Developing New Technology for Local Tumor Control: A Bioengineering Approach Andrew Wright MD Department of Surgery 1/25/02

Background Greater than one half of patients with colorectal cancer will develop liver metastases at some point in their clinical course Greater than one half of patients with colorectal cancer will develop liver metastases at some point in their clinical course Surgical resection of an isolated liver tumor offers a five-year survival between 25 and 38%, compared to a 0% five-year survival without resection Surgical resection of an isolated liver tumor offers a five-year survival between 25 and 38%, compared to a 0% five-year survival without resection

Background Only 10–20% of patients with liver tumors will have disease amenable to surgical resection due to high surgical risk or unfavorable anatomy Only 10–20% of patients with liver tumors will have disease amenable to surgical resection due to high surgical risk or unfavorable anatomy

Radiofrequency Ablation High-frequency (460 kHz) alternating current flows from electrical probe through tissue to ground High-frequency (460 kHz) alternating current flows from electrical probe through tissue to ground Probe insertion Extension of prongs RF current application

Radiofrequency Ablation 12-prong “Leveen” probe, 4 cm diameter (Radiotherapeutics) Cool-Tip probe (17-gauge needle) (Radionics) 9-prong “Starburst” probe, 5 cm diameter (Rita Medical)

Radiofrequency Ablation Bioheat Equation Bioheat Equation  Lesion  (Energy Applied x Local Tissue Factors) – Energy Lost Temperature Change Thermal Conductivity and heat constant Current Density * Electric Field Constant Heat loss through blood flow

Finite Element Modeling Determine material and electrical properties of tissue and ablation system Determine material and electrical properties of tissue and ablation system Develop geometric model Develop geometric model Solve Bioheat equation Solve Bioheat equation

Finite Element Modeling

Bioengineering Approach Define Problem Define Problem Determine Possible Solutions Determine Possible Solutions Model Model Test Test Refine Refine

Define Problem Local recurrence as high as 30% Local recurrence as high as 30%  Uneven or irregular heating  Heat sink vessels Several mm’s RF

Define Problem Local recurrence as high as 30% Local recurrence as high as 30%  Uneven or irregular heating  Heat sink vessels Difficult to treat large or multiple tumors Difficult to treat large or multiple tumors

Define Problem Local recurrence as high as 30% Local recurrence as high as 30%  Uneven or irregular heating  Heat sink vessels Difficult to treat large or multiple tumors Difficult to treat large or multiple tumors Poor imaging and localization Poor imaging and localization Ultrasound B-scan Before RF Ablation Ultrasound B-scan After RF Ablation

Possible Approaches Bioheat Equation Bioheat Equation  Lesion  (Energy Applied x Local Tissue Factors) – Energy Lost Temperature Change Thermal Conductivity and heat constant Current Density * Electric Field Constant Heat loss through blood flow

Potential Solution #1 Bipolar RF Ablation Bipolar RF Ablation  Increase current density between electrodes  Increase energy deposition  More uniform tissue heating

Bipolar RF Ablation

FEM predicts nearly double lesion volume with bipolar electrode FEM predicts nearly double lesion volume with bipolar electrode

Bipolar RF In vivo porcine liver In vivo porcine liver MonopolarBipolar

Bipolar RF Monopolar 3.93  1.8 cm 2 Monopolar 3.93  1.8 cm 2 Bipolar 12.2  3.0 cm 2 Bipolar 12.2  3.0 cm 2

Bipolar RF

Monopolar, d=2.3 mm Bipolar asymmetric, d=1.8 mm Bipolar symmetric, d=1.0 mm

Bipolar RF Problems Problems  Inability to control two electrodes independently  Difficult technical placement  Unable to treat multiple tumors

Potential Solution #2 Multiple Probe RF Ablation Multiple Probe RF Ablation  Allows overlapping treatment of large solitary tumors  Allows simultaneous treatment of multiple tumors

Multiple Probe RF Ablation MonopolarBipolar Disadvantage: electrical shielding between electrodes (Faraday cage) Disadvantage: electrical shielding between electrodes (Faraday cage)

Multiple Probe RF Ablation Block diagram of system

Multiple Probe RF Ablation MonopolarBipolarAlternating Monopolar

Multiple Probe RF Ablation Prototype Multiple Probe Device Prototype Multiple Probe Device  Computer controlled electromechanical switch

Multiple Probe RF Ablation Ex Vivo Testing Ex Vivo Testing

Multiple Probe RF Ablation In Vivo Testing In Vivo Testing

Multiple Probe RF Ablation Single Probe AblationSimultaneous Multiple Probe Ablation

Multiple Probe RF Ablation In Vivo Testing In Vivo Testing  Lesion Volume  Single 10.7 cm 3  Dual 17.3 cm 3 (per lesion)  Time to Target Temperature  Single 2.7 minutes  Dual 3.4 minutes

Multiple Probe RF Ablation Change to electrical switch Change to electrical switch  Increase number of probes  Increase speed of switching  Decrease load on generator Evaluate synergism of overlapping multiple probe RF ablations Evaluate synergism of overlapping multiple probe RF ablations

Potential Solution #3 Bioheat Equation Bioheat Equation  Lesion  (Energy Applied x Local Tissue Factors) – Energy Lost Tissue Impedance (resistivity) Tissue Impedance (resistivity)

