Ablative Treatment of Hepatocellular Carcinoma

Dr. Reda Hasan Tabashy, M.D.Associate Professor of Radiodiagnosis

NCI, Cairo University, Egypt

• No financial disclosure.

Hepatocellular CarcinomaStaging, Patient (ECOG)

Hepatocellular Carcinoma Staging, Liver (Child-Pugh)

Points

Parameters 123

Bilirubin (mg/dL) <22-3>3

Albumin (g/dL)>3.52.8- 3.5<2.8

Prothrombin (increased seconds)

1-34-6>6

Ascites NoneSlightModerate

Encephalopathy (grade)NoneI-IIIII-IV

Class A, 5-6 points; Class B, 7-9 points; Class C, 9-15 points

Hepatocellular Carcinoma Staging, Tumor (BCLC)

Stage Performance status

Tumor stageLiver function

Very early HCC, (Stage 0)

0Single < 2 cmChlid-pugh class A

Early HCC, (Stage A) 0Single or 3 nodules , < 3 cmChild-Pugh class A-B

Intermediate HCC, (Stage B)0Large /multinodularChild-Pugh class A-B

Advanced HCC, (Stage C)1-2Vascular invasion Extrahepatic spread

Child-Pugh class A-B

End-stage HCC, (Stage D)3-4Any Child-Pugh class C

Hepatocellular Carcinoma BCLC treatment algorithm

Hepatocellular Carcinoma Loco-regional treatment

Loco-regional Treatment

Percutaneous ablation Endovascular treatment

Chemoembolization Chemical ablation

Thermal ablation

Radioembolization Electroporation

Ultrasound ablation

Portal vein embolization

Chemoperfusion

Hepatocellular Carcinoma Patient selection for ablation

HCC patient: Without vascular/ biliary invasion / extrahepatic disease. And with good coagulation profile.

Very early stage (BCLC 0) HCC patient: Not candidate for transplantation. With single nodule ≤ 2 cm.

Early stage (BCLC A) HCC patient: Not candidate for surgery or transplantation. With single nodule ≤ 5 cm. Or with multiple nodules ≤ 3 No. and ≤ 3 cm in size.

Bridging treatment in patients waiting for transplantation. After successful TACE/surgery with residual nodule.

Percutaneous Ethanol Injection

Mechanism; Cytoplasm dehydration protein denaturation coagulative necrosis. Vascular endothelial injury platelet aggregation thrombosis and target lesion ischemia.

Indications; Nodular type HCC with firm capsule/ cirrhotic liver pseudo capsule.

Limits diffusion within the soft tissue consistency tumor. Increases concentration within target.

BCLC stage A, not for surgery or transplantation. Subcapsular HCC, or HCC near to critical structures (e.g, GB, liver hilum).

Total ethanol amount; Lesions less than 3 cm, V = 4/3 [(D/2 + 0.5)3]. Lesions 3-5 cm, V = 4/3 [(D/2)3]. Total amount not exceeds 60 mL.

.

Percutaneous Ethanol Injection

Conventional ethanol ablation; Uses 22-gauge needle with side and end holes. Low-dose ablation 2-5 mL./session for 6-12 sessions (2/week). High-dose ablation 5-10 mL./session for 3-6 sessions (2/week).

Multipronged ethanol ablation; 18-gauge needle with three retractable tines, each has four exit holes. Injection rotation injection maneuver. Advantages:

Homogenous ethanol distribution. Large amount in single injection before reflux. The retractable tines can be deployed for 5 cm.

Percutaneous Ethanol Injection

PEI is best injected under ultrasound guidance; Continuous real-time monitoring of the injection. Avoids excessive ethanol leakage outside the lesion.

Under local analgesia and conscious sedation. Disadvantages;

Multiple painful sessions. Uncontrolled instillation/inhomogeneous diffusion. Peripheral residual/recurrence. Not for large lesions.

Percutaneous Ethanol Injection

Radiofrequency ablationPhysics

RF energy is an alternating current with a frequency of 10-900 MHz.

RF waves applied for tissue ablation have a frequency of 500 kHz. When RF electric field is applied to the body, the interaction losses in moving ions and water molecules at a frequency of the

electric field, creating conduction current. The friction and ionic agitation generate heat that is produced

within the tissues near the electrode called “resistive heat”. “Joule effect”.

Radiofrequency ablationCoagulative necrosis

The aim for RF ablation is achieving and maintaining a 50-100ºC-temperature range throughout the entire target volume.

To destroy the entire tumor by using this heat to kill malignant cells and including 0.5-1 cm safety margin.

