Ablatherm

2. Ultrasound wave emission is based on transducer vibration. Alternation of positive and negative electrical voltage on both sides of the transducer results in alternation of transducer thickness ( dilatation and contraction ) and therefore acoustical pressure in the coupling medium. This acoustical pressure creates tissue movement (dilatation and contraction) which amplitude is directly related to the pressure level. As the tissue response is not perfectly elastic, energy is lost and converted into heat (hand clapping also creates temperature elevation in the same way). The heat is homogeneously distributed along the ultrasound path if the transducer is not focussed. Ultrasound wave emission is based on transducer vibration. Alternation of positive and negative electrical voltage on both sides of the transducer results in alternation of transducer thickness ( dilatation and contraction ) and therefore acoustical pressure in the coupling medium. This acoustical pressure creates tissue movement (dilatation and contraction) which amplitude is directly related to the pressure level. As the tissue response is not perfectly elastic, energy is lost and converted into heat (hand clapping also creates temperature elevation in the same way). The heat is homogeneously distributed along the ultrasound path if the transducer is not focussed.

3. By using spherical shaped transducer, the ultrasound beam is concentrated on the transducer focus point, resulting in a maximum of pressure concentrated at this point. As tissue heating is directly related to pressure maximum, the lesion is formed at the transducer focus. By using spherical shaped transducer, the ultrasound beam is concentrated on the transducer focus point, resulting in a maximum of pressure concentrated at this point. As tissue heating is directly related to pressure maximum, the lesion is formed at the transducer focus.

4. The “thermal dose” is the total energy absorbed by the tissue. It can be defined as a combination of the temperature of the tissue and the time of exposure. When it overpasses a determined threshold, the thermal dose can cause the death of tissue cells. For example 43°C during 120 min or 56°C during 1 sec can produce similar irreversible tissue lesions. The tissue temperature increase is due to the normal ultrasound energy absorption by the tissue (Thermal effect). Due to high negative pressure alternation very small air bubbles are formed in front of the transducer focus (Cavitation effect). These bubbles helps to absorb more acoustical energy and to increase the tissue heating. Thanks to the unique Ablatherm® HIC (HIFU Induced Cavitation) technology, each shot creates a large and reproducible lesion which spans from the anterior to the posterior prostate capsula. These air bubbles are preferentially formed in front of the transducer focus explaining the non symmetrical lesion positioning with respect to the transducer focus. The lesion extension is about 3/4 in front of the transducer focus and 1/4 beyond. The principle of thermal dose also explains why the lesion starts at the transducer focus (where the temperature is maximum) and progresses toward the transducer during the firing sequence.The “thermal dose” is the total energy absorbed by the tissue. It can be defined as a combination of the temperature of the tissue and the time of exposure. When it overpasses a determined threshold, the thermal dose can cause the death of tissue cells. For example 43°C during 120 min or 56°C during 1 sec can produce similar irreversible tissue lesions. The tissue temperature increase is due to the normal ultrasound energy absorption by the tissue (Thermal effect). Due to high negative pressure alternation very small air bubbles are formed in front of the transducer focus (Cavitation effect). These bubbles helps to absorb more acoustical energy and to increase the tissue heating. Thanks to the unique Ablatherm® HIC (HIFU Induced Cavitation) technology, each shot creates a large and reproducible lesion which spans from the anterior to the posterior prostate capsula. These air bubbles are preferentially formed in front of the transducer focus explaining the non symmetrical lesion positioning with respect to the transducer focus. The lesion extension is about 3/4 in front of the transducer focus and 1/4 beyond. The principle of thermal dose also explains why the lesion starts at the transducer focus (where the temperature is maximum) and progresses toward the transducer during the firing sequence.

5. To treat the prostate, the transducer is previously covered with a balloon filled with coupling liquid. Then it is inserted into the patient’s rectum and positioned close to the rectum wall in such a way that the base of the biological lesion stops close to the prostate capsula. The transducer movements allow to accurately position the focal point and to define the appropriate lesion depth (Dynamic Focusing) to match the prostate shape. This precise positioning prevents from any rectal wall damage. To treat the prostate, the transducer is previously covered with a balloon filled with coupling liquid. Then it is inserted into the patient’s rectum and positioned close to the rectum wall in such a way that the base of the biological lesion stops close to the prostate capsula. The transducer movements allow to accurately position the focal point and to define the appropriate lesion depth (Dynamic Focusing) to match the prostate shape. This precise positioning prevents from any rectal wall damage.

6. Contiguous shots are delivered repeatedly to obtain a complete treatment of the whole gland in a short time, while preserving the rectal wall and the surrounding tissues. Contiguous shots are delivered repeatedly to obtain a complete treatment of the whole gland in a short time, while preserving the rectal wall and the surrounding tissues.

