Introduction to Radio Frequency Ablation AngioDynamics, Inc. Introduction to Radio Frequency Ablation

Radio Frequency Ablation What is RFA? Internal Use Only – Not for Distribution

AngioDynamics RITA RFA Devices RF Energy at 460khz moves from the generator, to the device, through the patient and back to the generator using a monopolar connection via dispersive pads on the patients thighs. The RF energy causes the cells adjacent to the device to spin as they line up with the positive and negative poles within the alternating current. This spinning causes frictional heat that disperses across the tissue adjacent to the device and this causes cell death. Internal Use Only – Not for Distribution

Internal Use Only – Not for Distribution Mono-polar RFA Internal Use Only – Not for Distribution

Internal Use Only – Not for Distribution Stages of RF Ablation Frictional Heating Conductive Heating Over Time Internal Use Only – Not for Distribution

Internal Use Only – Not for Distribution RF Ablation with Infusion A/I A/T A/T = Active electrode and Temperature Monitor A/I = Active electrode with Infusion = Infusion = Conduction Internal Use Only – Not for Distribution

Metastatic Colorectal Cancer Benefit to Patients Metastatic Colorectal Cancer Internal Use Only – Not for Distribution

Incidence of Metastatic Colorectal Cancer World wide incidence: 400,000 colorectal cancer patients 60-70% patients will develop metastases Source: Easton Associates Internal Use Only – Not for Distribution

Colorectal Cancer: epidemiology 30% of patients with metastases will present with “liver only” disease Only 20-25% of patients with liver metastases are candidates for surgical resection 45% of patients that die from Mcrc will die with liver only disease. Internal Use Only – Not for Distribution Source: Easton Associates.

Internal Use Only – Not for Distribution Chemotherapy Survival Advantage in First-Line Metastatic Colorectal Cancer No active drug ~4-6 mo 5-FU/LV 1960’s 12-14 mo IFL ~ 15-16 mo FOLFOX4 2004 ~ 20 mo IFL + bevacizumab 20.3 mo FOLFOX/FOLFIRI 21.5 mo FOLFOX/FOLFIRI + biologics ? 6 12 18 24 Median OS (mo) Internal Use Only – Not for Distribution

RFA for Metastatic Colorectal Liver Cancer Cleveland Clinic Series: Prospective study of RFA in CRC liver metastases conducted in North America; Published in Journal of Clinical Oncology; 135 Patients enrolled 1997-2002 Allowed virtually “all comers” to enter the study Goals: Determine predictors for survival at the time of RFA for colorectal liver metastases; Estimate incremental benefit of RFA as adjunct to chemo over systemic chemotherapy alone Internal Use Only – Not for Distribution

Results (1), median overall survival: 28. 9 months (2.4 years) post RFA, 44.6 months from diagnosis of metastases (Kaplan Meier) While the primary analyses for prognostic factors set T0 at the time of RFA, the authors went through the effort of collecting data regarding the date of first diagnosis of metastatic disease retrospectively, based on chart review. As measured from the date of diagnosis of metastatic disease, median survival was 44.6 months; as measured from time of RFA, the prospective portion of the study, median survival was 28.9 months. I emphasize again that this was in a population 80% of whom had already failed 1st line chemotherapy. Internal Use Only – Not for Distribution

Internal Use Only – Not for Distribution Median Survival 1st Line chemotherapy median survival 21.5 Months 2nd line chemotherapy traditional survival 11-14 Months RFA + Chemotherapy Median Survival 28.9 Months (from 2nd line RFA) 44.6 Months (from diagnosis of metastases) Internal Use Only – Not for Distribution

RFA Benefit to the Patient By adding RFA to therapy for patients with non-resectible liver disease we can double that patients expected survival. That Means… One more Christmas with the Grand Kids One More Spring Time in Her Tulip Garden One More Birthday with His Sister Internal Use Only – Not for Distribution

AngioDynamics RFA Device Indication: Internal Use Only – Not for Distribution

WINDOW READINGS Wattage is Pre-Set at 150-250 Watts Thermo Pads monitor the temperature of the dispersive pads on the patients legs. Wattage is Pre-Set at 150-250 Watts Ablation temperatures are displayed in this area. The generator will automatically calculate the average temp of the ablation zone. Temperature is Pre-Set at 105C Internal Use Only – Not for Distribution

