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European Urology

Volume 58, issue 6, pages e53-e62, December 2010

Prostate Cancer

Systematic Review of the Efficacy and Safety of High-Intensity Focussed Ultrasound for the Primary and Salvage Treatment of Prostate Cancer eulogo1

Marisa Warmuth, Tim Johansson and Philipp Mad

Accepted 6 September 2010, Published online 15 September 2010, pages 803 - 815

Abstract Full Text Full-Text PDF (301 KB) Create Platinum Slide Series

Fig. 1 Literature selection process (PRISMA flow diagram).PICOS = Population, Intervention, Control, Outcome, Study design; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

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References in context

  • Fig. 1 shows the detailed literature selection process.
    Go to context

Table 1 Comparison of the two currently available high-intensity focussing ultrasound devices

Ablatherm Integrated Imaging 6 x X. Rebillard, M. Soulie, E. Chartier-Kastler, et al. High-intensity focused ultrasound in prostate cancer; a systematic literature review of the French Association of Urology. BJU Int. 2008;101:1205-1213 Crossref. , 14 x P. Tsakiris, S. Thüroff, J. de la Rosette, et al. Transrectal high-intensity focused ultrasound devices: a critical appraisal of the available evidence. J Endourol. 2008;22:221-229 , and 15 x R. Illing, A. Chapman, R. Illing, A. Chapman. The clinical applications of high intensity focused ultrasound in the prostate. Int J Hyperthermia. 2007;23:183-191 Crossref. Sonablate 500 12 x HIFU – what does the treatment involve? UKHIFU High Intensity Focussed Ultrasound Web site. http://www.ukhifu.co.uk/hifu-treatment.htm. Retrieved May 17, 2010. , 13 x R. Illing, M. Emberton, R. Illing, M. Emberton. Sonablate-500: transrectal high-intensity focused ultrasound for the treatment of prostate cancer. Expert Rev Med Devices. 2006;3:717-729 Crossref. , 14 x P. Tsakiris, S. Thüroff, J. de la Rosette, et al. Transrectal high-intensity focused ultrasound devices: a critical appraisal of the available evidence. J Endourol. 2008;22:221-229 , and 15 x R. Illing, A. Chapman, R. Illing, A. Chapman. The clinical applications of high intensity focused ultrasound in the prostate. Int J Hyperthermia. 2007;23:183-191 Crossref.
Company EDAP TMS SA, France Focus Surgery Inc, USA
Since 2005 2001
Approval Europe: CE mark for the treatment of localised prostate cancer; Australia; Canada; Russia; South Korea Europe: CE mark for the treatment of pts with primary prostate cancer or recurrent prostate cancer following prior therapy
Table Integrated table Standard operating table
Anaesthesia General, epidural, spinal General, epidural, spinal
Patient positioning Right lateral decubitus Lithotomy or supine
Mode of administration Transrectal Transrectal
Software Automated: Ablaview Semiautomated
Treatment algorithm(s) Three One
Power Predefined for each treatment algorithm: primary, salvage after EBRT failure, or repeat HIFU Adjusted manually by user
Treatment probe/transducer Single-treatment probe containing two ultrasound transducers Single-treatment probe containing two ultrasound transducers of different focal lengths (either 30/40 mm or 45/50 mm for larger prostate glands)
Frequency 7.5 MHz for imaging/treatment planning; 3 MHz for treatment 4 MHz for imaging/treatment planning and treatment
Focal point 45 mm from crystal 30–50 mm from crystal
Treatment planning Prostate is divided into a series of blocks Prostate is divided into treatment regions: anterior, middle, posterior on both right/left side
Ablation volume Adjustable ablation volume from 19 × 1.7 × 1.7 mm to 26 × 1.7 × 1.7 mm; total: 29–36 mm3 3 × 3 × 10–12 mm by each acoustic pulse; total: 21–47 mm3
Ablation temperature >85 °C 80–98 °C
Imaging Real time Real time
Active cooling system Yes Yes: Sonachill
Real-time rectal wall distance monitoring Yes Yes
Real-time rectal wall temperature monitoring Yes Yes
Postoperative treatment Temporary urinary catheter (urethral/suprapubic), prophylactic antibiotics, analgesics

Costs
 Device costs €550 000 €300 000
 Maintenance costs €45 000/yr €25 000/yr
 Disposables €550: Ablapack €100

CE = Conformité Européenne (European Conformity); EBRT = external-beam radiation therapy; HIFU = high-intensity focussed ultrasound; pts = patients.