7. HISTORIQUE DU PROJET ABLATHERM 1989 : Développement de la technologie et expérimentation sur des reins de rats 1990 : Traitement du cancer : faisabilité sur des tumeurs de Dunning 1991 : Traitement endorectal : faisabilité sur la prostate de chien 1992 : Évaluation de l’absence de nocivité du traitement sur l’adénome de la prostate 1993 : Évaluation de l’efficacité du traitement sur le cancer de la prostate 1995 : Amélioration des procédures de sécurité 1996 : Étude multicentrique Européenne 2000 : Marquage CE Ablatherm® The development of the ABLATHERM® is the result of a long and serious investigation process. From 1989 to 1991, different animal trials were performed in order to prove the safety and the efficacy of the method. During this period, several developments were achieved in order to get the transducer technology best fitted with the human anatomy, and to start human trials. Human trials started in 1992 using prototype devices. During this period, the HIFU treatment procedure was improved and finalized, always according to good clinical practices. In 1996, after several enhancements on the device safety and efficacy, a European Multicentric Study was performed. Finally, the CE mark was the result of 10 years of research and investigations. The development of the ABLATHERM® is the result of a long and serious investigation process. From 1989 to 1991, different animal trials were performed in order to prove the safety and the efficacy of the method. During this period, several developments were achieved in order to get the transducer technology best fitted with the human anatomy, and to start human trials. Human trials started in 1992 using prototype devices. During this period, the HIFU treatment procedure was improved and finalized, always according to good clinical practices. In 1996, after several enhancements on the device safety and efficacy, a European Multicentric Study was performed. Finally, the CE mark was the result of 10 years of research and investigations.

8. Marquage CE Ablatherm® en 2000

9. The Ablatherm is made of three modules: - The command module with a computer and its complete equipment package. The computer is the principal user interface used to perform the treatment. Its friendly user interface makes it very easy to command the treatment and the probe modules. -The treatment module is mobile with all the electronics associated to the device embedded inside. This integrated system provides also a support for the patient. - The probe module is an endorectal probe with a electrical piezo therapy transducer and an ultrasound biplane imaging probe. The Ablatherm is made of three modules: - The command module with a computer and its complete equipment package. The computer is the principal user interface used to perform the treatment. Its friendly user interface makes it very easy to command the treatment and the probe modules. -The treatment module is mobile with all the electronics associated to the device embedded inside. This integrated system provides also a support for the patient. - The probe module is an endorectal probe with a electrical piezo therapy transducer and an ultrasound biplane imaging probe.

14. After each shot, the probe rotates in order to aim at the next lesion area. The system waits 5 seconds in order for the cavitation phenomenon to decrease, then a burst of ultrasound waves is applied during 5 seconds. Before each shot, the rectum position is detected with a A mode probe placed at the center on the therapy transducer. This detection prevents from rectal wall damage due to any kind of movement. The temperature of the cooling fluid inside the rectum is continuously calculated, in order to prevent from any damage of the rectum due to a warming of the rectal wall. After each shot, the probe rotates in order to aim at the next lesion area. The system waits 5 seconds in order for the cavitation phenomenon to decrease, then a burst of ultrasound waves is applied during 5 seconds. Before each shot, the rectum position is detected with a A mode probe placed at the center on the therapy transducer. This detection prevents from rectal wall damage due to any kind of movement. The temperature of the cooling fluid inside the rectum is continuously calculated, in order to prevent from any damage of the rectum due to a warming of the rectal wall.

15. MRI examinations performed early after the HIFU treatment provide a qualitative assessment of the necrosis. Indeed, MRI imaging allows the visualization of the treated volume as demonstrated in a clinical trial: after gadolinium injection, the treated area appears as an hypo-intense area and a surrounding 6-8 mm ring of contrast enhancement. Biopsies taken in the ring evidence also a complete necrosis in this ring. MRI examinations performed early after the HIFU treatment provide a qualitative assessment of the necrosis. Indeed, MRI imaging allows the visualization of the treated volume as demonstrated in a clinical trial: after gadolinium injection, the treated area appears as an hypo-intense area and a surrounding 6-8 mm ring of contrast enhancement. Biopsies taken in the ring evidence also a complete necrosis in this ring.

16. For a qualitative assessment of the tissue damages, histologic examination were performed at different times after HIFU. So, immediately after the HIFU treatment, biopsies evidenced a complete coagulation necrosis in the treated area. Later, after 3 months, fibrosis is replacing the necrotic tissue. For a qualitative assessment of the tissue damages, histologic examination were performed at different times after HIFU. So, immediately after the HIFU treatment, biopsies evidenced a complete coagulation necrosis in the treated area. Later, after 3 months, fibrosis is replacing the necrotic tissue.

17. Here, an example of the PSA evolution after a single treatment session (complete treatment of the gland) Elevated PSA level before the treatment PSA Peak immediately after the session Nadir PSA obtained 3 months after the treatment Low (< 1ng/ml) and stable follow-up PSA level Here, an example of the PSA evolution after a single treatment session (complete treatment of the gland) Elevated PSA level before the treatment PSA Peak immediately after the session Nadir PSA obtained 3 months after the treatment Low (< 1ng/ml) and stable follow-up PSA level

18. Here is an example of the PSA evolution after a partial treatment of the gland at the first session , with a need for a second session Elevated PSA level before the treatment PSA Peak immediately after the first session Nadir PSA obtained within 3 months after the 1st session and showing a residual PSA level Rising PSA level following the Nadir : indication for a 2nd treatment session Then, low and stable follow-up PSA level. Here is an example of the PSA evolution after a partial treatment of the gland at the first session , with a need for a second session Elevated PSA level before the treatment PSA Peak immediately after the first session Nadir PSA obtained within 3 months after the 1st session and showing a residual PSA level Rising PSA level following the Nadir : indication for a 2nd treatment session Then, low and stable follow-up PSA level.