Multiple Device Designs Internal Use Only – Not for Distribution

Device Options Advantage XL and Semi Flex: Available with both rigid and flexible trocars. Can complete 1-5cm ablations with a single placement. Flexible trocar is designed with IR in mind so that the device can be placed in the treatment zone and flexed to clear the CT gantry for correct placement confirmation. Also MRI compatible Optional MRI cable required for use in MRI setting. Internal Use Only – Not for Distribution

Device Options Advantage Talon: Completes 1-4cm ablations with single stage deployment Side Deployment System means you can place within 1cm of vital structures with confidence. Ideal for lung, surface lesions in liver or exophitic lesions in kidney. Available in 15cm, 25cm and Semi Flexible designs for open, laparoscopic and CT guided procedures. Saline infusion technology means faster ablation times 4cm ablation in as fast as 11.5 minutes. Internal Use Only – Not for Distribution

Device Options Advantage XLI Enhanced: The Flagship of Rita devices can complete 1cm-7cm ablations. Utilizes Saline Infusion Technology for larger faster ablations. Saline cools the tissue around the tines to prevent charring and acts as a virtual tine to expand treatment volumes as well as speed ablation times. Available in 12cm, 25cm trocar lengths for percutaneous, open or laparoscopic procedures. Internal Use Only – Not for Distribution

Device Options Advantage New Uniblate! Only single needle electrode with scalable ablation capabilities and TRULY able to shape ablations Perfect for cases when physician does not want to deploy tines Close proximity to critical structures or low resolution imaging Internal Use Only – Not for Distribution

RFA Core Selling Message Because Temperature Matters Temperature is The Only True Measure of Cell Death Real time temperature monitoring lets you know when heat sinks occur during the ablation and helps to guide better outcomes. Lowest Rates for Local Recurrence Scalability Means Flexibility One device can be used for ablations from 1-7cm No Need for Overlapping Ablations (in tumors up to 5cm) Reduces Risk of Local Tumor Recurrence Saves OR and CT Time Device Options Means Better Control Multiple unique device designs available to treat tumors in a variety of tissues or locations. Providers are not restricted to one device design for the variety of tumor sizes, shapes or locations that they treat. Internal Use Only – Not for Distribution

Internal Use Only – Not for Distribution How does it all begin? Using imaging techniques like ultrasound, CT or MRI the surgeon or radiologist will place the tip of the device at the proximal or distal edge of the tumor (depending on the device design) and then deploy the tines on the device to the prescribed starting point. XL and XLI Enhanced devices begin at 2cm and then are deployed as each sequential target temperature is reached. For larger ablations the final two stages will require a “cooking phase” of 6-7 minutes each. XL and XLI Enhanced are considered “stage deployment devices”. Talon and Uniblate devices may be deployed directly to the final desired ablation size and are considered “single stage devices”. Internal Use Only – Not for Distribution

RITA StarBurst XLi enhanced  protocol 4 cm Ablation 5 cm Ablation 2 3 4 2 3 4 5 2 cm 105°C 3 CM 105 °C 4 cm 105°C hold for 6 Minutes 2 cm 105°C 3 CM 105 °C 4 cm 105°C hold for 6 Minutes 5 cm 105°C hold for 6 Minutes Pump .10 ml/min for All Deployments Internal Use Only – Not for Distribution

RITA StarBurst XLi enhanced  protocol 6 cm Ablation 7 cm Ablation 2 3 4 5 6 2 3 4 5 6 7 2 cm 105°C 3 cm 105 °C 4 cm 105°C 5 cm 105°C hold for 6 Minutes 6 cm 105°C hold for 6 Minutes 2 cm 105°C 3 cm 105 °C 4 cm 105°C 5 cm 105°C hold for 6 Minutes 6 cm 105°C hold for 6 Minutes 7 cm 105°C hold for 6 Minutes Pump .10 ml/min for All Deployments Internal Use Only – Not for Distribution

Proper Positioning is the Key to Destroying Targeted Tumors Device Placement Proper Positioning is the Key to Destroying Targeted Tumors Internal Use Only – Not for Distribution

Talon 2cm Tumor Device Positioning Place the tip of the device at the distal edge of the tumor and then deploy to 4cm. Internal Use Only – Not for Distribution

Progression of Ablation The tip of the trocar should be placed 1cm from the center of the intended ablation area for a 3cm or 4cm ablation, and 1.5cm for a 5cm ablation, as shown below: Insulated Not insulated Placement of the StarBurstTM XL Note: The larger surface area at the tip of the trocar and longer ablation time will help to propagate the ablation to the proximal edge for the 4cm and 5cm ablations. Similarly, the 3cm ablation will likely grow beyond the proximal edge. The smaller surface area at the distal tip will prevent the lesion from growing too far beyond the distal edge in a 4cm or 5cm ablation. 3cm ablation 4cm ablation 5cm ablation }1cm }1.5cm Progression of Ablation Over Time Internal Use Only – Not for Distribution

