1. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Ablatherm Ablatherm ® The The HIFU Treatment for Localized Prostate Cancer HIFU TECHNOLOGY POWERED BY EDAP

2. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Ultrasound Waves Generation Plane transducer Ultrasound waves emission by transducer electro-mechanical vibrations Tissue motion Tissue heating Acoustical pressure +++ --- Physical Principle Treatment Description Technology 1 / 4

3. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Focused transducer Emitting ultrasound waves Tissue heating Over 85°C Acoustical pressure Focused Ultrasound Waves Physical Principle Treatment Description Technology 2 / 4

4. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Tissue Lesion Formation 3L/4L/4 D Thermal effects + Cavitation effects + Time exposure = Tissue lesion Physical Principle Treatment Description Technology 3 / 4 Temperature Simulation INSERM U 556 Temperature Simulation INSERM U 556 Thermal Dose Simulation INSERM U 556 Thermal Dose Simulation INSERM U 556 Lesion L = 24 mm max D = 1.7 mm HIC Technology H IFU I NDUCED C AVITATION

5. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Local Increase of Tissue Temperature HIFUHYPERTHERMIA l High Temperature (>85 °C) l Short Time (< 5 Sec.) l Low Temperature (< 45 °C) l Long Duration (>1 Hr) Time Temp. Physical Principle Two different approaches to reach the destruction threshold : Temp. Time Treatment Description Technology 4 / 4

6. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Transducer Positioning Precise lesion positioning with Dynamic Focusing Physical Principle Sparing of surrounding tissue Treatment Description Technology 1 / 2

7. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Lesion Distribution within the Prostate Each shot consists of a burst of ultrasound waves with a duration of 5 seconds The focal volume is very small: 19- 24 mm in length by 1.7 mm in diameter The firing head moves until the whole targeted volume is treated Physical Principle Treatment Description Technology 2 / 2 Treatment Simulation Treatment Simulation

8. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS History of the Ablatherm Project 1989: Preliminary experiments on rats kidneys and technology development 1990: Cancer treatment - feasibility: Dunning tumors 1991: Endorectal approach - feasibility: canine prostate 1992: Treatment safety - evaluation: human B.P.H. 1993: Treatment efficacy - evaluation: PCa 1995: Device safety improvements 1996: European Multicentric Study 2000:CE Mark Ablatherm ® ë History 1 / 2

9. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS CE Mark Ablatherm CE Marked January 2000 ë History 2 / 2

10. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Device Description General Description ER Probe Device 1 / 1 RF Power Imaging and Firing System Computer Electronics and safeties + Disposable Endorectal Probe Cooling Motors Patient Support User Interface Command Module Treatment Module Probe Module

11. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Imaging Position Firing Position Endorectal Probe The therapy transducer (focuses at 40 mm, operates at 3 MHz) and the 7,5 MHz biplane imaging probe are coupled in a latex balloon filled with a coupling fluid (Ablasonic TM ) General Description ER Probe Device 1 / 2

12. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Imaging / Treatment Position The targeted prostatic volume is localized with the bi-plan ultrasound imaging probe Imaging Position Firing Position High-energy ultrasound waves are focused through the rectal wall to the targeted prostate area General Description ER Probe Device 2 / 2 Click on one of the above images for animation

13. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Main Steps of a Treatment Probe preparation (A blapak ® disposable) Patient installation (Immobilization) Prostate localization (Apex identification) - Longitudinal imaging - Transversal imaging Treatment (Safety controls)Treatment Patient removal Probe cleaning and disinfection Summary PositioningTreatment 1 / 1

14. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Infra-red light Reflector Patient Indicator light is ON Patient Installation (Immobilization) SummaryPositioningTreatment Patient positioned in right lateral decubitus position Patient movement detector Treatment 1 / 1

15. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Treatment (Safety Controls) Main safety features Power / Firing sequence Probe position Patient movement Rectum position Temperature Treatment Summary Positioning Treatment Click on the above image for an animation of the control interface 1 / 1

16. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS MRI performed day 2 after HIFU Session Imaging PSA/Follow- up Conclusio n Effects 1 / 2 MRI shows the boundaries of the necrotic tissue The treated area appears as a hypo-intense area surrounded by a 6-8 mm thick ring of contrast enhancement

17. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Tissue Development Complete destruction of the glandular tissue due to coagulation necrosis lesion which reaches the capsula and the periprostatic fat The necrotic prostatic tissue is replaced by a fibrotic tissue (including the capsula) 48 hours 3 months Imaging PSA/Follow- up Conclusio n Effects 2 / 2

18. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Typical PSA after Ablatherm 0 50 100 150 200 250 m-93m-94m-95m-96m-97m-98m-99 date 1 HIFU Session Last PSA 0.2 ng/ml Negative Biopsies Complete response after one HIFU session Nadir PSA reached at 3 months Imaging Conclusio n PSA/Follow- up PSA (ng/ml) Effects 1 / 3

19. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Multiple Ablatherm Sessions 0 5 10 15 20 25 30 35 40 45 50 nov-95nov-96nov-97nov-98 Date PSA (ng/ml) 2 HIFU Sessions Positive Biopsies Negative Biopsies Last PSA 0 ng/ml 0,3 ng/ml Partial treatment at the first session In case of rising PSA, a second HIFU session can be performed PSA Follow- up Conclusio n Effects Imaging 2 / 3

20. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Typical PSA after Ablatherm Quality of life assessment (IPSS - QOL)* Imaging Conclusio n PSA/Follow- up * Data collected in Munich (October 1, 2000) 52% of the patients with the same or an improved QOL Variation without clinical significance HIFU treatment does not adversely affect HIFU treatment does not adversely affect the patients QOL the patients QOL Effects 3 / 3

21. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Clinical Effects Imaging PSA/Follow- up Conclusio n With Ablatherm ®, the urologist: complete necrosis l obtains a complete necrosis of prostate tumors in the treated area without damaging the surrounding tissues, and without adversely affecting QOL early assessment l has an early assessment of the treatment efficacy (PSA nadir, histology…) repeat l can repeat the treatment, since no maximum dose exists Effects 1 / 1

22. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Evidence-based Efficacy Conclusio n Adverse Events Results European Multicentric Study l Large cohort of patients: European Multicentric Study Results from Lyon l Long term follow-up: Results from Lyon Results from Munich l Optimal Efficacy: Results from Munich Results from Munich l Minimal Morbidity: Results from Munich Long Term EM Study Efficacy

23. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Evidence-based Efficacy Conclusio n Adverse Events Results Long Term EM Study Efficacy European Multicentric Study l Large cohort of patients: European Multicentric Study Results from Lyon l Long term follow-up: Results from Lyon Results from Munich l Optimal Efficacy: Results from Munich Results from Munich l Minimal Morbidity: Results from Munich Ref: C. Chaussy, S. Thüroff, G. Vallancien, W. Wieland, H.J. Kiel, A. Le Duc, F. Desgranchamps, J. de la Rosette, A. Gelet HIFU for the Treatment of Localized Prostate Cancer: Efficacy Results of the European Multicentric Study The Journal Of Urology, May 2001, Vol. 165, 5:388

24. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Patients included from 1995 to 1999, in 6 European sites: A. Gelet, Lyon - France C. Chaussy, S. Thüroff, Münich - Germany C. Chaussy, S. Thüroff, Münich - Germany W. Wieland, H.J. Kiel, Regensburg - Germany W. Wieland, H.J. Kiel, Regensburg - Germany G. Vallancien, Paris - France G. Vallancien, Paris - France A. Le Duc, F. Desgranchamps, Paris - France A. Le Duc, F. Desgranchamps, Paris - France J. de la Rosette, Nijmegen - The Netherlands J. de la Rosette, Nijmegen - The Netherlands n = 559 patients up to 51 months follow-up Large Cohort: European Multicentric Study EM Study Long Term Results Conclusio n Adverse Events Efficacy 1 / 5 The Journal Of Urology, May 2001

25. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Mean age: 69 years (range 45 - 88) n=402 n=35 n=8 n=104 n=10 EM Study Results Long TermConclusio n Adverse Events Efficacy STUDY POPULATION Large Cohort: European Multicentric Study 2 / 5 The Journal Of Urology, May 2001

26. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS T1-T2 Population Patients baseline characteristics < 10 10 - 20 > 20 Total PSA (ng/ml) 50.9% 33.0% 16.1% 100% 2 - 4/G1 5 - 7/G2 8 - 10/G3 Total Gleason score 10.5% 73.2% 16.3% 100% 0 1 2 3 4 5 6 Total # Positive biopsy samples 0.7% (TURP) 28.4% 29.5% 19.6% 6.5% 4.6% 10.7% 100% EM Study Results Long TermConclusio n Adverse Events Efficacy Large Cohort: European Multicentric Study 3 / 5 The Journal Of Urology, May 2001

27. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Overall results observed in the T1 - T2 population Negative biopsy rate 87.2% Nadir PSA ng/ml 25th percentile median 75th percentile after complete treatment 0.00.10.4after partial treatment 0.10.62.2 EM Study Results Long TermConclusio n Adverse Events Efficacy Large Cohort: European Multicentric Study 4 / 5 The Journal Of Urology, May 2001

28. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Low-risk patients: T1-T2a and PSA 10 ng/ml and Gleason score 6 Intermediate-risk patients: T2b or 10 < PSA 20 ng/ml or Gleason sc. = 7 High-risk patients: T2c or PSA > 20 ng/ml or Gleason score 8 Stratification of the results according to the initial disease-related risk level Negative biopsy rate Low risk patients Intermediate risk patients High risk patients 92.1% 92.1% 86.4% 86.4% 82.1% 82.1% EM Study Results Long TermConclusio n Adverse Events Efficacy Large Cohort: European Multicentric Study 5 / 5 The Journal Of Urology, May 2001

29. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Evidence-based Efficacy Conclusio n Adverse Events Results Long Term EM Study Efficacy European Multicentric Study l Large cohort of patients: European Multicentric Study Results from Lyon l Long term follow-up: Results from Lyon Results from Munich l Optimal Efficacy: Results from Munich Results from Munich l Minimal Morbidity: Results from Munich Ref: L. Poissonnier, A. Gelet et al. - Résultats du traitement par ultrasons focalisés transrectaux du cancer localisé de la prostate (120 Patients avec PSA à 10 ng/ml) - Progrès en Urologie, 2003, vol. 13, p. 60-72

30. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Long-term Follow-up: Results from Lyon Total population: n=120 Clinical Stage Gleason Score Age (years) PSA Value (ng/ml) Prostate Volume (cc) 2 - 6:n = 77 7 - 10:n = 43 71.2 5.3 5.67 2.47 33.6 15.5 Inclusion criteria:Localized prostate cancer (T1-T2) HIFU: primary care for PCa treatment Initial PSA 10 Ng/mL EM Study Long Term Results Conclusio n Adverse Events Efficacy 1 / 3 Progrès en Urologie, 2001 T1: n = 61 T2: n = 59

31. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Long Term Results EM Study Conclusio n Adverse Events Efficacy Long-term Follow-up: Results from Lyon Overall Disease Free Rate (DFR) FAILURE CRITERION Positive random sextant biopsy Positive random sextant biopsy (whatever the PSA level ) OR OR (even if negative control biopsies) –biochemical evidence of 3 consecutive rising in PSA level –PSA velocity > 0.75 ng/ year Months l Follow up: Up to 96 months l Negative Biopsies: 85.8% (103/120) l Nadir PSA < 0.5: 75% (90/120) l Mean prostate volume: 14.6 14.1 cc DFR (%) 2 / 3 Progrès en Urologie, 2003

32. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Long Term Results EM Study Conclusio n Adverse Events Efficacy Long-term Follow-up: Results from Lyon DFR according to the baseline Gleason Score DFR % Months 3 / 3 Progrès en Urologie, 2001 p<0.05

33. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Evidence-based Efficacy Conclusio n Adverse Events Results Long Term EM Study Efficacy European Multicentric Study l Large cohort of patients: European Multicentric Study Results from Lyon l Long term follow-up: Results from Lyon Results from Munich l Optimal Efficacy: Results from Munich Results from Munich l Minimal Morbidity: Results from Munich

34. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Optimal Efficacy: Results from Munich Results Long Term EM Study Conclusio n Adverse EventsEfficacy Patients evaluable for PSA nadir and/or stability: n = 104 Patients evaluable for PSA nadir and/or stability: n = 104 Mean follow-up: 1 year Mean follow-up: 1 year Inclusion criteria:Localized prostate cancer (T1-T2) HIFU : primary care for PCa treatment First treatment session : 3 MHz - 5 sec Stability: ASTRO definition Non stable PSA: Non stable PSA: Biochemical evidence of 3 consecutive rising in PSA level from nadir, measured at least 3 months apart 1 / 2

35. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Results Long Term EM Study Conclusio n Adverse EventsEfficacy Optimal Efficacy: Results from Munich Negative Biopsy Rate 88.9 % 10th percentile 30th percentile Median 70th percentile 90th percentile 0.000.000.000.282.10 Nadir PSA (ng/ml) PSA Stability Rate 84.1 % Results observed on the overall population: 2 / 2

36. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Evidence-based Efficacy Conclusio n Adverse Events Results Long Term EM Study Efficacy European Multicentric Study l Large cohort of patients : European Multicentric Study Results from Lyon l Long term follow-up : Results from Lyon Results from Munich l Optimal Efficacy : Results from Munich Results from Munich l Minimal Morbidity : Results from Munich Ref: C. Chaussy, S. Thüroff - High Intensity Focused Ultrasound: Complications and Adverse Events Molecular Urology, 2000, Vol. 4, 3:183-7

37. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Death (Intra and post-op) Fistula Rectal wall burn Hemorrhoïdal pain Stress incontinence Grade I (average 27 days) Grade II (average 32 days) Grade III (TURP) Urge incontinenceUrg encyUTIs Significant hematuria Immediate post-treatment retention Total erectile dysfunctionEjaculation problems Last 100 patients EM Study Adverse Events Results Long Term EM Study Conclusio n Adverse Events Efficacy Minimal Morbidity: Results from Munich 1 / 1 Molecular Urology, 2000 00019210713010022100

38. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Ablatherm is now an evidence-based valuable treatment option Results Long Term EM Study Conclusio n Adverse Events Efficacy 4 Large cohort of patients studied 4 Long term follow-up available 4 Optimal efficacy proven 4 Minimal morbidity observed Evidence-based Efficacy 1 / 2

39. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Situation Where are we today? ABLATHERM is a treatment option with a proven efficacy and a low morbidity 24 sites using an ABLATHERM in routine daily practice in Europe More than 3500 patients treated as of April 31, 2003 Results Long Term EM Study Conclusio n Adverse Events Efficacy 2 / 2

40. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Indications As a first choice therapy As a first choice therapy As a salvage therapy As a salvage therapy In case of local recurrence LOCALIZED PROSTATE CANCER Indications 1 / 1

41. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Benefits Non-Invasive: no port, no seeds, no radiation Effective: precise and definitive necrosis of the targeted area Early Feedback: nadir PSA after only 3 months Quality of Life: minimal side effects Repeatable: if needed at any time during follow up Adaptable: to the physician and the patients therapeutic goals No Therapeutic alternative options still open post Ablatherm Impasse: Benefits 1 / 1

42. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Positioning 1. Offers unique therapeutic advantages versus other existing therapies 2. Can be used as first choice therapy as well as salvage therapy 3. Offers economic benefits versus other existing therapies 4. Allows the urologists to remain the sole therapist during the overall patient management Positioning 1 / 1 The HIFU Treatment for Localized Prostate Cancer, that

43. HIFU ë History History Technology ABLATHERM Treatment Positioning Benefits Device CLINICAL Effects Results Indications HIGHLIGHTS Ablatherm® Positioning The HIFU Treatment for Localized Prostate Cancer