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Prostate Cancer

Focal High Intensity Focused Ultrasound of Unilateral Localized Prostate cancer: A Prospective Multicentric Hemiablation Study of 111 Patients

By: Pascal Rischmanna , Albert Geletb c d, Benjamin Richec e, Arnauld Villersf, Gilles Pasticierg, Pierre Bondilh, Jean-Luc Jungi, Hubert Bugelj, Jacques Petitk, Harry Toledanol, Stéphane Mallickm, Olivier Rouvièrec d n, Muriel Rabilloudc e, Hélène Tonoli-Catezb and Sebastien Crouzetb c d

European Urology, Volume 71 Issue 2, February 2017, Pages 267-273

Published online: 01 February 2017

Keywords: Prostate cancer, Focal therapy, High-intensity focused ultrasound, Hemiablation, Prospective trial

Abstract Full Text Full Text PDF (813 KB)

Abstract

Background

Up to a third of patients with localized prostate cancer have unilateral disease that may be suitable for partial treatment with hemiablation.

Objective

To evaluate the ability of high intensity focused ultrasound (HIFU) to achieve local control of the tumor in patients with unilateral localized prostate cancer.

Design, setting, and participants

The French Urological Association initiated a prospective IDEAL multi-institutional study (2009–2015), to evaluate HIFU-hemiablation as a primary treatment.

Intervention

Multiparametric magnetic resonance imaging and biopsy were used for unilateral cancer diagnosis and control, and HIFU-hemiablation.

Outcome measurements and statistical analysis

Primary: absence of clinically significant cancer (CSC) on control biopsy at 1 yr (CSC: Gleason score ≥ 7 or cancer core length > 3 mm regardless of grade or > 2 positive cores). Secondary: presence of any cancer on biopsy, biochemical response, radical treatment free survival, adverse events, continence (no pad), erectile function (International Index of Erectile Function-5 ≥ 16), and quality of life (European Organization for Research and Treatment of Cancer QLQ-C28) questionnaires.

Results and limitations

One hundred and eleven patients were treated (mean age: 64.8 yr [standard deviation 6.2]; mean prostate-specific antigen: 6.2 ng/ml [standard deviation 2.6]; 68% low risk, 32% intermediate risk). Of the 101 patients with control biopsy, 96 (95%) and 94 (93%) had no CSC in the treated and contralateral lobes, respectively. Mean prostate-specific antigen at 2 yr was 2.3 ng/ml (standard deviation 1.7). The radical treatment-free survival rate at 2 years was 89% (radical treatments: six radical prostatectomies, three radiotherapies, and two HIFU). Adverse events were Grade 3 in 13%. At 12 mo continence and erectile functions were preserved in 97% and 78%. No significant decrease in quality of life score was observed at 12 mo. One limitation is the number of low-risk patients included in this study.

Conclusions

At 1 yr, HIFU-hemiablation was efficient with 95% absence of clinically significant cancer associated with low morbidity and preservation of quality of life. Radical treatment-free survival rate was 89% at 2 yr.

Patient summary

This report shows that high intensity focused ultrasound half-gland treatment of unilateral prostate cancer provides promising results with high cancer control and low morbidity.

Take Home Message

Prospective evaluation of high intensity focused ultrasound-hemiablation strategy for the treatment of unilateral localized prostate cancer in 111 patients. Post hemi-high intensity focused ultrasound radical treatment-free survival rate was 89%. Continence rate was 97% and erectile function was preserved in 78% of potent patients.

Keywords: Prostate cancer, Focal therapy, High-intensity focused ultrasound, Hemiablation, Prospective trial.