19. The targeted volume can be precisely defined, and the treatment leads to a complete necrosis in these areas without damaging of the surrounding tissues An early evaluation of the treatment efficacy is possible, with a nadir PSA obtained within 3 months Since no maximum dose exists, HIFU treatment can be repeated if needed. The targeted volume can be precisely defined, and the treatment leads to a complete necrosis in these areas without damaging of the surrounding tissues An early evaluation of the treatment efficacy is possible, with a nadir PSA obtained within 3 months Since no maximum dose exists, HIFU treatment can be repeated if needed.

20. In order to have an opinion on a new treatment, based on facts and not only on feeling, the urologist needs information: from a large number of patients: this information is provided by the results of the European Multicentric Study, with the 559 patients included from Nov. 1995 to Nov. 1999. from the long-term follow-up: Dr Albert Gelet (Lyon, France) was involved in the clinical development since the first pilot study. His own cohort of patients includes therefore patients treated from 1993 in the prostate cancer indication. Of course, since 1993, the device was dramatically optimized, for efficacy as well as for safety. As a consequence, the results described in Albert Gelet papers, even if very satisfactory, could be considered as a “worst-case scenario”, better results being observed with the current treatment parameters. Information on the efficacy expected with the current treatment parameters is provided with the results from Munich. Indeed, Munich is the site with the higher patients recruitment. Therefore, Drs C. Chaussy and S. Thuroff have a sufficient number of patients treated with the current treatment parameters in order to provide relevant results. Similarly, the tolerance expected with the current device, including all the safety features, and used according to the standard procedure was described in a Munich team’s publication.In order to have an opinion on a new treatment, based on facts and not only on feeling, the urologist needs information: from a large number of patients: this information is provided by the results of the European Multicentric Study, with the 559 patients included from Nov. 1995 to Nov. 1999. from the long-term follow-up: Dr Albert Gelet (Lyon, France) was involved in the clinical development since the first pilot study. His own cohort of patients includes therefore patients treated from 1993 in the prostate cancer indication. Of course, since 1993, the device was dramatically optimized, for efficacy as well as for safety. As a consequence, the results described in Albert Gelet papers, even if very satisfactory, could be considered as a “worst-case scenario”, better results being observed with the current treatment parameters. Information on the efficacy expected with the current treatment parameters is provided with the results from Munich. Indeed, Munich is the site with the higher patients recruitment. Therefore, Drs C. Chaussy and S. Thuroff have a sufficient number of patients treated with the current treatment parameters in order to provide relevant results. Similarly, the tolerance expected with the current device, including all the safety features, and used according to the standard procedure was described in a Munich team’s publication.

22. From 1995 to 1999, the so-called European Multicentric Study was carried out in six different sites. In total, 559 patients were included during this 4 year period. In fact, the recruitment was very low during the first two years, then progressively increased, and there was a very high recruitment rate in 1999. Therefore, it is a big cohort, but with a relatively short mean follow-up duration (50 % of the patients were followed one year or less, and 50 % more than one year, but up to 4 years for the first patients included in this study). During the course of this study, 4 prototypes generations were used: 1) 2.25 MHz, 4 seconds for the shot duration 2) < 3MHz, ? 4.5 sec. 3) 3 MHz, 4.5 sec. 4) 3MHz, 5 sec. It was statistically demonstrated that the evolution of the technical parameters was accompanied with an improvement of the efficacy performances. In parallel, the safety features were implemented, with a sharp improvement of morbidity. The European Multicentric Study results have therefore to be considered as a “worst-case scenario”, as this study is mixing the results from patients treated with these 4 prototypes. From 1995 to 1999, the so-called European Multicentric Study was carried out in six different sites. In total, 559 patients were included during this 4 year period. In fact, the recruitment was very low during the first two years, then progressively increased, and there was a very high recruitment rate in 1999. Therefore, it is a big cohort, but with a relatively short mean follow-up duration (50 % of the patients were followed one year or less, and 50 % more than one year, but up to 4 years for the first patients included in this study). During the course of this study, 4 prototypes generations were used: 1) 2.25 MHz, 4 seconds for the shot duration 2) < 3MHz, ? 4.5 sec. 3) 3 MHz, 4.5 sec. 4) 3MHz, 5 sec. It was statistically demonstrated that the evolution of the technical parameters was accompanied with an improvement of the efficacy performances. In parallel, the safety features were implemented, with a sharp improvement of morbidity. The European Multicentric Study results have therefore to be considered as a “worst-case scenario”, as this study is mixing the results from patients treated with these 4 prototypes.

