June 6-10, 2004CRI Workshop, Haifa Treatment Planning for Radiofrequency Ablation of Liver Tumors Ariela Sofer, George Mason University Masami Stahr, George Mason University Bradford J. Wood, National Institutes of Health

June 6-10, 2004CRI Workshop, Haifa Agenda Introduction: Liver Cancer and Radiofrequency Ablation The Temperature Distribution Challenges in Treatment Planning Final Thoughts

June 6-10, 2004CRI Workshop, Haifa Agenda Introduction: Liver Cancer and Radiofrequency Ablation The Temperature Distribution Challenges in Treatment Planning Final Thoughts

June 6-10, 2004CRI Workshop, Haifa Primary and Secondary Liver Tumors Primary liver cancer is among the most common cancers worldwide: –Over one million new cases annually –Death rate ~ occurrence rate Even higher rates for colorectal carcinoma metastases (“secondary tumors”) in the liver Surgical resection - the gold standard of therapy But most patients are poor candidates for surgery Radiofrequency ablation - a promising treatment option for unresectable hepatic tumors.

June 6-10, 2004CRI Workshop, Haifa Radiofrequency Ablation (RFA) A noninvasive technique for killing tumors by heat. A needle electrode is placed at the tumor site and an electrical current applied. This generates frictional heat. Heat in excess of 50 o c will kill the tumor.

June 6-10, 2004CRI Workshop, Haifa Ablation Treatment Planning Determine the number of needles, their position, size, and power applied, to guarantee that the entire tumor is killed while damage to vital healthy tissue is limited.

June 6-10, 2004CRI Workshop, Haifa May be safely performed on an outpatient basis with conscious sedation Complex cases may require general anesthesia and overnight observation. Commonly performed percutaneously May also be implemented in open or laparoscopic surgery Treatment sessions about minutes long. Features of RFA

June 6-10, 2004CRI Workshop, Haifa Can treat small and (sometimes) mid-size tumors. May convert an inoperable patient into a surgical candidate. RFA for Liver Tumors

June 6-10, 2004CRI Workshop, Haifa No long-term, prospective randomized clinical trials yet. However, early results are optimistic and suggest that RFA provides safe and effective local treatment of some cancers, with very small complication rates. Failures of RFA often associated with under- ablation and/or failure to create an adequate tumor-free margin Higher success rates for HCC tumors than for metastases RFA for Liver Tumors

June 6-10, 2004CRI Workshop, Haifa The Needle Electrodes A variety of RF needle electrodes in different sizes and configurations.

June 6-10, 2004CRI Workshop, Haifa The RFA Procedure A closed-loop circuit is made by placing grounding pads on the thighs and connecting then in series with the generator, and the needle electrode. Ultrasound and/or CT used for guidance

June 6-10, 2004CRI Workshop, Haifa At 50 o c protein is damaged permanently and cell membranes fuse. Coagulation necrosis. Alternating current at high frequency (500 KHz) is applied. Tissue ions are agitated as they attempt to follow the changes in direction of AC. Frictional heat. Heat extends to adjacent tissue by conductance RF Heating Mechanism

June 6-10, 2004CRI Workshop, Haifa More on Thermal Damage 45 o C: heating for several hours irreversible damage 42 o C: tissue susceptible to chemo / radiation 50 o C: heating 4-6 minutes irreversible damage 60 o C-100 o C: near immediate protein coagulation 100 o C-110 o C: tissue vaporizes and carbonizes

June 6-10, 2004CRI Workshop, Haifa Factors Impeding Ablation Temperatures > 100 o C: –Charring of tissue close to needle that prevents transfer of heat to tissue further away. –Vaporization. Gas acts as insulator. Blood vessels near the tissue: – convection of thermal energy away from the target tissue into the cooler blood.

June 6-10, 2004CRI Workshop, Haifa Increasing the Lesion Size Internally cooled electrodes Saline solution injection Energy pulsing Hepatic blood flow reduction

June 6-10, 2004CRI Workshop, Haifa CT: Pre-treatment RFA Before and After

June 6-10, 2004CRI Workshop, Haifa Killed tumor cells are replaced by fibrosis and scar tissue CT: Pre-treatmentCT: 6 months after RFA Before and After Consecutive CT images - the input to the 3-D optimization

June 6-10, 2004CRI Workshop, Haifa The Ablation Process Nitrogen micro-bubbles gradually create a hyperechogenic area on ultrasound that provides a rough estimation of the treated tissue Larger tumors can be treated by multiple needles with overlapping treatment regions. Because of changes in conductivity of ablated tissues, and because microbubbles can obscure visualization, the deepest tumor regions should be treated first.