References in context

  • The differences between Ablatherm and Sonablate treatments mainly concern patient positioning, treatment algorithms, imaging, and technical details. Table 1 provides a detailed comparison of the latest types of the two systems that have been employed in studies published in the literature (Ablatherm Integrated Imaging and Sonablate 500) [5,12–15].
    Go to context

Table 2 Inclusion criteria

Population Men with localised (T1–T2, N0–Nx, M0) and locally advanced (T3–T4, N0–Nx, M0) prostate cancer
Men with recurrent prostate cancer after treatment failure of radical prostatectomy or external-beam radiation therapy
Intervention High-intensity focussed ultrasound
Ablatherm (prototypes, Maxis, Integrated Imaging) by EDAP TMS, France, and/or
Sonablate (200, 500) by Focus Surgery Inc, USA
Control Radical prostatectomy with/without dissection of pelvic lymph nodes
External-beam radiation therapy (with/without hormone therapy) or interstitial brachytherapy
Active surveillance/watchful waiting
Outcomes
 Efficacy Clinical (surrogate outcomes): PSA kinetics, biopsy results
Patient relevant: 5-yr survival, disease-free survival, overall survival, quality of life
 Safety Morbidity: acute/chronic urinary retention, urinary incontinence, urinary tract infection, stricture/stenosis (bladder neck/ureter), erectile dysfunction, rectourethral fistula, chronic pain
Mortality
Study design
 Efficacy All prospective studies, >50 patients
 Safety All prospective studies, >50 patients

PSA = prostate-specific antigen.

References in context

  • As can be seen in Table 2, we defined inclusion criteria for the literature search using the PICOS (Population, Intervention, Control, Outcome, Study design) approach.
    Go to context