23. This cohort includes several sub-populations : most of the patients are T1-T2 patients treated with HIFU as first choice therapy. It is the T1-T2 population, including 402 patients. There are also 10 T3-T4 patients, 104 patients treated with HIFU after orchidectomy or a long hormonotherapy, 8 patients treated for local recurrence after prostatectomy, and 35 patients treated with HIFU for local recurrence after radiation therapy. The mean age of the overall cohort is 69 years, ranging from 45-88. It is important to underline that all the patients included in the study were not suitable candidates for a radical prostatectomy. Not suitable candidates for prostatectomy means that the patients were not fulfilling the criteria for the surgery, or refused the surgery. This cohort includes several sub-populations : most of the patients are T1-T2 patients treated with HIFU as first choice therapy. It is the T1-T2 population, including 402 patients. There are also 10 T3-T4 patients, 104 patients treated with HIFU after orchidectomy or a long hormonotherapy, 8 patients treated for local recurrence after prostatectomy, and 35 patients treated with HIFU for local recurrence after radiation therapy. The mean age of the overall cohort is 69 years, ranging from 45-88. It is important to underline that all the patients included in the study were not suitable candidates for a radical prostatectomy. Not suitable candidates for prostatectomy means that the patients were not fulfilling the criteria for the surgery, or refused the surgery.

24. The baseline characteristics of the population: The T1-T2 patients were mainly presenting with a PSA level under 10 ng/ml, with a moderate differenciation at histology, and with 1 to 3 positive cores at the sextant biopsy (4 patients - 0.7% without positive cores, but with positive chips at the TURP; all the patients had a histology-based positive diagnosis for prostate cancer). It should be noted that almost 16% were presenting with high risk prognostic factors, such as PSA > 20, tumor cells poorly differentiated, and 5 or 6 positive cores for 6 samples biopsied (sextant biopsies were performed during the course of the study).The baseline characteristics of the population: The T1-T2 patients were mainly presenting with a PSA level under 10 ng/ml, with a moderate differenciation at histology, and with 1 to 3 positive cores at the sextant biopsy (4 patients - 0.7% without positive cores, but with positive chips at the TURP; all the patients had a histology-based positive diagnosis for prostate cancer). It should be noted that almost 16% were presenting with high risk prognostic factors, such as PSA > 20, tumor cells poorly differentiated, and 5 or 6 positive cores for 6 samples biopsied (sextant biopsies were performed during the course of the study).

25. In the overall T1-T2 population, negative biopsies (= all the biopsies performed during the patients follow-up were negative for cancer in all the cores) were observed in 87.2% of the patients. For the nadir PSA observed after a complete treatment: - at least 25% of the patients presented a nadir PSA at 0.0 - at least 50% of the patients presented a nadir PSA at 0.1 or less - at least 75% of the patients presented a nadir PSA at 0.4 or less. (this presentation of the results with percentiles allows to give a better approach on the population distribution according to the PSA nadir values) When a partial treatment is administered, voluntarily (i.e. potency sparing treatment) or due to a very large prostate size, prostate tissue is let in place. As a consequence, a residual PSA level is observed in these cases. If the tissue let in place is healthy, the residual PSA level will remain stable. If there is residual tumors, PSA level will rise and a second treatment session is indicated for the patient in order to target the non treated area (for large prostates: after 6 months, the prostate shrinkage will allow to target the anterior part of the prostate which was not accessible at the first treatment session).In the overall T1-T2 population, negative biopsies (= all the biopsies performed during the patients follow-up were negative for cancer in all the cores) were observed in 87.2% of the patients. For the nadir PSA observed after a complete treatment: - at least 25% of the patients presented a nadir PSA at 0.0 - at least 50% of the patients presented a nadir PSA at 0.1 or less - at least 75% of the patients presented a nadir PSA at 0.4 or less. (this presentation of the results with percentiles allows to give a better approach on the population distribution according to the PSA nadir values) When a partial treatment is administered, voluntarily (i.e. potency sparing treatment) or due to a very large prostate size, prostate tissue is let in place. As a consequence, a residual PSA level is observed in these cases. If the tissue let in place is healthy, the residual PSA level will remain stable. If there is residual tumors, PSA level will rise and a second treatment session is indicated for the patient in order to target the non treated area (for large prostates: after 6 months, the prostate shrinkage will allow to target the anterior part of the prostate which was not accessible at the first treatment session).

26. Finally, a special highlight on the biopsy results according to the disease related initial risk level. There is a consensus for the definition of “low, intermediate or high risk patient”, which are mentioned here. Please, note that these definitions only concern the T1-T2 patients so : For the low risk patients, with cancer involving less than half a lobe, PSA < 10 and low Gleason sum, 92 % of them presented negative biopsies For the intermediate risk patients, that’s to say with cancer involving more than half a lobe, but only 1 lobe or PSA between 10 to 20, or Gleason sum = 7, 86.4 % of them presented negative biopsies And for the high risk patients with cancer involving both lobes, or PSA more than 20 or Gleason sum equal or more than 8, 82.1 % of them presented negative biopsies. Finally, a special highlight on the biopsy results according to the disease related initial risk level. There is a consensus for the definition of “low, intermediate or high risk patient”, which are mentioned here. Please, note that these definitions only concern the T1-T2 patients so : For the low risk patients, with cancer involving less than half a lobe, PSA < 10 and low Gleason sum, 92 % of them presented negative biopsies For the intermediate risk patients, that’s to say with cancer involving more than half a lobe, but only 1 lobe or PSA between 10 to 20, or Gleason sum = 7, 86.4 % of them presented negative biopsies And for the high risk patients with cancer involving both lobes, or PSA more than 20 or Gleason sum equal or more than 8, 82.1 % of them presented negative biopsies.