June 6-10, 2004CRI Workshop, Haifa Other Thermal Ablation Techniques Microwave Ablation Laser Ablation Ultrasound Ablation Cryoblation

June 6-10, 2004CRI Workshop, Haifa Agenda Introduction: Liver Cancer and Radiofrequency Ablation The Temperature Distribution Challenges in Treatment Planning Final Thoughts

June 6-10, 2004CRI Workshop, Haifa Temperature Distribution: the Bioheat Equation change in energy stored within heat conducted in heat conducted out heat generated within = + - tissue density specific heat thermal conductivity T=T(x,t) temp.  = div  =grad heat loss to blood perfusion RFA heat source

June 6-10, 2004CRI Workshop, Haifa T=T(x,t) temp. heat loss to blood perfusion The Bioheat Equation: The Heat Source RFA heat source V=V(x,t) electrical potential electrical conductivity

June 6-10, 2004CRI Workshop, Haifa The Bioheat Equation – Boundary Conditions Electrical Potential Temperature

June 6-10, 2004CRI Workshop, Haifa Numerical Solution of Bioheat Equation Via the finite element method. Here: FEMLAB Electrical PotentialTemperature Distribution

June 6-10, 2004CRI Workshop, Haifa Numerical Solution of Bioheat Equation: Slice Electrical PotentialTemperature Distribution

June 6-10, 2004CRI Workshop, Haifa Heat Loss from Blood Vessels blood density flow rate blood temperature specific heat Small vessels: Large vessels:  Heat transport solved inside vessel.  Flow field: incompressible Navier-Stokes eqs.

June 6-10, 2004CRI Workshop, Haifa Effect of Blood Flow (Large Vessel) needle blood vessel convective heat transport by blood

June 6-10, 2004CRI Workshop, Haifa Agenda Introduction: Liver Cancer and RadioFrequency Ablation The Temperature Distribution Challenges in Treatment Planning Final Thoughts

June 6-10, 2004CRI Workshop, Haifa The Ideal Ablation Treatment Plan Entire tumor (+ 1cm margin) is killed No thermal damage to critical organs In reasonable time! Limited damage to healthy tissue

June 6-10, 2004CRI Workshop, Haifa Further Considerations No. of puncture holes Is resection part of overall treatment plan? Convenient access

June 6-10, 2004CRI Workshop, Haifa Treatment Planning Features Small number of decision variables: –Number of needles and their configuration –Placement of needles But (potentially) lots of state variables: –Temperature at grid points on volume of interest Temperature requires solution of a set of coupled partial differential equations

June 6-10, 2004CRI Workshop, Haifa Treatment Planning Features (cont’d) Temperature “dose” is not cumulative IMRT key factor: Total dose RFA key factor: Maximum dose

June 6-10, 2004CRI Workshop, Haifa Challenge: Constraints Governed by PDE’s Each 3-D PDE solution takes many minutes The optimization involves repeated PDE’s Moreover, as needle position changes, the needle boundary “moves” and entire mesh changes But treatment plans must be available within just a few hours

June 6-10, 2004CRI Workshop, Haifa Challenge: Large Tumors - Multiple Needles Overlapping spheres? Overlapping cylinders? Images from Dodd. et als, Radiographics 2000 Added combinatorial complexity!

June 6-10, 2004CRI Workshop, Haifa Challenge: What Objective? What Constraints? Minimize: underheating in tumor Whileprohibiting damage to critical structure limit damage to normal tissue But - may lead to many slightly underheated cells. Or to an awkward lesion shape Minimize: damage to critical structure Whilekilling every cell in tumor limiting damage to normal tissue May not be achievable or medically acceptable Minimize: damage to normal tissue While: killing every cell in tumor prohibiting damage to critical structure But - may not be achievable

June 6-10, 2004CRI Workshop, Haifa Challenge: Those Pesky Coefficients Factors affecting thermal properties of tissue: –normal tissue –cirrhotic tissue –HCC –metastases –vascularization –effect of temperature on parameters

June 6-10, 2004CRI Workshop, Haifa Challenge: Complexity of Energy Sources Needle Electrodes: –Single, multiple, multi tined Energy Deposition –Pulsed, impedance regulated, internally cooled Adjuvant Therapies –Use of saline solution to alter electrical and thermal conductivity

June 6-10, 2004CRI Workshop, Haifa Agenda Introduction: Liver Cancer and Radiofrequency Ablation The Temperature Distribution Challenges in Treatment Planning Final Thoughts

June 6-10, 2004CRI Workshop, Haifa Final Thoughts RFA treatment planning poses many complex mathematical and practical challenges Much to learn from the radiation therapy community Research relevant not only to RFA, but other thermal ablation modalities