1. Introduction

Treatment of favorable-risk localized prostate cancer remains controversial. Because prostate cancer is multifocal in 40% of men, whole gland therapy is used as standard treatment of localized prostate cancer [1]. However, the Prostate Cancer Intervention versus Observation Trial failed to demonstrate a significant survival advantage for radical surgery compared with the watchful waiting [2]. Active surveillance (AS) has been adopted as an option to decrease the risk of overtreatment in men who have favorable-risk disease and long-term outcomes of large AS series are now available [3]. Focal therapy is emerging as an alternative in the management of selected patients [4]. The aim is to achieve a good long-term control of the cancer with a minimal morbidity and to minimize the risk of subsequent radical therapy. Approximately 20% of men who are candidates for radical surgery have unilateral cancers and could be amenable for hemiablation [5]. The fundamental challenge is to accurately assess the spatial distribution of cancer within the gland [6]. High intensity focused ultrasound (HIFU) might be one of the best techniques for focal therapy because it is performed under real-time control. It can also be repeated while standard curative therapies (external beam radiotherapy [EBRT] and radical surgery) remain viable options if necessary. The French Association of Urology conducted a multi-institutional study to evaluate HIFU-hemiablation as a primary treatment for unilateral prostate cancer. The primary objective was the local control of the tumor.

2. Patients and methods

This prospective Stage 2b early dispersion and exploration IDEAL paradigm [7] study was conducted in 10 centers in France and was nationally approved by the Lyon Sud-Est III Ethics Committee (registration: 2009-034B) under EudraCT 2009-A00664-53 (Lyon, France). All participants provided written informed consent.

Treatment-naïve patients with T1/T2 clinical stage were considered for inclusion. Before inclusion, all patients underwent multiparametric magnetic resonance imaging (mpMRI) including T2-weighted, diffusion-weighted, and dynamic contrast-enhanced imaging at 1.5T or 3T. Focal lesions were scored using the Likert 5-level suspicion score from 1 (definitely benign) to 5 (definitely malignant) [8]. Diagnostic biopsies were random (≥ 12 cores) and targeted on any mpMRI lesions with a suspicion score ≥3 (at least two cores per lesion). All suspicious MRI targets on the contralateral side were rebiopsied before inclusion. Only patients showing unilateral cancer (≤ 2 adjacent sextants) with a Gleason score ≤7 (3 + 4) were included. Patients with a biopsy confirmed mpMRI lesion located <6 mm from the apex or <5 mm from the sagittal midline were excluded.

transurethral resection of the prostate (TURP) were performed to either reduce the prostate volume (for those with a prostate > 50 cc) or for those with pretreatment obstructive symptoms. TURP was performed either >2 mo prior to HIFU or combined with the HIFU procedure under the same anesthesia.

Hemiablation was performed with the Ablatherm Integrated Imaging medical device (EDAP TMS France, Vaulx-en-Velin, France) under spinal or general anesthesia in patients in the right lateral decubitus position. The hemiablation treatment was performed with a 4-mm safety prostate tissue margin (untreated zone) at the apex in order to optimize sphincter preservation. The midline was defined by the urethra or Foley catheter position. Ipsilateral nerve sparing was not attempted.

Patients were seen at 3 mo, 6 mo, 12 mo, and every 6 mo. Follow-up mpMRI with subsequent 12-core random biopsies and targeted biopsies to any suspicious lesion at MRI were scheduled 6–12 mo after treatment.

The primary outcome was the absence of clinically significant cancer (CSC) defined as cancer with a Gleason score ≥7 or cancer core length >3 mm regardless of grade or >2 positive cores.

Secondary outcomes were the presence of any cancer on biopsy, biochemical (PSA variations) response, and radical treatment-free survival rate. All adverse events were collected and Clavien classified. Additionally, urinary function was evaluated using the International Prostate Symptom Score (IPSS). Incontinence was defined by the need of pads. Erectile dysfunction was defined as an International Index of Erectile Function (IIEF-5) score <16 [9]. Health-related quality of life was measured using the third version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C28).

The description of patients’ characteristics was carried out using the relative and absolute frequencies for the qualitative characteristics, and the mean and standard deviation (SD) for the quantitative ones. The duration of follow-up and time to reach the PSA nadir were described using the median, minimum, and maximum values.

The probability of positive control biopsy was estimated with its 95% confidence interval (CI), built using the normal approximation of the binomial distribution. The probability of radical treatment-free survival at 24 mo was estimated using the Kaplan-Meier method. The evolutions of the different scores (ie, the IPSS score, the IIEF-5 score, and the EORTC QLQ-C28 score) between inclusion and 12 mo were described by the median, minimum, and maximum values. The evolutions were tested using the Wilcoxon test. All the analysis was carried out using the SAS software, version 9.3 (SAS Institute Inc., Cary, NC, USA).

