy and systemic toxicity however no proven survival benefit compared to conv. TACE

• CRC-Mts: TTP of 5-6 mo in salvage population; limited if >25% tumor load

Drug-eluting TACE

Indication

• HCC (similar to conv. TACE) • colorectal cancer liver mts.

(salvage, downstaging)

Outcome/Limitations

• HCC: improved local efficacy and systemic toxicity however no proven survival benefit compared to conv. TACE

• CRC-Mts: TTP of 5-6 mo in salvage population; limited if >25% tumor load

Discussion

Evaluation of TACE for treatment of colorectal liver

metastases between the 1980s and 1990s showed

heterogeneous results. Response rates in patients with and

without prior systemic treatments ranged from 25 to 100 %

and median survival from 7 to 23 months [16]. Since 1998,

several trialshaveevaluated TACE in patientswho had liver

metastases refractory to systemic treatment. In the majority

of studies, combinations of cisplatin, doxorubicin, and

mitomycin with particles of polyvinyl alcohol (PVA) or

collagen for embolization had been used but with varying

protocols [16–20]. Again heterogeneous results were

reported with objective response ranging between 2 and

63 %, progression-free survival between 3 and 8 months,

and overall survival between 8.6 and 14 months [16, 17, 19,

20]. Outcomeafter TACE appearsto behighly variable, and

only limited data are available to determine which sub-

groups of patients will have benefit from this treatment. In

2011, the study by Albert et al. [20] showed that patients

who had one or two lines of systemic treatment before

TACE had better outcome (median survival 11–12 months)

compared with patients after 3–5 lines (median survival

Fig. 3 Two large metastases involving both liver lobes (A). Plane

Dyna CT image just after TACE showing uptake of contrast added to

the suspension of loaded microspheres during embolization of the

lesion in segment 7 (B). At 3 months partial response (EASL) with

70 % tumor necrosis and stable disease (RECIST) with minimal

progression in size (C). At 6 months extensive multinodular progres-

sion at the margin of both lesions (D)

Table 3 Median time to progression and median survival after

TACE in relation to liver tumor involvement and grade of tumor

vascularization

Median TTP (mo) Median survival (mo)

Liver tumor involvement (%)

\ 25 10* 21*

26–50 4.5 7

51–75 3* 5*

Grade of vascularization

1 3.5 6

2 7.5 10

3 6 12

* p\ 0.005

P. Huppert et al.: Transcatheter Arterial Chemoembolization

123

Author's personal copy

CL I NI CA L I NV ESTI GA TI ON

Transcatheter Ar ter ial Chemoembolization (TACE) of ColorectalCancer Liver Metastases by Ir inotecan-Eluting Microspheresin a Salvage Patient Population

Peter Hupper t • Thorsten Wenzel • Huber tus Wietholtz

Received: 18 January 2013 / Accepted: 14 April 2013

Ó Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2013

Abstract

Purpose This prospective study evaluated the effective-

ness and safety of TACE using irinotecan loaded super-

absorbent polymer (SAP) microspheres for treatment of

colorectal cancer liver metastases (CCLM) in a salvage

setting of patients.

Methods A total of 71 TACE procedures were performed

in 29 patients with liver only or liver-dominant CCLM. In

all patients, systemic chemotherapy before TACE had

failed. Two hundred milligrams of irinotecan were loaded

into 50–100 mg of SAP microspheres (HepaSphereTM

Microspheres) considering tumor size and vascularization.

TACE was performed selectively with respect to tumor

distribution. Response was evaluated following RECIST

and EASL criteria, respectively. Median follow-up after

last TACE was 8 (range 1–54) months. All patients had

died at time of analysis.

Results All TACE procedures were performed success-

fully; 35–400 mg (mean 168.3 mg) of irinotecan loaded in

13–100 mg (mean 48.3 mg) SAP microspheres were

injected during individual sessions. No major complica-

tions occurred. Three, 6, and 12 months after first TACE

complete and partial response was present in 72, 32 %, 0 of

patients by EASL criteria and stable disease was seen in

86, 48, and 8 % with no complete and no partial response

by RECIST criteria. Median overall survival after first

TACE was 8 months, and median time to progression was

5 months. Median overall survival was longer in patients

with limited (\ 25 %) compared with extensive ([ 50 %)

intrahepatic disease (21 vs. 5 months, p\ 0.005).

Conclusions TACE using irinotecan loaded SAP micro-

spheres is safe and effective in terms of tumor necrosis.

Survival benefit in a salvage setting seems to be limited in

patients with advanced intrahepatic tumor load.

Keywor ds Transarterial chemoembolization Liver

metastases Colorectal cancer Irinotecan: superabsorbent

polymer microspheres

Introduction

Patientswith liver metastases from colorectal cancer have a

poor prognosis. Fewer than 25 % are candidates for cura-

tive resection or percutaneous ablation, and of those who

do, 70 % will suffer from relapse within 3 years [1]. Sys-

temic first-l ine 5-fluorouracil (5-FU)-based treatments in

combination with irinotecan or oxaliplatin and monoclonal

antibodies offer response rates (RR) of 31–62 %, median

progression-free survival (PFS) of 6.9–10.6 months, and

median overall survival (OS) of 14–21.5 months [2–5].

However, in patients refractory to these treatments second-

or third-line systemic treatments are far less effective with

RR of 4–21 % and median PFS of 2.5–4.8 months [6–8].

In asalvage setting with metastases that have progressed

and are limited or dominant to the liver, regional treat-

ments, such as transcatheter arterial chemoembolization

(TACE), offer the possibi lity of temporary local tumor

P. Huppert (& )

Department of Diagnostic and Interventional Radiology,

Klinikum Darmstadt GmbH, Grafenstrasse 9, 64283 Darmstadt,

Germany

e-mail: huppert@klinikum-darmstadt.de

T. Wenzel

Department of Medical Oncology, Klinikum Darmstadt GmbH,

Grafenstrasse 9, 64283 Darmstadt, Germany

H. Wietholtz

Department of Gastroenterology, Klinikum Darmstadt GmbH,

Grafenstrasse 9, 64283 Darmstadt, Germany

123

Cardiovasc Intervent Radiol

DOI 10.1007/s00270-013-0632-0

Author's personal copy

Summary

• Thermal ablation, transhepatic biliary drainage and portal

vein embolization are established techniques with well

defined indications.

• cTACE is limited to HCC, CCC and NET, however deTACE and

radioembolization have potential to improve results of

transarterial treatment in selected patients with primary liver

tumors and liver metastases.

State of the art

treatment options for primary liver malignancies

and metastatic disease

Peter Huppert

Prof. of Radiology and Neuroradiology

Klinikum Darmstadt

Certified Vascular and Oncologic Center