Table 3 Ablatherm high-intensity focussed ultrasound: primary therapy

Study Blana et al [18] x A. Blana, F.J. Murat, B. Walter, et al. First analysis of the long-term results with transrectal HIFU in patients with localised prostate cancer. Eur Urol. 2008;53:1194-1203 Abstract, Full-text, PDF, Crossref. Poissonnier et al [27] x L. Poissonnier, J.-Y. Chapelon, O. Rouvière, et al. Control of prostate cancer by transrectal HIFU in 227 patients. Eur Urol. 2007;51:381-387 Abstract, Full-text, PDF, Crossref. Colombel et al [34] x M. Colombel, L. Poissonnier, X. Martin, A. Gelet. Clinical results of the prostate HIFU project. Eur Urol Suppl. 2006;5:491-494 Abstract, Full-text, PDF, Crossref. Lee et al [24] x H.M. Lee, J.H. Hong, H.Y. Choi, H.M. Lee, J.H. Hong, H.Y. Choi. High-intensity focused ultrasound therapy for clinically localized prostate cancer. Prostate Cancer Prostatic Dis. 2006;9:439-443 Crossref. Blana et al [19] x A. Blana, B. Walter, S. Rogenhofer, W.F. Wieland. High-intensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience. Urology. 2004;63:297-300 Crossref. Walter et al [33] x B. Walter, S. Rogenhofer, W.F. Wieland, A. Blana. Combination from TUR-P and high-intensity focused ultrasound (HIFU) for the treatment of localized prostate cancer—experience with 70 patients. J Urologie Urogynakologie. 2004;11:5-10 Chaussy et al [21] x C. Chaussy, S. Thüroff, C. Chaussy, S. Thüroff. The status of high-intensity focused ultrasound in the treatment of localized prostate cancer and the impact of a combined resection. Curr Urol Rep. 2003;4:248-252 Crossref. Thüroff et al [28] x S. Thüroff, C. Chaussy, G. Vallancien, et al. High-intensity focused ultrasound and localized prostate cancer: efficacy results from the European multicentric study. J Endourol. 2003;17:673-677 Chaussy et al [20] x C. Chaussy, S. Thüroff, C. Chaussy, S. Thüroff. Results and side effects of high-intensity focused ultrasound in localized prostate cancer. J Endourol. 2001;15:437-440 discussion 447–8 Crossref. Gelet et al [23] x A. Gelet, J.Y. Chapelon, R. Bouvier, et al. Transrectal high intensity focused ultrasound for the treatment of localized prostate cancer: factors influencing the outcome. Eur Urol. 2001;40:124-129 Crossref. Chaussy et al [22] x C.G. Chaussy, S. Thüroff, C.G. Chaussy, S. Thüroff. High-intensive focused ultrasound in localized prostate cancer. J Endourol. 2000;14:293-299 Crossref.
Country DE/FR: 2 centres FR FR KR DE DE DE DE/FR/NL: 6 centres DE FR DE
Patients, No. 140 227 242 58 146 70 271 (A: prospective: HIFU 96; B: retrospective: TURP + HIFU 175) 402 184 102 65 (A: global, n = NA vs B: selective treatment, n = NA)
Patients, age, yr (range) M: 70 (45–87) Ø 69 ± 6 Ø 71 ± 6 Ø 70 ± 6 Ø 70 ± 7 Ø 67 ± 6 A: Ø 66 ± 8; B: Ø 68 ± 7 Ø 70 ± 7 Ø 72 (59–81) Ø 71 ± 6 NA
Tumour stage T1a–T2cNxM0 T1–T2 T1cT2 T1–T2 T1–T2N0M0 T1–T2bN0M0 T1–T2c T1–T2N0-NxM0 T1–T2NxM0 T1b–T2 Localised
Neoadjuvant ADT, % of pts 16 33 NA 29 43 NA NA 0 NA 8 NA
TURP prior to/combined with HIFU, % of pts NA 78 100 91 NA 100 65 NA NA NA NA
Follow-up, mo (range) Ø 77 ± 12 Ø 28 ± 20; M: 21 (12–107) NA Ø 14 ± 4 Ø 23 (4–62) Ø 15 ± 7 A: Ø 19 ± 12, B: Ø 11 ± 6 Ø 14 (0–51) Ø 6, M: 4 (0–30) Ø 19 (3–76) Ø 10 (1–18)

ADT = androgen-deprivation therapy; DE = Germany; FR = France; HIFU = high-intensity focussed ultrasound; KR = Republic of Korea; M = median; NA = not available; NL = Netherlands; Ø = mean plus or minus standard deviation; pts = patients; TURP = transurethral resection of the prostate.

References in context

Table 4 Evidence profile: Ablatherm high-intensity focussed ultrasound

No. of studies/patients Study design Methodological quality Consistency of results Directness of evidence Magnitude of effect, % Other modifying factors1 Level of evidence
Outcome: biochemical disease-free survival rate
 2/367 Observational, case series Serious limitations2 (−1) No important inconsistency Direct 66–77 at 5 yr, 69 at 7 yr Publication bias likely Very low

Outcome: negative biopsy rate
 10/1849 Observational, case series Serious limitations2 (−1) Important inconsistency Direct 86 at 3 mo, 65–94 (point in time not specified) Publication bias likely; lack of precise data Very low

Outcome: overall survival rate
 1/140 Observational, case series Serious limitations2 (−1) Only one trial Direct 90 at 5 yr, 83 at 8 yr Publication bias likely Very low

Outcome: prostate-cancer specific survival rate
 1/140 Observational, case series Serious limitations2 (−1) Only one trial Direct 100 at 5 yr, 98 at 8 yr Publication bias likely Very low