Tumor Resistivity Electrical properties of normal liver and tumor (K12/TRb) measured in an in vivo rat liver model Electrical properties of normal liver and tumor (K12/TRb) measured in an in vivo rat liver model

Tumor Resistivity Finite Element Model Finite Element Model Tumor diameter = 2 cm

Tumor Resistivity Current Density Current Density 500 kHz100Hz

Tumor Resistivity Temperature Temperature 500 kHz100Hz

Tumor Resistivity Lesion Difference Lesion Difference Gray circle represents tumor boundary

Tumor Resistivity Human? Human?  Colorectal metastasis to liver

Alternative Solution Microwave Ablation Microwave Ablation  Theoretical advantages over radiofrequency ablation  No ground pad  Not limited by tissue charring and impedance changes  Use of Multiple Probes

Microwave Ablation Larger zone of active heating Larger zone of active heating 1-2 cm MW 1-2 mm MW

Microwave Ablation MW RF

Multiple Probe Ablation Null Hypothesis Null Hypothesis  Because microwave and radiofrequency ablation are both heat based, there will be no difference in ablation size or lesion pathology between the two technologies

Methods Microwave Ablation Microwave Ablation  Vivant Medical prototype system  10 minute ablation, 40 Watts Radiofrequency Ablation Radiofrequency Ablation  RITA Medical Systems Starburst  10 minute ablation, 3cm deployment 100 o C target temperature

Microwave Ablation System Vivant Medical 13g, 15cm dipole antenna 915MHz generator Fiberoptic temperature monitor

Radiofrequency Ablation System RITA Medical 14g, 15cm expandable array 460 kHz generator Integrated thermocouple

Lesion Volume * * * p=.02

Lesion Length * * ▪ ▪ ◦ * p<.001 ▪ p=.02 ◦ p<.001 ◦

Lesion Diameter

Pathology RFA MW Immediate 48 o 4 weeks

Laboratory Data * * p<0.001 No significant difference in AST, ALT, LDH, Alkaline Phosphatase, WBC, or HCT No significant difference in AST, ALT, LDH, Alkaline Phosphatase, WBC, or HCT

CT Imaging 48 Hours4 Weeks

Microwave Ablation Pathological and radiologic characteristics similar between RF and MW ablation Pathological and radiologic characteristics similar between RF and MW ablation MW lesions larger than RF MW lesions larger than RF MW ablation technically easier than multiple-prong RF ablation MW ablation technically easier than multiple-prong RF ablation

Multiple Probe Microwave Ablation Hypothesis Hypothesis  Multiple probe hepatic ablation will result in synergistically larger lesion sizes by shielding lesion center from blood- flow mediated cooling

Methods Microwave Protocol Microwave Protocol  Domestic Swine  10 minute ablation, 40 Watts Single Probe Ablation Single Probe Ablation Multiple Probe Ablation Multiple Probe Ablation  3 parallel probes in triangular array  Separation between probes varied from 0.5 to 3.5cm

Methods Microwave Protocol Microwave Protocol Single ProbeMultiple Probe

Assessment Lesion dimensions calculated Lesion dimensions calculated Multiple Probe lesions scored for shape Multiple Probe lesions scored for shape ScoreCriteria 1Discontinuous 2 >25% Deflection % Deflection 4 <10% Deflection 5Round

Results

Size by Separation Size by Separation

Results Lesion Shape Lesion Shape

Results Lesion Shape Lesion Shape

Results

5 Probes 5 Probes

Microwave Ablation Microwave ablation has several theoretical advantages over RF ablation Microwave ablation has several theoretical advantages over RF ablation Multiple probe microwave ablation may allow for treatment of larger, more complex tumors as well as simultaneous treatment of multiple tumors Multiple probe microwave ablation may allow for treatment of larger, more complex tumors as well as simultaneous treatment of multiple tumors Multiple probe ablation may improve treatment of tumors near blood vessels Multiple probe ablation may improve treatment of tumors near blood vessels

Microwave Ablation Phase I Clinical Study Phase I Clinical Study

Improved imaging Physical characteristics of tissue change with ablation Physical characteristics of tissue change with ablation RF echo-signal after a 1 0 C Temperature Increase Base Line RF echo-signal Initial Speed of Sound Tissue Dependent Parameter

Improved Imaging Ultrasound B-scan Before RF Ablation Thermal Image After 2 Minutes Thermal Image After 10 seconds

Improved Imaging Ultrasound B-scan Before RF Ablation Ultrasound B-scan After RF Ablation Softer Region (Normal Tissue) Elastogram Showing The Thermal Lesion Stiffer Region (Thermal Lesion)

Future Directions Further development and clinical testing Further development and clinical testing  Multiple Probe RF  Variable-frequency RF  Microwave Ablation  Elastography and Thermal Monitoring

Future Directions Modify local tissue factors Modify local tissue factors  Tumor-specific ablation sensitizers  Adjuvant or neo-adjuvant chemotherapy Alternative Technologies Alternative Technologies  Biomolecular Engineering  Confocal Microwave  ?

Acknowledgments David Mahvi MD David Mahvi MD Fred Lee MD Fred Lee MD John Webster PhD John Webster PhD Dieter Haemmerich PhD Tomy Varghese PhD Tyler Staelin MD Chris Johnson Vivant Medical http//rf-ablation.engr.wisc.edu