3. Results

Between November 2009 and August 2014, 111 patients were included at 10 centers. Demographics and preoperative data are presented in Table 1.

Table 1

Pre-high intensity focused ultrasound (HIFU) characteristics

HIFU (N = 111)
Mean age, yr (median) [Q1–Q3]a64.8 ± 6.2 (64.9) [61–69]
Mean prostate volume at diagnostic, cc (median) [Q1–Q3]44.2 ± 22.2 (40.0) [28–55]
Mean prostate volume before HIFU, cc (median) [Q1–Q3]31.6 ± 12.3 (28.3) [23–39]
Mean PSA, ng/ml (median) [Q1–Q3]6.2 ± 2.5 (5.6) [4.7–7.6]
Clinical stage, n (%)
 T177 (69)
 T233 (30)
 Unknown1 (1)
No. of diagnostic biopsies sessions before treatment, n (%)
 Unknown1
 =145 (41)
 =230 (27)
 ≥335 (32)
Side of positive biopsies, n (%)
 Right55 (49)
 Left56 (51)
Mean no. of biopsy samples analyzed, (median) [Q1–Q3]20.6 ± 8.9 (18.0) [12–28]
Positive samples, n (%)
 =145 (41)
 ≥266 (59)
Sextant affected, n (%)
 1 sextant75 (68)
 2 sextants (base + med, med + apex)36 (32)
Gleason score, n (%)
 ≤682 (74)
 =729 (26)

a Eight-one percent of patients had a life expectancy over 10 yr, 19% had a life expectancy between 5 yr and 10 yr.PSA = prostate-specific antigen.

Of the 111 patients, 43 (39%) had Prostate Cancer Research International Active Surveillance (PRIAS) criteria; out of them 33 had mpMRI target. Two patients did not undergo mpMRI because of a pacemaker (n = 1) or a hip prosthesis (n = 1).

TURP was performed prior to treatment in 26 patients who had a mean prostate volume of 69.9 cc (SD 23.3). Additionally, 41 patients had concomitant TURP. The mean treated volume was 16.1 cc (SD 5.1), representing 51% of the pre-HIFU prostate volume.

No patient was lost to follow-up. Control biopsy was performed in 101 patients. The 10 missing biopsies were due to patient refusal, contraindication, or death from other cause. Results are summarized in Table 2. One patient who presented with a T2 disease had only seven samples because of anticoagulation treatment.

Table 2

Follow-up biopsy results

HIFU (N = 101)
Mean no. of cores ± SD, (median) [Q1–Q3]12.4 ± 3.3 (12) [12–14]
Biopsy findings, n (%)
 (–) Negative68 (67)
 (+) Untreated lobe19 (19)
 (+) Treated lobe12 (12)
 (+) Bilateral2 (2)
Mean size of cancer core length ± SD (median) [Q1–Q3] (N = 33)2.5 ± 2.0 (2.0) [1–4]
Gleason score, n (%)
 ≤626 (79)
 =74 (12)
 ND (foci < 1 mm)3 (9)
Sextant affected, n (%) (N = 33)
 1 sextant22 (67)
 2 sextants (base + med, med + apex)9 (27)
 3 sextants (base + med + apex)2 (6)
Localization, n (%) (N = 33)
 Apex9 (27)
 Apex + base + TZ1 (3)
 Apex + middle6 (18)
 Apex + base + middle1 (3)
 Base5 (15)
 Base + middle3 (9)
 Middle8 (24)
Clinically significant cancer, n (%)
 Treated lobe5 (5)
 Untreated lobe7(7)

HIFU = high intensity focused ultrasound; ND = not determined; SD = standard deviation; TZ = transition zone.

Of the 101 patients, 12 (12%; 95% CI: 6–18) had CSC (five ipsilateral and seven contralateral). Twenty-one patients (21%; 95% CI: 13–29) had a non-CSC (seven ipsilateral, 12 contralateral, and two bilateral).

Absence of any cancer in the treated lobe was 86% (95% CI: 79–93; 87/101). Absence of any cancer in the whole gland was 67% (95% CI: 58–77; 68/101).

Positive biopsies in the treated lobe were situated at the apex in eight of 12 patients (67%) of which five (63%) were CSC.