Outcome: adverse events urinary tract3
 4/702–11/19074 Observational, case series Serious limitations2 (−1) Important inconsistency Direct 2–58 Publication bias likely Very low

Outcome: adverse events potency5
 8/1714 Observational, case series Serious limitations2 (−1) Important inconsistency Direct 18–0 Publication bias likely Very low

Outcome: adverse events rectum6
 1/184–6/9697 Observational, case series Serious limitations2 (−1) Important inconsistency Direct 0–15 Publication bias likely Very low

Outcome: pain
 6/927 Observational, case series Serious limitations2 (−1) No important inconsistency Direct 1–6 Publication bias likely Very low

Outcome: IEFF (30-point scale)
 No evidence

  Outcome: IPSS (35-point scale)
 4/671 Observational, case series Serious limitations2 (−1) Important inconsistency Direct Improved by 1–4 points, or worsened by 3 points (baseline vs last follow-up) Publication bias likely Very low

Outcome: IPSS-Quality of Life (6-point scale)
 3/525 Observational, case series Serious limitations2 (−1) No important inconsistency Direct Changed by ±1 point (baseline vs last follow-up) Publication bias likely Very low

IEFF = International Index of Erectile Function; IPSS = International Prostate Symptom Score.

1 Low incidence, lack of precise data, strong or very strong association, high risk of publication bias, dose-efficacy gradient, residual confounding plausible.

2 All observational studies have been downgraded from low quality to very low quality because of case series with lack of control group; further factors lowering the quality of evidence apply, such as the likely occurrence of publication bias.

3 Adverse events urinary tract: bladder neck/urethral stricture/stenosis, prolonged urinary retention, urinary tract infection, urinary incontinence.

4 Not all adverse events concerning urinary tract were assessed in all studies.

5 Adverse events potency: impotence/erectile dysfunction.

6 Adverse events rectum: rectal burn, rectourethral fistula.

7 Not all adverse events concerning rectum were assessed in all studies.

References in context

  • Table 4 shows the evidence profile of Ablatherm HIFU as a primary therapy option in prostate cancer.
    Go to context

Table 5 Ablatherm high-intensity focussed ultrasound: salvage therapy

Study Colombel et al [34] x M. Colombel, L. Poissonnier, X. Martin, A. Gelet. Clinical results of the prostate HIFU project. Eur Urol Suppl. 2006;5:491-494 Abstract, Full-text, PDF, Crossref. Gelet et al [36] x A. Gelet, J.Y. Chapelon, L. Poissonnier, et al. Local recurrence of prostate cancer after external beam radiotherapy: early experience of salvage therapy using high-intensity focused ultrasonography. Urology. 2004;63:625-629 Crossref. Gelet et al [35] x A. Gelet, J.Y. Chapelon, R. Bouvier, et al. Transrectal high-intensity focused ultrasound: minimally invasive therapy of localized prostate cancer [published correction appears in J Endourol 2000;14:697]. J Endourol. 2000;14:519-528 Crossref.
Country FR FR FR
Patients, No. 71 71 82
Patients, age, yr NA Ø 67 ± 6 Ø 71 ± 6
Tumour stage Local recurrence Local recurrence (T1–T3) T1–T2
Primary treatment EBRT EBRT EBRT
Neoadjuvant ADT, % of pts NA 30 9
TURP prior to/combined with HIFU, % of pts NA NA NA
Follow-up, mo (range) Ø 15 Ø 15 (6–86) Ø 18

ADT = androgen-deprivation therapy; EBRT = external-beam radiation therapy; FR = France; HIFU = high-intensity focussed ultrasound; NA = not available; Ø = mean plus or minus standard deviation; pts = patients; TURP = transurethral resection of the prostate.