28. Here is the description of Dr Albert Gelet cohort of patients, with long-term results available. This patients were potentially curable with a local treatment, according to their pre-treatment PSA level: all patients had PSA ? 10 in this population selection. On the other hand, all these patients were not low-risk patients, as clinical stages T2b-T2c and Gleason sum ? 7 were not excluded from the analysis. On this slide, it is interesting to note the prostate volume before Ablatherm® treatment… then to see on the next slide that this volume is reduced by 50% after Ablatherm® treatment.Here is the description of Dr Albert Gelet cohort of patients, with long-term results available. This patients were potentially curable with a local treatment, according to their pre-treatment PSA level: all patients had PSA ? 10 in this population selection. On the other hand, all these patients were not low-risk patients, as clinical stages T2b-T2c and Gleason sum ? 7 were not excluded from the analysis. On this slide, it is interesting to note the prostate volume before Ablatherm® treatment… then to see on the next slide that this volume is reduced by 50% after Ablatherm® treatment.

29. For the presentation of his results, Dr Albert Gelet is using a very strict evaluation criterion, combining both the biopsy and the PSA results. Even with this strict criterion, he observed a 77.5% success rate (and just remember that some of these patients were treated with the first device prototype!). The disease free curve: at the beginning of the curve (point 0 = day 0 for all the patients), none of the patients are considered as a failure. Each time a failure occurred (according to the failure definition), the curve presents a step down. It is interesting to note that all the failures after Ablatherm treatment occurred early during the patient follow-up: within 20 months. After this period, the curve is presenting a superb plateau: this is a very good indicator for the extrapolation of any short-term results.For the presentation of his results, Dr Albert Gelet is using a very strict evaluation criterion, combining both the biopsy and the PSA results. Even with this strict criterion, he observed a 77.5% success rate (and just remember that some of these patients were treated with the first device prototype!). The disease free curve: at the beginning of the curve (point 0 = day 0 for all the patients), none of the patients are considered as a failure. Each time a failure occurred (according to the failure definition), the curve presents a step down. It is interesting to note that all the failures after Ablatherm treatment occurred early during the patient follow-up: within 20 months. After this period, the curve is presenting a superb plateau: this is a very good indicator for the extrapolation of any short-term results.

30. When Dr Albert Gelet results are stratified according to the cancer aggressiveness (given by the Gleason score), better results (85% success) are observed with the less aggressive cancers. This is the same for any cancer treatment: aggressive tumors are more likely to have a regional or general extension, even if classified as “clinically localized” (under-staging, due to the limits of the cancer work-up). For prostate cancer, extraprostatic localization of the disease will lead to a rising PSA level, even if the Ablatherm treatment was locally effective (patients with negative biopsies).When Dr Albert Gelet results are stratified according to the cancer aggressiveness (given by the Gleason score), better results (85% success) are observed with the less aggressive cancers. This is the same for any cancer treatment: aggressive tumors are more likely to have a regional or general extension, even if classified as “clinically localized” (under-staging, due to the limits of the cancer work-up). For prostate cancer, extraprostatic localization of the disease will lead to a rising PSA level, even if the Ablatherm treatment was locally effective (patients with negative biopsies).

31. In order to have an opinion on a new treatment, based on facts and not only on feeling, the urologist needs information: from a large number of patients: this information is provided by the results of the European Multicentric Study, with the 559 patients included from Nov. 1995 to Nov. 1999. from the long-term follow-up: Dr Albert Gelet (Lyon, France) was involved in the clinical development since the first pilot study. His own cohort of patients includes therefore patients treated from 1993 in the prostate cancer indication. Of course, since 1993, the device was dramatically optimized, for efficacy as well as for safety. As a consequence, the results described in Albert Gelet papers, even if very satisfactory, could be considered as a “worst-case scenario”, better results being observed with the current treatment parameters. Information on the efficacy expected with the current treatment parameters is provided with the results from Munich. Indeed, Munich is the site with the higher patients recruitment. Therefore, Drs C. Chaussy and S. Thuroff have a sufficient number of patients treated with the current treatment parameters in order to provide relevant results. Similarly, the tolerance expected with the current device, including all the safety features, and used according to the standard procedure was described in a Munich team’s publication.In order to have an opinion on a new treatment, based on facts and not only on feeling, the urologist needs information: from a large number of patients: this information is provided by the results of the European Multicentric Study, with the 559 patients included from Nov. 1995 to Nov. 1999. from the long-term follow-up: Dr Albert Gelet (Lyon, France) was involved in the clinical development since the first pilot study. His own cohort of patients includes therefore patients treated from 1993 in the prostate cancer indication. Of course, since 1993, the device was dramatically optimized, for efficacy as well as for safety. As a consequence, the results described in Albert Gelet papers, even if very satisfactory, could be considered as a “worst-case scenario”, better results being observed with the current treatment parameters. Information on the efficacy expected with the current treatment parameters is provided with the results from Munich. Indeed, Munich is the site with the higher patients recruitment. Therefore, Drs C. Chaussy and S. Thuroff have a sufficient number of patients treated with the current treatment parameters in order to provide relevant results. Similarly, the tolerance expected with the current device, including all the safety features, and used according to the standard procedure was described in a Munich team’s publication.