XLi Enhanced Device Placement 7cm ablation (5cm lesion) 6cm ablation (4cm lesion) 5cm ablation (3cm lesion) 4cm ablation (2cm lesion) 1.5cm from center 1.5cm from center 1.5cm from center 2cm from center 0.5cm from proximal edge of ablation area 1.0cm from proximal edge 1.5cm from proximal edge 1.5cm from proximal edge Note: Once the device is placed, deploy to final ablation size to check placement. Always ensure that the deployed device is at least 1cm away from anything not intended for ablation. 8cm ablation (6cm lesion) Requires multiple (at least 6) overlapping 7cm ablations 2cm 2cm from center of each ablation area 2cm 1.5cm from proximal edge of each ablation area Internal Use Only – Not for Distribution

Internal Use Only – Not for Distribution 7 cm PLANNING Internal Use Only – Not for Distribution

Internal Use Only – Not for Distribution 7 cm Device Placement Internal Use Only – Not for Distribution

Internal Use Only – Not for Distribution 7 cm Ablation Pre Treatment Post Treatment Internal Use Only – Not for Distribution

Internal Use Only – Not for Distribution How does it end? Once the prescribed “cooking time” has passed and the timer on the generator reaches zero the system will enter a “cool down” period of 30 seconds. At the end of the cool down cycle the average of the temperatures should remain above 60C and if that end point is reached then the ablation is considered complete. If temperatures are below 60C then the surgeon or radiologist may decide to continue the ablation for another 5 minutes. Vasculature and anatomy within the ablation zone may cool the tissue too quickly and create a “heat sink” where heat is drawn away from the intended ablation zone. Internal Use Only – Not for Distribution

The AngioDynamics Advantage “Because Temperature Matters” RITA RFA utilizes patented thermo based technology to insure proper destruction of targeted cancer tissue. No other device on the market is able to monitor the temperature of the ablation zone at the margins. Temperature is the only true measure of cell death Impedance or lack of tissue conductivity is not a good predictor of response Internal Use Only – Not for Distribution

Internal Use Only – Not for Distribution “The extent and nature of thermal injury are dependent on two important factors, Temperature & RF Application Duration.” If you are not able to measure temperature along with time, are you willing to chance erroneous results and a high percentage of recurrences? (V. Krishnamurthy, Applied Radiology, Oct. 2003) Internal Use Only – Not for Distribution

Internal Use Only – Not for Distribution Thermal Cell Death Temperature (°C) < 40 40-49 49-70 70-100 100-200 >200 Cellular Effect No significant cell damage Reversible cell damage Irreversible cell damage (denaturation) Coagulation (collagens converted to glucose) Desiccation (boiling of intra- and extra- cellular water) Carbonization Through years of studies, parameters for tissue cell damage or death based on temperature has been established. This is what RITA uses as foundation for its technology. Tissue Death Cell death occurs at about 50C Three factors affecting the heating of tissue to the point of cell death are: - Distance from the electrode - RF current intensity (Current/surface area of the electrode) - Duration of the application of RF current. Internal Use Only – Not for Distribution

Ablation Challenge Impedance Control It may be possible to measure the ablation process through impedance, but the question becomes how consistent and reproducible is impedance as an endpoint? Studies such as this one suggest impedance will not roll-off a certain percentage of the time. In this case it was 53%. Because the impedance never rolled off, meant that the intended tumors were not completely ablated. This caused a high recurrence rate. Internal Use Only – Not for Distribution Arata et al. J Vasc Interv Radiol 2001

AngioDynamics Advantage “Because Temperature Matters” Temperature as an end point measurement: Provides a Better Predictor of Treatment Response Lowers Local Recurrence Rates Extends Patient Survival V. Krishnamurthy, Applied Radiology, Oct. 2003 Arata et al. J Vasc Interv Radiol 2001 Van Duijnhoven, Annals of Surgical Onc., 2006 Internal Use Only – Not for Distribution

AngioDynamics Advantage Scalable Design Means that… One device can be used for ablations from 1-7cm No Need for Overlapping Ablations In the treatment of tumors up to 5cm Reduces Risk of Local Tumor Recurrence Saves OR and CT Time Device Options Mean Greater Flexibility Multiple unique device designs available to treat tumors in a variety of tissues or locations. Internal Use Only – Not for Distribution