Current Findings on High Intensity Focused Ultrasound (HIFU) Thomas J Polascik, MD, FACS Professor of Surgery

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1 Current Findings on High Intensity Focused Ultrasound (HIFU) Thomas J Polascik, MD, FACS Professor of Surgery

2 Outline Whole gland abla6on selec6on and outcomes Focal abla6on - Eligibility and pa6ent selec6on Outcomes Salvage HIFU Oncological outcomes Predictors of success Func6onal outcomes

3 General SelecEon Criteria Gland volume < 40cc ADT, TUR? Minimal calcifica6ons Anterior vs posterior lesions Volume of 6ssue ablated Post- treatment FU PSA, imaging, biopsy

4 Whole Gland - PaEent CharacterisEcs Author # patients Age PSA Volume (ml) Stage GS Gland Downsizing Thuroff (2013) 704 Mean: 68 Mean: 10 Mean: 22 T1: 12% T2: 89% 6-67% 7 28% 8 5% ADT: 30% TUR: 75% Ganzer (2013) 538 Mean: 68 Mean: 11 Mean: 21 T1: 41% T2: 55% T3: 4% 6-75% 7 16% 8 8% **1.3% - unk ADT: 36% TUR: NR Crouzet (2013) 1,002 Median: 71 Median: 7.7 Median: 23 T1: 52% T2: 45% T3: 3% 6-55% 7 35% 8 8% **1.5% - ukn ADT: 39% TUR: 94% Uchida (2015) 918 Median: 68 Median: 8.6 Median: 22 T1: 61% T2: 36% T3: 4% 6 49% 7 37% 8 14% ADT: 59% TUR: 15% Dickinson (2016) 569 Median: 65 Median: 7 Mean: 40 T1: 29% T2: 55% T3: 15% 6-52% ADT: 13% 7 Dr. Thomas 43% Polascik TUR: 21% 8 4% **1.2%-ukn

5 Whole Gland Cancer Outcomes Author FU (yrs) PSA Nadir (ng/ ml) bdfs Biopsy Survival Thuroff (2013) Mean 5.3 Mean: years: 84-92% 10 years: 60-68% NR At 10 years: CSS: 99% Ganzer (2013) Mean 8.1 Mean: years: 81% 10 years: 61% 76/297 (26%) OS: 86% CSS: 97% Crouzet (2013) Median 6.4 Median: years: Low risk: 76% Int. risk: 63% High risk: 57% 289/774 (37%) At 10 years: OS: 80% CSS: 97% Uchida (2015) Median 6.5 NR 5 years: 57% 10 years: 49% 96/758 (12.7%) At 10 years: OS: 88.6% DSS: 97% Dickinson (2016) Median 3.6 Median: years: Low risk: 87% Int. risk: 63% High risk: 58% 85/180 (47%) At 5 years: OS: 95%

6 Whole Gland FuncEonal Outcomes Author Erectile function (%potent) Continence Complications Thuroff (2013) In previously potent: 55% >3 months incontinence: 3% Total: 16% (UTI, BOO, fistula, BNC) Ganzer (2013) In previously potent: 25% Incontinence: Grade 1: 14% Grade 2: 2% Grade 3: 0.7% UTI: 10% Fistula: 0.7% BOO: 28% Crouzet (2013) In those with IIEF-5 17: 42% Incontinence: Grade 1: 19% Grade 2/3: 5% UTI: 4% Fistula: 0.4% BOO: 17% Stenosis: 9% Uchida (2015) In IIEF-5 <8: 6 months: 58% 12 months: 51% 24 months: 35% Incontinence: 2.3% Stricture: 20% Epididymitis: 6% Fistula: 0.1% Dickinson (2016) In previously potent: 39% Incontinence in those who were pad free: 12% Dr. UTI: Thomas 8% Polascik Epididymo-orchitis: 3% Fistula: 0.13%

7 Primary Focal AblaEon- PaEent SelecEon Eligibility Low risk: If pa6ent does not wish to go on AS Intermediate risk - Comprehensive staging is necessary Biomarkers Bx Imaging High risk: If metasta6c evalua6on is nega6ve * Donaldson IA, Alonzi R, BarraY D, et al. Focal therapy: pa6ents, interven6ons, and outcomes- - a report from a consensus mee6ng. Eur Urol. 2015;67(4):771-7.

8 Primary Focal AblaEon- PaEent SelecEon Means for pa6ent selec6on: mpmri * : Ideal : 3T If 1.5 T endorectal coil is essential Minimum sequences: T1, T2, DCE and DWI Experienced, specialized radiologist should report results No consensus on MRI being an alternative for saturation biopsies TTMB ** : In men with +Bx and - mpmri *Muller BG, van den Bos W, Brausi M, et al. Role of mul6parametric magne6c resonance imaging (MRI) in focal therapy for prostate cancer: a Delphi consensus project. BJU Int. 2014;114(5): **Crawford ED, Rove KO, Barqawi AB, et al. Clinical- pathologic correla6on between transperineal mapping biopsies of the prostate and three- dimensional reconstruc6on of prostatectomy specimens. Prostate. 2013;73(7):

9 mpmri and PaEent SelecEon The preferred tool for: Diagnosis Planning FU The downside * : mpmri underes6mates the true border of prostate cancer by 0.5 cm 2 Overall sensi6vity of only 47% US Food and Drug Administra6on (FDA). Public Workshop AUA- FDA- SUO Workshop on Par6al Gland Abla6on for Prostate Cancer, May 17, FDA website.