The mean follow-up was 30.4 mo (SD 14.1), with 71% followed-up longer than 24 mo. Mean PSA nadir was 1.9 ng/ml (SD 1.5), median time to nadir was 5.7 mo (Q1–Q3: 2.8–9.9). Mean PSA at 6 mo, 12 mo, and 24 mo were 2.3 (SD 1.7) ng/ml, 2.5 (SD 2.1) ng/ml, and 2.3 (SD 1.7) ng/ml, respectively. At 2 yr, the mean PSA level decrease was 63% compared with baseline.

Second line treatments were 16 AS, six radical prostatectomies, three EBRT, nine second HIFU treatments (seven focal HIFU and two radical HIFU [with one due to rising PSA without control biopsy]). Four patients had a third line treatment (two EBRT, one radical prostatectomy, and one androgen deprivation therapy; Fig. 1). The radical treatment-free survival rate at 2 yr was 89% (95% CI: 81–94; Fig. 2).

gr1

Fig. 1

Additional treatments.

HIFU = high intensity focused ultrasound.

gr2

Fig. 2

Radical treatment-free survival rate curve.

CI = confidence interval.

Robotic radical prostatectomies were performed with unilateral preservation of neurovascular bundles. Gleason score was 6 in one patient and 7 in six patients (3 + 4 n = 4; 4 + 3 n = 2). The pathological stage was pT2 in four patients and pT3a in three patients. Positive margins were observed in three patients. The mean postoperative PSA nadir was 0.06 ng/ml.

Patients treated with EBRT received a mean dose of 75.6 Gy. The mean nadir PSA was 0.24 ng/ml.

Eighty patients completed the IPSS questionnaire at both inclusion and 12 mo follow-up showing an improvement with a mean decrease of 3 (95% CI: 1.6; 4.4; Fig. 3A).

gr3

Fig. 3

Functional results over a 12-mo follow-up period. (A) Evaluation of lower urinary tract symptoms (International Prostate Symptom score [IPSS]). (B) Evaluation of erectile function (International Index of Erectile Function [IIEF-5] score). (C) Evaluation of general quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ-C28] score).

Continence was evaluated for 102 patients at both baseline and 12 mo. At 1 yr, the proportion of pad-free patients was 97% compared with 99% at inclusion. These three (3%) had Grade I stress incontinence.

At baseline, 51 patients had good erectile function (IIEF-5 ≥ 16) and 40 (78%) returned to this status at 12 mo. The mean difference of IIEF-5 score from baseline to 12 mo was 1.2 (95% CI: –0.4; 2.7; Fig. 3B).

Seventy-six patients completed both inclusion and 12 mo EORTC QLQ-C28 questionnaire. The mean increase from baseline to 12 mo was 0.4 (95% CI: –1.0; 1.7; Fig. 3C).

Fourteen patients underwent Clavien Grade III adverse events: 11 Grade IIIa and three Grade IIIb (chronic urine retention leading to TURP). Complications are detailed in Table 3. Two patients died from other causes: pancreatic and ethmoidal bone cancers.

Table 3

High intensity focused ultrasound-related or possibly related adverse events (105 patients having completed the 12-mo follow-up visit)

Clavien grading system scoreN
IIIIIIaTransient acute urine retention5
Urinary meatus stricture1
Gross hematuria5
IIIbChronic urine retention or poor urinary flow3
IIDeep phlebitis1
Superficial phlebitis1
Urinary tract infection18
Orchitis8
Prostatitis8
ITransient urge incontinence4
Transient dysuria17
Tissue sloughing/lower urinary tract symptoms7
Hematospermia2
Anejaculation16
Transient anal and perineal pain10

4. Discussion

Whole-gland HIFU for localized prostate cancer started in the early 1990s and several centers have reported long-term results [10], [11], and [12]. The 10-yr cancer specific and metastasis free survivals ranged from 94% to 97% and 94% to 95%, respectively [9] and [10]. Literature evidence of focal HIFU is limited due to the recent development of this concept. Donaldson et al [13] defined, in a 2014 consensus meeting, several metrics for the evaluation of focal therapies. Of note, acceptable cancer control after focal therapy was defined as a retreatment rate <20%, and a whole-gland salvage treatment rate ≤10% which is in line with our 8.1% and 10.8% rates, respectively. Focal or multifocal nonwhole-gland HIFU was considered as feasible, but safety and effectiveness were to be improved [14] and [15].