32. In order to consider that a treatment for prostate cancer is efficient, nadir PSA gives a good indication, but the PSA stability is even more important: a stable PSA level evidences the absence of cancerous disease (even if part of the prostate is let in place). In Munich, 104 T1-T2 patients treated with the current treatment parameters are now available for PSA stability (according to the definition of PSA stability, the patients have to be followed for roughly 1 year after nadir in order to be evaluable for PSA stability).In order to consider that a treatment for prostate cancer is efficient, nadir PSA gives a good indication, but the PSA stability is even more important: a stable PSA level evidences the absence of cancerous disease (even if part of the prostate is let in place). In Munich, 104 T1-T2 patients treated with the current treatment parameters are now available for PSA stability (according to the definition of PSA stability, the patients have to be followed for roughly 1 year after nadir in order to be evaluable for PSA stability).

33. In this group of patients, an overall negative biopsy rate at 88.9% was observed, and 84,1% of the patients were presenting with a stable PSA level after Ablatherm (according to the ASTRO definition for PSA stability). Very low nadir PSA was observed: 60% of the patients had a nadir PSA at 0.00 ng/ml (includes the 60th percentile), the 10 following percents were between 0.00 and 0.28 ng/ml.Only 10% of the patients presented a nadir at 2.10 ng/ml or more, which is coherent with the biopsy results. In this group of patients, an overall negative biopsy rate at 88.9% was observed, and 84,1% of the patients were presenting with a stable PSA level after Ablatherm (according to the ASTRO definition for PSA stability). Very low nadir PSA was observed: 60% of the patients had a nadir PSA at 0.00 ng/ml (includes the 60th percentile), the 10 following percents were between 0.00 and 0.28 ng/ml.Only 10% of the patients presented a nadir at 2.10 ng/ml or more, which is coherent with the biopsy results.

34. In order to have an opinion on a new treatment, based on facts and not only on feeling, the urologist needs information: from a large number of patients: this information is provided by the results of the European Multicentric Study, with the 559 patients included from Nov. 1995 to Nov. 1999. from the long-term follow-up: Dr Albert Gelet (Lyon, France) was involved in the clinical development since the first pilot study. His own cohort of patients includes therefore patients treated from 1993 in the prostate cancer indication. Of course, since 1993, the device was dramatically optimized, for efficacy as well as for safety. As a consequence, the results described in Albert Gelet papers, even if very satisfactory, could be considered as a “worst-case scenario”, better results being observed with the current treatment parameters. Information on the efficacy expected with the current treatment parameters is provided with the results from Munich. Indeed, Munich is the site with the higher patients recruitment. Therefore, Drs C. Chaussy and S. Thuroff have a sufficient number of patients treated with the current treatment parameters in order to provide relevant results. Similarly, the tolerance expected with the current device, including all the safety features, and used according to the standard procedure was described in a Munich team’s publication.In order to have an opinion on a new treatment, based on facts and not only on feeling, the urologist needs information: from a large number of patients: this information is provided by the results of the European Multicentric Study, with the 559 patients included from Nov. 1995 to Nov. 1999. from the long-term follow-up: Dr Albert Gelet (Lyon, France) was involved in the clinical development since the first pilot study. His own cohort of patients includes therefore patients treated from 1993 in the prostate cancer indication. Of course, since 1993, the device was dramatically optimized, for efficacy as well as for safety. As a consequence, the results described in Albert Gelet papers, even if very satisfactory, could be considered as a “worst-case scenario”, better results being observed with the current treatment parameters. Information on the efficacy expected with the current treatment parameters is provided with the results from Munich. Indeed, Munich is the site with the higher patients recruitment. Therefore, Drs C. Chaussy and S. Thuroff have a sufficient number of patients treated with the current treatment parameters in order to provide relevant results. Similarly, the tolerance expected with the current device, including all the safety features, and used according to the standard procedure was described in a Munich team’s publication.