References in context

Table 6 Evidence profile: salvage high-intensity focussed ultrasound

No. of studies/patients Study design Methodological quality Consistency of results Directness of evidence Magnitude of effect, % Other modifying factors1 Level of evidence
Outcome: biochemical disease-free survival rate
No evidence

Outcome: negative biopsy rate
3/224 Observational, case series Serious limitations2 (−1) Important inconsistency Direct 80 at 15 mo, 78–80 (point in time not specified) Publication bias likely; lack of precise data Very low
Outcome: overall survival rate
No evidence

Outcome: prostate-cancer specific survival rate
No evidence

Outcome: adverse events urinary tract3
1/82–3/2244 Observational, case series Serious limitations2 (−1) Important inconsistency Direct 1–35 Publication bias likely Very low
Outcome: adverse events potency5
1/82 Observational, case series Serious limitations2 (−1) Only one trial Direct 77 Publication bias likely Very low
Outcome: adverse events rectum6
3/224 Observational, case series Serious limitations2 (−1) No important inconsistency Direct 1–6 Publication bias likely Very low
Outcome: pain
1/82 Observational, case series Serious limitations2 (−1) Only one trial Direct 1 Publication bias likely Very low
Outcome: IEFF (30-point scale)
No evidence

Outcome: IPSS (35-point scale)
No evidence

Outcome: IPSS-Quality of Life (6-point scale)
No evidence

IEFF = International Index of Erectile Function; IPSS = International Prostate Symptom Score.

1 Low incidence, lack of precise data, strong or very strong association, high risk of publication bias, dose-efficacy gradient, residual confounding plausible.

2 All observational studies have been downgraded from low quality to very low quality because of case series with lack of control group; further factors lowering the quality of evidence apply, such as the likely occurrence of publication bias.

3 Adverse events urinary tract: bladder neck/urethral stricture/stenosis, prolonged urinary retention, urinary tract infection, urinary incontinence.

4 Not all adverse events concerning urinary tract were assessed in all studies.

5 Adverse events potency: impotence/erectile dysfunction.

6 Adverse events rectum: rectourethral fistula.

References in context

  • Table 6 shows the evidence profile of Ablatherm HIFU in the salvage setting in prostate cancer.
    Go to context

Table 7 Sonablate high-intensity focussed ultrasound: primary therapy

Study Ahmed et al [17] x Ahmed HU, Zacharakis E, Dudderidge T, et al. High-intensity-focused ultrasound in the treatment of primary prostate cancer: the first UK series. Br J Cancer 2009 7;101:19–26. Mearini et al [25] x L. Mearini, L. D’Urso, D. Collura, et al. Visually directed transrectal high intensity focused ultrasound for the treatment of prostate cancer: a preliminary report on the Italian experience. J Urol. 2009;181:105-111 discussion 111–2 Uchida et al [32] x T. Uchida, S. Shoji, M. Nakano, et al. Transrectal high-intensity focused ultrasound for the treatment of localized prostate cancer: eight-year experience. Int J Urol. 2009;16:881-886 Crossref. Muto et al [26] x S. Muto, T. Yoshii, K. Saito, et al. Focal therapy with high-intensity-focused ultrasound in the treatment of localized prostate cancer. Jpn J Clin Oncol. 2008;38:192-199 Crossref. Uchida et al [31] x T. Uchida, H. Ohkusa, H. Yamashita, et al. Five years experience of transrectal high-intensity focused ultrasound using the Sonablate device in the treatment of localized prostate cancer. Int J Urol. 2006;13:228-233 Crossref. Uchida et al [30] x T. Uchida, H. Ohkusa, Y. Nagata, et al. Treatment of localized prostate cancer using high-intensity focused ultrasound. BJU Int. 2006;97:56-61 Crossref. Uchida et al [29] x T. Uchida, S. Baba, A. Irie, et al. Transrectal high-intensity focused ultrasound in the treatment of localized prostate cancer: a multicenter study. Hinyokika Kiyo. 2005;51:651-658
Country GB: 2 centres IT: 2 centres JP JP JP JP JP: multicentre
Patients, No. 172 163 517 70 (A: full ablation 41; B: focal ablation 29) 181 63 72
Patients, age Ø 64 ± 8 (47–88) M (IQR): 72 (68–75) M: 68 (45–88) M: 72 (61–80) M: 70 (45–88) M: 71 (45–87) M: 72 (45–79)
Tumour stage ≤T1c–T3bN0M0 T1c–T3aN0M0 T1c–T3N0M0 T1c–T2N0M0 T1c–T2bN0M0 T1c–T2bN0M0 T1c–T2bN0M0
Neoadjuvant ADT, % of pts 29 0 66 34 52 0 0
TURP prior to/combined with HIFU, % of pts 0 0 NA NA NA 0 NA
Follow-up, mo. (range) Ø 12 ± 8 (5–25) M: 24 (12–41) M: 24 (2–88) M: 34 (8–45) M: 18 (4–68) M: 22 (3–63) M: 14 (2–24)