Radiofrequency ablationThermal lesion

The dimensions of RF thermal lesion are related to the;

Current intensity. Heat-tissue interaction;

Current density. Tissue heat conduction.

Tumor sensitivity to heat. Heat loss or convection.

Radiofrequency AblationSystem

RFA system components;RF generator;

Power generation. Control.

User interface panel.RF electrode;

Delivers energy to the tumor. Creating a volume of high current density and localized heating.

Dispersive electrode, grounding pad; Disperse energy over a large surface area, preventing skin burn.

Resistive element, tumor/tissues; Tissues are poor conductor to electricity (electrical impedance).

Radiofrequency AblationUnipolar systems

Cool-tip RF system E-series, Covidien; Generator;

200 W power generator with pulsed energy. In pulsed fashion, greater local current density deposited in a shorter time while

preventing tissue boiling near the electrode by allowing for heat dissipation in this region, and the volume of coagulation necrosis may be increased.

Depends on tissue impedance and temperature monitoring by the thermocouples at the electrode tip.

Radiofrequency AblationUnipolar systems

Cool-tip RF system E-series, Covidien; Electrodes;

17 G internally cooled RF electrodes with six different exposure lengths. The electrodes contain 2 central lumens that enable the delivery of chilled saline to the tip of

the electrode and returns of the warmed saline effluent to maintain the tip temperature below 25ºC.

Simultaneous application of a cluster of three cooled–tip electrodes spaced 0.5 cm apart produces larger mass (4-5 cm) of coagulation.

Radiofrequency AblationMultipronged systems

Designed to increase the size of the lesion to be ablated and decrease the number of needle passes.

The needle has a stainless steel insulated trocar with 1.0 cm of exposed primary electrode and expandable metal secondary

electrodes at the distal end of the trocar.

Radiofrequency AblationMultipronged systems

StarBurst 1500 XL RF system, Angiodynamics: 250 W power generator.

Depends on temperature monitoring during ablation by the thermocouples at the arrays tips.

7-cm thermal lesion can be produced in single session. The tip of the electrode is placed in the anterior border of the tumor.

Radiofrequency AblationMultipronged systems

RF 3000 system, Boston Scientific: 200 W power generator.

Depends on the measurement of tissue impedance. LeVeen needle electrode with multiple array diameter up to 5 cm.

The tip of the electrode is placed in the centre of the tumor.

Radiofrequency AblationBipolar systems

CelonSURGICAL, Olympus: CelonLab POWER:

Frequency 470 kHz with wide range of power levels 1-250 W. Integrated resistance controlled automatic power algorithm.

3 bipolar channels can be attached at same time. Depends on 3D impedance feedback control.

CelonPOWER-Monitor software. CelonAquaflow III: Peristaltic pump with three rotors.

Radiofrequency AblationBipolar systems

Celon ProSurge applicator: Bipolar electrode: The current flows between two electrodes at the tip of

one applicator. Multipolar electrodes: Flow between all possible combinations if two or

three applicators are used. No grounding pads. Closed liquid circuit for high coagulation efficacy.

Resulting faster and more focal heating between electrodes. The active length ranges from 2-4cm.

MRI compatible ones. Pacemaker patients treatment. Open surgical and endoscopic

applicator design.

Radiofrequency AblationImaging

57 year old female with 4 cm HCC:

Radiofrequency AblationImaging

47 year old male with 4 cm HCC:

Radiofrequency AblationImaging

60 year old male with 4 cm HCC:

Radiofrequency AblationImaging

67 year old male with 6 cm HCC:

Radiofrequency AblationImaging

57 year old male with 6 cm HCC:

Radiofrequency AblationImaging

47 year old male with three HCC:

Microwave Tissue AblationPhysics

Microwave radiation is an electromagnetic energy in the 300 MHz to 300 GHz range.

Microwave ablation devices operate at either 9.5 MHz or 2.4 GHz. Microwave heating produced as a result of dielectric hysteresis

(rotating dipoles) of the water molecules. Microwaves agitate water molecules in the surrounding tissue,

producing friction and heat , thus inducing cellular death by coagulative necrosis.

Microwave Tissue AblationWhy

Advantages of MW over RFA; Microwaves penetrate through biological material, including those with low

electrical conductivity, as lungs, bone, and dehydrated/charred tissue. Can be continuously applied to produce extremely high temp. (150 °C)

improving ablation efficacy by increase thermal conduction into surrounding tissues.

No heat sink effect of the blood flow and air. No grounding pads. Multiple antennas can be used simultaneously. Less painful.

The end result is:Higher intratumoral temp.

Larger tumor ablation volume.Shorter ablation time.