Hemiablation is different from the index tumor ablation or multifocal approach used by the Ahmed et al [16], [17], and [18]. The main advantage of hemiablation is to minimize the problem of safety margin to apply around the MRI target and to be a more reproducible and standardizable strategy.

Our CSC definition is consistent with the 2014 consensus meeting [13]. In our series 88.1% of patients had histological absence of CSC after treatment, which exceeds the 80.8% absence of CSC after index lesion treatment published by Ahmed et al [18] and is in line with the 92% absence of CSC of the multifocal study [17]. In the treated side, 5% of our patients still have CSC. This rate might be due to the apical safety margin defined in the treatment protocol (100% of positive ipsilateral control biopsies are localized at the apex). The Ablatherm HIFU technical limitations (penetration depth of 26 mm) may explain some residual disease at the anterior part.

The 6.9% rate of CSC in the untreated lobe is in concordance with the 5% negative predictive value of mpMRI and biopsies [19]. While our patients’ recruitment started in 2009 we should expect that the recent improvements of both MR-imaging and HIFU technology may overcome these limitations and provide even better results. Of note, the apical and anterior technical limitations are no longer an issue with the Focal One HIFU device (EDAP TMS France, Vaulx-en-Velin, France). This new device also allows for peri-procedure evaluation of the treatment effect with contrast-enhanced ultrasound allowing live adjustment of the treatment.

A strength of our study is the combination of the longest follow-up in literature with more than 90% control biopsy compliance. Our 86.1% negative biopsy rate in the treated lobe is similar to other recently published HIFU studies: 65.4% in the Ahmed et al [18] study and 83.6% in the Feijoo et al [20] study. Van Velthoven et al [21] reported the outcomes of 50 hemi-HIFU patients but follow-up biopsies were not performed in patients with stable PSA.

In our study, 11 patients received a salvage radical treatment (six radical prostatectomy, three EBRT, and two HIFU) which were uneventful with no observed increase in complexity or morbidity. This underscores the fact that HIFU-hemiablation strategy does not burn bridges for further curative treatments.

Functional outcomes: the 97.2% rate of pad-free continent patients in our study is consistent with outcomes reported in literature (90%, 100%, 92.3%, and 94%) [16], [17], [18], [20], and [21]. The preservation of potency was obtained in 52.3%, 76.9%, and 80% in previous published studies and 78.4% in our study [18], [20], and [21] and preservation of erection sufficient for penetration was 100% in the Ahmed et al [17] multifocal study. These functional outcomes likely contributed to the observed quality of life preservation with no statistical difference between baseline and follow-up evaluation. The rate of Grade IIIb complications of 2.7% in our study was similar to the 2.8% observed by Feijoo et al [20] using the Ablatherm device and not dissimilar from the 7.2% observed by Ahmed et al [18] using the Sonablate device.

Some limitations should be discussed. The 30.4 mo follow-up of our series could be considered as too short, but is actually the longest follow-up in literature of focal treatment studies with systematic control biopsy. However, assuming that patients are properly followed on a long-term basis, we have shown that further treatments were feasible without additional morbidity. Furthermore, definitive oncological results should need more than 10 yr to be validated which is far too long for new treatment modality evaluation. Out of our baseline population, 10 patients fulfilled the PRIAS criteria and did not have MRI target thus might not have been treated initially [22]. However, all had refused AS and were candidates for conservative treatment.

Hemiablation is one of the options for partial prostate gland treatment. Although no consensus has been reached on candidate selection or on treatment modality, the use of focal therapy has been proposed as ideal for patients with low-risk features and visible lesions at mpMRI and/or significant cancer at biopsy (cancer core length > 3 mm and/or Gleason score 3 + 4) [13].