ADT = androgen-deprivation therapy; GB = United Kingdom; HIFU = high-intensity focussed ultrasound; IQR = interquartile range; IT = Italy; JP = Japan; M = median; NA = not available; pts = patients; Ø = mean plus or minus standard deviation; TURP = transurethral resection of the prostate.

References in context

  • As shown in Table 7, between 63 and 517 patients were treated with Sonablate HIFU who were recruited consecutively in four case series [25,29,30,32].
    Go to context

Table 8 Evidence profile of Sonablate high-intensity focussed ultrasound

No. of studies/patients Study design Methodological quality Consistency of results Directness of evidence Magnitude of effect, % Other modifying factors1 Level of evidence
Outcome: biochemical disease-free survival rate
6/1066 Observational, case series Serious limitations2 (−1) Important inconsistency 78–84 at 1 yr, 0–91 at 2 yr, 20– 6 at 3 yr, 45– 4 at 5 yr Publication bias likely Very low
Outcome: negative biopsy rate
5/885 Observational, case series Serious limitations2 (−1) Important inconsistency 19–89 at 6 mo, 77–84 at 12 mo Publication bias likely Very low
Outcome: overall survival rate
No evidence

Outcome: prostate-cancer specific survival rate
No evidence

Outcome: adverse events urinary tract3
2/242–7/12384 Observational, case series Serious limitations2 (−1) Important inconsistency Direct 1–30 Publication bias likely Very low
Outcome: adverse events potency5
4/833–5/10056 Observational, case series Serious limitations2 (−1) Important inconsistency Direct 1–39 Publication bias likely Very low
Outcome: adverse events rectum7
1/72–5/10968 Observational, case series Serious limitations2 (−1) No important inconsistency Direct 0–2 Publication bias likely Very low
Outcome: pain
No evidence

Outcome: IEFF (30-point scale)
1/172 Observational, case series Serious limitations2 (−1) Only one trial Direct Worsened by 6 points (baseline vs 12 mo post HIFU) No Very low
Outcome: IPSS (35-point scale)
4/671 Observational, case series Serious limitations2 (−1) No important inconsistency Direct Changed by ± 1 point (baseline vs 12 mo post HIFU) Publication bias likely Very low
Outcome: IPSS-Quality of Life (6-point scale)
No evidence

HIFU = high-intensity focussed ultrasound; IEFF = International Index of Erectile Function; IPSS = International Prostate Symptom Score.

1 Low incidence, lack of precise data, strong or very strong association, high risk of publication bias, dose-efficacy gradient, residual confounding plausible.

2 All observational studies have been downgraded from low quality to very low quality because of case series with lack of control group; further factors lowering the quality of evidence apply, such as the likely occurrence of publication bias.

3 Adverse events urinary tract: bladder neck/ urethral stricture/ stenosis, prolonged urinary retention, urinary tract infection, urinary incontinence.

4 Not all adverse events concerning urinary tract were assessed in all studies.

5 Adverse events potency: impotence/ erectile dysfunction, retrograde ejaculation.

6 Not all adverse events concerning potency were assessed in all studies.

7 Adverse events rectum: rectal burn, rectourethral fistula, stool incontinence.

8 Not all adverse events concerning rectum were assessed in all studies.

References in context

  • The evidence profile of Sonablate HIFU as a primary treatment option for prostate cancer is shown in Table 8.
    Go to context

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