Microwave Tissue AblationSystems

Acculis MTA system (Angiodynamics); Generator with 2.45 GHz operating frequency. Generator power 60 to 140 W. Internally cooled antennas. Temperature monitoring. Single 14G antenna with active 1.7 cm.

.

Microwave Tissue AblationSystems

Evident MWA system (Covidien): Generator with 915 MHz operating frequency. Generator power 45 W. Internally cooled antennas. Separately placed thermocouple. Single 14G with exposure length 3.7 cm.

Microwave Tissue AblationSystems

MicroThermiX (BSD Medical Corporation): Generator with 915 MHz operating frequency. Generator power 180 W. Three antennas can be used simultaneously. Internally cooled antennas. Temperature monitoring. 14G antenna with active length 2 or 4.1 cm.

Microwave Tissue AblationImaging

Microwave Tissue AblationImaging

Irreversible ElectroporationCell membrane and IRE

The function of the cell membrane is: To separate the intracellular and extracellular environment and To control the transport processes between the interior and the exterior of

the cell according to the cell needs. Electroporation is a way to increase cell membrane permeability

by subjecting it to an electrical field.

Irreversible ElectroporationCell membrane and IRE

Electroporation: The process of creating nanopores / “holes” in the cell membrane using an

electrical field.

Electrical Field

CellPermeabilized /

PoratedCell Membrane

Irreversible ElectroporationCell membrane and IRE

REReversible Electroporation

IREIrreversible Electroporation

complete tissue death by means of apoptosis or ‘‘apoptosis-mimetic’’

necrosis1.

Cell membrane is temporarily “porated”

allowing for application in:

Cell

Electrical Field

Electro-genetherapy2

Electro-chemotherapy2

Cell death occurs by apoptosis: This immune mediated cell death allows:

Cellular clearance of debris. Creates minimal tissue distortion.

Irreversible ElectroporationApoptosis

IREIrreversible Electroporation

Apoptosis Immune system responseMacrophages aid in

clearing cell debris - Phagocytosis

Cell

Electrical Field

Irreversible ElectroporationNon-thermal ablation

IRE is a non-thermal ablative technique;

The electric field created by IRE is devoid of any joule heating Application of short pulse, high voltage DC current. Rapid series of short electrical pulses (from µS to Ms). Cell death occurs in the ablation zone.

Irreversible ElectroporationSystem

NanoKnife, Angiodynamics); Generator;

Treatment Planning Software for procedure planning. Up to 6 outputs with automatic ‘switching’.

Applied pulses: Pulse length,20-100 µs. Number 10-100 pulses. Volts/Cm 500-5000.

Irreversible ElectroporationSystem

NanoKnife, (Angiodynamics); AccuSync Synchronization device;

External synchronization device. The ECG trigger monitor automatically detects the R wave.

Irreversible ElectroporationSystem

NanoKnife, (Angiodynamics);NanoKnife Monopolar Electrodes;

Active length adjustable from 0 – 4 cm. Per-procedure ;

One activator monopolar electrode. Up to 5 monopolar electrodes.

Irreversible Electroporation Predictable ablation

Single bipolar electrode;

Irreversible ElectroporationPredictable ablation

Multiple Unipolar electrodes; By using electrode spacer. Up to 6 electrodes. Spacing should be from 1.0 – 2.2 cm. Electrodes should be parallel.

Irreversible Electroporation Predictable ablation

Probe 1 Probe 2

Irreversibly Electroporated(Ablation) Zone

Probe 3

2cm’s

2cm’s 2cm’s

3 cm’s

3 cm’s

Irreversible Electroporation Why

No heat sink effect; IRE is a non-thermal technology; Incomplete treatment secondary to the

“heat sink” effect appear not to be applicable. No heat sink effect was evident adjacent to vessels with complete necrosis

adjacent and often surrounding patent vasculature.

Ablation precision on a cellular level; Very precise ablation area on a cellular level – No transition zone. A cell is either destroyed by IRE or not.

Irreversible Electroporation Why

No evidence of damage to vascular or critical structures; Micro and Macro Vasculature. Collagen Structures. Non-target organ area. Bile Ducts. Urethra. Ejaculatory Ducts. Neurovascular Bundle. Renal Collecting system.

No evidence of; Bile leaks. Strictures. Vascular thrombosis.

Irreversible Electroporation Imaging

CT or Ultrasound can be used with NanoKnife: Pre-procedure, During ablation, and Post-procedure.

MR Imaging: May be used pre & post procedure. NanoKnife® electrodes are not MRI Compatible.