35. Concerning the safety results, adverse events were homogeneously assessed using a detailed questionnaire in 315 patients (München experience, Stefan Thüroff’s publication in Molecular Urology, 2001). Among these 315 patients, the last 100 were treated with the last safety features, such as cooling, and with improved clinical procedures leading to more efficacy and also to more safety. And you can then observe the direct impact of these improvements in the limitation of the side effects. This impact has to be underlined for the fistula and the other rectal adverse events occurrence rate, thanks to the cooling system and the check of the rectal wall distance before each shot. There is also a sharp improvement in stress incontinence occurrence rate, due to the definition of a security margin from the apex. Since the CE Mark device is available (i.e. more than 1000 patients treated) no grade III (total) stress incontinence occurred. A notable impact on urgency and infections is reported, due to a better patient management, with a systematic detection of urinary tract infections in the follow-up. In fact, only immediate post-treatment retention due to the prostate necrosis, so with a need for a urinary tube for a few days as after a TURP, and absence of ejaculation (coagulation of the seminal ducts) are systematically expected for all patients. Concerning the safety results, adverse events were homogeneously assessed using a detailed questionnaire in 315 patients (München experience, Stefan Thüroff’s publication in Molecular Urology, 2001). Among these 315 patients, the last 100 were treated with the last safety features, such as cooling, and with improved clinical procedures leading to more efficacy and also to more safety. And you can then observe the direct impact of these improvements in the limitation of the side effects. This impact has to be underlined for the fistula and the other rectal adverse events occurrence rate, thanks to the cooling system and the check of the rectal wall distance before each shot. There is also a sharp improvement in stress incontinence occurrence rate, due to the definition of a security margin from the apex. Since the CE Mark device is available (i.e. more than 1000 patients treated) no grade III (total) stress incontinence occurred. A notable impact on urgency and infections is reported, due to a better patient management, with a systematic detection of urinary tract infections in the follow-up. In fact, only immediate post-treatment retention due to the prostate necrosis, so with a need for a urinary tube for a few days as after a TURP, and absence of ejaculation (coagulation of the seminal ducts) are systematically expected for all patients.

36. In order to have an opinion on a new treatment, based on facts and not only on feeling, the urologist needs information: from a large number of patients: this information is provided by the results of the European Multicentric Study, with the 559 patients included from Nov. 1995 to Nov. 1999. from the long-term follow-up: Dr Albert Gelet (Lyon, France) was involved in the clinical development since the first pilot study. His own cohort of patients includes therefore patients treated from 1993 in the prostate cancer indication. Of course, since 1993, the device was dramatically optimized, for efficacy as well as for safety. As a consequence, the results described in Albert Gelet papers, even if very satisfactory, could be considered as a “worst-case scenario”, better results being observed with the current treatment parameters. Information on the efficacy expected with the current treatment parameters is provided with the results from Munich. Indeed, Munich is the site with the higher patients recruitment. Therefore, Drs C. Chaussy and S. Thuroff have a sufficient number of patients treated with the current treatment parameters in order to provide relevant results. Similarly, the tolerance expected with the current device, including all the safety features, and used according to the standard procedure was described in a Munich team’s publication.In order to have an opinion on a new treatment, based on facts and not only on feeling, the urologist needs information: from a large number of patients: this information is provided by the results of the European Multicentric Study, with the 559 patients included from Nov. 1995 to Nov. 1999. from the long-term follow-up: Dr Albert Gelet (Lyon, France) was involved in the clinical development since the first pilot study. His own cohort of patients includes therefore patients treated from 1993 in the prostate cancer indication. Of course, since 1993, the device was dramatically optimized, for efficacy as well as for safety. As a consequence, the results described in Albert Gelet papers, even if very satisfactory, could be considered as a “worst-case scenario”, better results being observed with the current treatment parameters. Information on the efficacy expected with the current treatment parameters is provided with the results from Munich. Indeed, Munich is the site with the higher patients recruitment. Therefore, Drs C. Chaussy and S. Thuroff have a sufficient number of patients treated with the current treatment parameters in order to provide relevant results. Similarly, the tolerance expected with the current device, including all the safety features, and used according to the standard procedure was described in a Munich team’s publication.

38. Patients, T1 ou T2, N0-M0 : PSA < 15 ng/ml 4/6 biopsies (ou 2/3 maximum), score Gleason < 7 volume prostatique < 50 cc non candidat ou refus de prostatectomie sans traitement hormonal avant Suivi à 2 ans sur critère principal carcinologique: PSA /6mois et biopsies (x 6) à 6, 12 et 24 mois de tolérance évènements indésirables questionnaires : IPSS et sexualité de coût : consultations, médicaments, soins, arrêt travail

39. 93 patients évaluables à 6 mois PSA : 2,5 ± 3,2 ng/ml Biopsies négatives : 68 (73,1%) après 1ère session PSA : 1,8 ± 2,17 55 patients avec volume prostatique < 35 cc Biopsies négatives : 43 (78%) après 1ère session PSA : 1,6 ± 1,95