Partial gland treatment could be considered as an intermediate option between AS and radical treatments. Long-term outcomes of large AS series of men with favorable-risk prostate cancer are available [3]. Our rate of 10.8% radical treatments at 2 yr is better than the 16% and 24% rates of conversion to radical treatment described in the Klotz et al [23] study and PRIAS series [22]. Beside these oncological outcomes, one should not underestimate the psychological burden associated with AS-delay therapy versus the value of an immediate and effective therapy in 89% of the patients.

AS and partial gland therapy should be viewed as complementary options. Among patients unfit for AS, those with unilateral localized Gleason 7 tumor could potentially benefit from tissue-preserving treatment. The best candidates for AS are patients without any mpMRI target; conversely, patients with suspicious mpMRI findings (lesion > 10 mm and Prostate Imaging Reporting and Data System [PI-RADS] 4–5) with positive targeted biopsies might be good candidates for partial gland therapy [24]. Nevertheless PI-RADS was challenged [25] and revised PI-RADS provides moderately reproducible MR-imaging scores for the detection of clinically relevant disease [26]. Further research should determine whether the presence of a lesion on mpMRI is predictive of progression in AS patients and therefore justify a more aggressive—but not radical—approach.

5. Conclusions

HIFU-hemiablation of unilateral localized prostate cancer provides promising local control with 95% absence of clinically significant cancer at 1 yr. The morbidity was low with preservation of the quality of life. Radical treatment-free survival rate was 89% at 2 yr. The efficacy of HIFU partial prostate gland therapy should be evidenced by comparative studies conducted versus standards of care.


Author contributions: Pascal Rischmann had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Rischmann, Gelet, Villers, Pasticier.

Acquisition of data: Rischmann, Gelet, Villers, Pasticier, Bondil, Jung, Bugel, Petit, Toledano, Mallick, Rouvière, Tonoli-Catez, Crouzet.

Analysis and interpretation of data: Rischmann, Crouzet, Gelet, Rouvière.

Drafting of the manuscript: Rischmann, Crouzet, Gelet.

Critical revision of the manuscript for important intellectual content: Villers, Rouvière.

Statistical analysis: Riche, Rabilloud, Gelet, Tonoli-Catez.

Obtaining funding: Rischmann.

Administrative, technical, or material support: None.

Supervision: Rischmann, Gelet.

Other: None.

Financial disclosures: Pascal Rischmann certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Rischmann is a consultant for EDAP-TMS, Vaulx-en-Velin, France, and stock owner of EDAP TMS shares; Gelet is a consultant for EDAP-TMS, Vaulx-en-Velin, France; Crouzet is a consultant for EDAP-TMS, Vaulx-en-Velin, France; Pasticier is a consultant for EDAP-TMS, Vaulx-en-Velin, France; Toledano is a consultant for EDAP-TMS, Vaulx-en-Velin, France; Mallick is a consultant for EDAP-TMS, Vaulx-en-Velin, France.

Funding/Support and role of the sponsor: None.

Acknowledgments: Grant from the Association Française d’Urologie.

Appendix A. Supplementary data

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Footnotes

a Department of Urology, Rangueil University Hospital, Toulouse, France

b Department of Urology and Transplantation Surgery, Edouard Herriot Hospital, Lyon, France

c Department of Urology, Université de Lyon, Lyon, France

d INSERM Unit 1032, LabTau, Université de Lyon, Lyon, France

e Hospices Civils de Lyon, Service de Biostatistiques, Lyon, France

f Department of Urology, Huriez Hospital, Lille University, France

g Department of Urology, CHU Pellegrin, Bordeaux, France

h Department of Urology, General Hospital of Chambéry, Chambéry, France

i Department of Urology, Pasteur Hospital, Colmar, France

j Department of Urology, University Hospital of Rouen, Rouen, France

k Department of Urology and Transplantation, South Hospital of Amiens, Amiens, France

l Department of Surgical Urology, North Hospital of Marseille, Marseille, France

m Department of Urology, Saint-Michel Clinic, Toulon, France

n Department of Radiology, Edouard Herriot Hospital, Lyon, France

Corresponding author. Department of Urology, Centre Hospitalier Universitaire de Rangueil, 1, Avenue Jean Poulhès TSA 50032, Toulouse, 31059 Cedex 9, France. Tel. +33 5 61 32 32 40; Fax: +33 5 61 32 32 30.

Please visit www.eu-acme.org/europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.

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