Irreversible Electroporation Imaging

Irreversible Electroporation Imaging

Irreversible Electroporation Imaging

Irreversible Electroporation Anesthesia

Relaxant general anesthesia is required for IRE. Anesthetic with propofol induction, maintenance with

oxygen/air/sevoflurane, and variable opioid regimes usually involving fentanyl or remifentanil.

Non-depolarizing muscle relaxants used. Monitoring with oximetry, noninvasive arterial blood pressure, 5-

lead electrocardiograph (ECG), temperature probe, bispectral index, and capnography.

Defibrillator in-room. Before procedure Twitch test of 0 or 1.

Irreversible Electroporation May be not applicable

Contraindications: As the procedure based on high voltage pulses, it is not recommended in:

Ablation of lesions in the thoracic area in the presence of implanted cardiac pacemakers or defibrillators.

Ablation of lesions in the vicinity of implanted electronic devices or implanted devices with metal parts.

Patient history of epilepsy or cardiac arrhythmia. Recent history of myocardial infarction.

Disadvantages; Generation of dangerous electrical harmonics, cardiac arrhythmia, muscle

contractions. Need general anesthesia with difficult monitoring. Accurate needle positioning is a must. Lack of coagulation around the needle insertion site, bleeding.

High Intensity Focused Ultrasound Basic principle

Piezoelectric transducer operates at frequencies of 200kHz - 4MHz.1- Thermal effect; Acoustic energy.

An energy produced in the focal volume with intensity of 100-10,000 W/cm3, a peak compression pressure of 70MPa, and a peak rarefaction pressure of 20 MPa.

Rise of cell temperature in the target volume with coagulative necrosis at 65o – 85o C.

High Intensity Focused Ultrasound Basic principle

2- Mechanical effect; Cavitation. At a high pressure amplitude, small gas pockets in fluids grow to

microbubbles ( by rectified diffusion). Stable cavitation, The pressure waves causes these bubbles to expand and

contract. Increase energy loss within the target lesion. Inertial cavitation, violent collapse and destruction producing shock

waves with high pressure and temperature. Micro-streaming effect, shear injury by the rapid moving fluid.

High Intensity Focused Ultrasound Thermal lesion

Each sonication is limited to focal volume of 0.2-5 mm3.

Limited duration to few seconds. To cover large volume multiple and overlapping sonications needed.

High Intensity Focused Ultrasound Guidance

US-guidance; Model -JC system; Chongqing, China. FEP-BY system; Yuande engineering, China.

MR-guidance; ExAblate 2000 ; InSightec, Israel.

Aspect USMR

Ease and frequency of useHigh Low

Real-time ablation monitoringVariableExcellent

Temperature imagingLowHigh

Cost LowHigh

Post ablative imaging role LimitedExcellent

Operator dependentHighlyModerate

High Intensity Focused Ultrasound Further development

Electrical focusing: To increase focal region size and decrease time;

Simultaneous multiple focal points. Fast electronic scanning. Correction of beam aberrations.

US guidance: To allow real-time treatment monitoring; US-based thermometry. Tissue coagulation detection.

High Intensity Focused Ultrasound Motion management

Movement hamper HIFU for three reasons; Loss of treatment efficiency. Risk of unintended lesions. MR imaging monitoring artifacts.

High Intensity Focused Ultrasound Motion management

Motion management; Motion suppression;

Motion suppression with breath hold. Self breath hold. Self breath hold with respiratory monitoring. Passive breath hold.

Motion suppression with sustained respiration. Gating under continuous breathing. Single lung ventilation. High frequency jet ventilation.

Motion tracking;

High Intensity Focused Ultrasound Imaging

High Intensity Focused Ultrasound Imaging

Take Home Points

HCC patient: Without vascular/ biliary invasion / extrahepatic disease. And with good coagulation profile.

Very early stage (BCLC 0) HCC patient: Not candidate for transplantation. With single nodule ≤ 2 cm.

Early stage (BCLC A) HCC patient: Not candidate for surgery or transplantation. With single nodule ≤ 5 cm. Or with multiple nodules ≤ 3 No. and ≤ 3 cm in size.

Bridging treatment in patients waiting for transplantation. After successful TACE/surgery with residual nodule.

Proper patient selection

Radiofrequency ablation is still the standard ablative treatment with long-term results (effectiveness, complications, and long term survival).

Microwave Ablation/ IRE are indicated in larger lesions near vascular structure.

For high risk patients and tumors PEI/ IRE are indicated.

Proper ablative technique selection

Take Home Points

Ultrasound / CT guidance. Use recent navigation and robotic targeting. Avoid vital structures. Be aware of the complications and how to manage.

Take Home Points

Proper image guidance, approach and treatment planning