40. Concerning the safety results, adverse events were homogeneously assessed using a detailed questionnaire in 315 patients (München experience, Stefan Thüroff’s publication in Molecular Urology, 2001). Among these 315 patients, the last 100 were treated with the last safety features, such as cooling, and with improved clinical procedures leading to more efficacy and also to more safety. And you can then observe the direct impact of these improvements in the limitation of the side effects. This impact has to be underlined for the fistula and the other rectal adverse events occurrence rate, thanks to the cooling system and the check of the rectal wall distance before each shot. There is also a sharp improvement in stress incontinence occurrence rate, due to the definition of a security margin from the apex. Since the CE Mark device is available (i.e. more than 1000 patients treated) no grade III (total) stress incontinence occurred. A notable impact on urgency and infections is reported, due to a better patient management, with a systematic detection of urinary tract infections in the follow-up. In fact, only immediate post-treatment retention due to the prostate necrosis, so with a need for a urinary tube for a few days as after a TURP, and absence of ejaculation (coagulation of the seminal ducts) are systematically expected for all patients. Concerning the safety results, adverse events were homogeneously assessed using a detailed questionnaire in 315 patients (München experience, Stefan Thüroff’s publication in Molecular Urology, 2001). Among these 315 patients, the last 100 were treated with the last safety features, such as cooling, and with improved clinical procedures leading to more efficacy and also to more safety. And you can then observe the direct impact of these improvements in the limitation of the side effects. This impact has to be underlined for the fistula and the other rectal adverse events occurrence rate, thanks to the cooling system and the check of the rectal wall distance before each shot. There is also a sharp improvement in stress incontinence occurrence rate, due to the definition of a security margin from the apex. Since the CE Mark device is available (i.e. more than 1000 patients treated) no grade III (total) stress incontinence occurred. A notable impact on urgency and infections is reported, due to a better patient management, with a systematic detection of urinary tract infections in the follow-up. In fact, only immediate post-treatment retention due to the prostate necrosis, so with a need for a urinary tube for a few days as after a TURP, and absence of ejaculation (coagulation of the seminal ducts) are systematically expected for all patients.

41. Technique innovante et fiable Apprentissage simple Très bonne tolérance Plus de 73% de contrôle maladie à 6 mois MAIS en 1 seule séance (78% si prostate < 35 cc)

42. The Ablatherm is now used in: France: - Edouard Herriot Hospital, Lyon (Dr A. Gelet) - IMM, Paris (Pr G. Vallancien) - Saint Joseph Clinic, Marseilles (Pr. Hermanowicz) - University Hospital, Caen (Pr. H. Bensadoun) - Pitié-Salpétrière, Paris (Pr F. Richard / Dr P. Conort) (MOBILE) - Rangeuil Hospital, Toulouse (Pr P. Rischmann) (MOBILE) - University Hospital, Strasbourg (Pr D. Jacqmin / Dr C. Saussine ) (MOBILE) - University Hospital, Rouen (Pr Grise / Dr Pfister ) (MOBILE) - Pasteur Hospital, Nice (Pr Amiel / Dr Chevallier ) (MOBILE) Germany: - Städtisches Krankenhaus, Munich (Pr C. Chaussy / Dr S. Thüroff) - St Josef Krankenhaus, Regensburg (Pr W. Wieland / Dr HJ. Kiel) - Allgemeines Krankenhaus Barmbek, Hamburg (Pr. R. Tauber, Dr. Pfeiffer) (MOBILE) Italy: - Ospedale Sant ’Anna, Como (Pr Comeri, Dr Conti) - San Giovanni Battista, Turin (Pr Ferrando, Dr Tasso) - DI VENERE GIOVANNI XXIII, Como (Pr. A. Traficante, Dr. A. Callea) Belgium: - AZ Middelheim, Antwerpen (Dr P. Van Erps) - Bordet Institute, Brussels (Pr R. Van Velthoven) Saudi Arabia: - Uro-Scientific Center, Jeddha The Ablatherm is now used in: France: - Edouard Herriot Hospital, Lyon (Dr A. Gelet) - IMM, Paris (Pr G. Vallancien) - Saint Joseph Clinic, Marseilles (Pr. Hermanowicz) - University Hospital, Caen (Pr. H. Bensadoun) - Pitié-Salpétrière, Paris (Pr F. Richard / Dr P. Conort) (MOBILE) - Rangeuil Hospital, Toulouse (Pr P. Rischmann) (MOBILE) - University Hospital, Strasbourg (Pr D. Jacqmin / Dr C. Saussine ) (MOBILE) - University Hospital, Rouen (Pr Grise / Dr Pfister ) (MOBILE) - Pasteur Hospital, Nice (Pr Amiel / Dr Chevallier ) (MOBILE) Germany: - Städtisches Krankenhaus, Munich (Pr C. Chaussy / Dr S. Thüroff) - St Josef Krankenhaus, Regensburg (Pr W. Wieland / Dr HJ. Kiel) - Allgemeines Krankenhaus Barmbek, Hamburg (Pr. R. Tauber, Dr. Pfeiffer) (MOBILE) Italy: - Ospedale Sant ’Anna, Como (Pr Comeri, Dr Conti) - San Giovanni Battista, Turin (Pr Ferrando, Dr Tasso) - DI VENERE GIOVANNI XXIII, Como (Pr. A. Traficante, Dr. A. Callea) Belgium: - AZ Middelheim, Antwerpen (Dr P. Van Erps) - Bordet Institute, Brussels (Pr R. Van Velthoven) Saudi Arabia: - Uro-Scientific Center, Jeddha