10 Author Patients Inclusion Criteria Staging SelecEon Barret ( ) 21 Unilateral 3 + cores GG 6 PSA <10 ct2a TVS Bx for focal HIFU in recent Van Velthoven ( ) 50 Ahmed ( ) 56 Unilateral, prostate <40cm 3 Any GG PSA < 15 ct2 Life expectancy at least 5 years Index and secondary lesion GG 4+3 PSA 20 T3a mpmri mpmri; TTMB or TRUS series: Chapelon ( ) 10 Monofocal NR Feijoo ( ) 67 Rischmann ( ) 111 Unilaterial <33% + bx GG 3+4 PSA <15 ct2a Unilateral 2 adjacent sextants Gleason 3+4 T2 mpmri mpmri

11 Primary Focal AblaEon - Outcomes Author FU duration (months) PSA nadir Bx recurrence Preserved Erectile function Continence Complications Barret ( ) Median: 9 (6-15) Median: 3.1 NR NR (med IIEF5 14) 100% AUR: 5 Van Velthoven ( ) Mean: 40 Mean: 0.9 6/8 (1 ipsilateral, 2 bilateral, 1 contralateral) 80% 94% UTI: 3 AUR: 4 Stricture: 2 Ahmed ( ) 12 Median: /52 (treated side -18) 77% Only pad free: 92% Pad and leak free: 88% Dysuria: 9 Hematuria: 36 UTI: 10 Fistula: 1 TURP: 1 TURBN: 2 Chapelon ( ) NR Mean: 3.5 0/10 80% 100% NR Feijoo ( ) Median: 12 Median: /67 (treated side - 11) 52% 100% UTI: 4 AUR: 4 TURP: 2 Rischmann ( ) Mean: 30 Mean: /101 (treated side- 12; 5 clinically significant) 78% 97% UTI: 18 Hematuria: 5 AUR: 5 Stricture: 1 TURP: 3

12 HIFU cohort: N = 55 Unilateral disease mpmri and mpmri -TRUS fusion RALP: pt2a Outcomes: No significant difference in salvage therapy free survival Better functional outcomes with HIFU

13 Salvage HIFU AblaEon Author Oncological control Continence Complications Murat (2009) PFS at 3 yrs: Low risk 53% Int. risk 42% High risk 25% 52% continent Artificial urinary sphincter 11% Ahmed (2012) bdfs at 3 yrs: 63% Pad and leak free 64% Pad free only 87% Fistula - 1 Baco (2014) PFS at 24 m 52% Pad free 75% Delayed pubic bone osteitis 2 (pubovesical fistula -1)

14 N=418 Mean FU 3.5 yrs Mean Pre- PSA 6.8 Mean PSA nadir 0.19ng/ml At 7 years: OSS 72% CSS 82% MFS 81% Salvage HIFU AblaEon Crouzet S, Blana A, Murat FJ, et al. Salvage high- intensity focused ultrasound (HIFU) for locally recurrent prostate cancer aner failed radia6on therapy: Mul6- ins6tu6onal analysis of 418 pa6ents. BJU Int. 2017

15 Factors associated with salvage HIFU failure and recurrence: History of ADT Pre- salvage GS Pre- salvage PSA Crouzet S, Blana A, Murat FJ, et al. Salvage high- intensity focused ultrasound (HIFU) for locally recurrent prostate cancer aner failed radia6on therapy: Mul6- ins6tu6onal analysis of 418 pa6ents. BJU Int. 2017

16 N=50 Biochemical failure 70% Metastasis - 24% Progression in 76% PFS: o 1 year 72% o 3 year 40% o 5 year 31% OS at 5 years 87% Post opera6ve PSA nadir was the only significant predictor for PFS or OS Salvage HIFU AblaEon Shah TT, Peters M, Kanthabalan A, et al. PSA nadir as a predic6ve factor for biochemical disease- free survival and overall survival following whole- gland salvage HIFU following radiotherapy failure. Prostate Cancer Prosta6c Dis. 2016;19(3):311-6.

17 Salvage HIFU AblaEon N= 81 Prospec6ve Mean FU 53 mos PSA nadir - <0.5 ng/ml OS 88% CSS 94%

18 Salvage HIFU FuncEonal Outcomes and ComplicaEons (Recent Series) Author Erectile function Incontinence Complications Shah et al (2016) Non significant median 3 point decrease in IIEF-5 score 31% Fistula 6% Osteonecrosis (pubic symphysis) 6% Bladder neck incision for BOO 54% Siddiqui et al (2016) IIEF-5 decreased from baseline Severe 3.7% Clavien 1 83% Clavien 2 8.6% Fistula 3.7% Crouzet (2017)* NR Grade II/III from 32% to 19% Artificial urinary sphincter from 15 to 5% BOO/stenosis 30 to 15% Urethro-rectal fistula from 9 to 0.6% * Reduc6on in incon6nence and complica6on rate following the introduc6on of specific post radia6on parameters

19 Whole gland : Summary Good CSS but high post- HIFU posi6ve biopsy rate High rates bladder neck contracture that require interven6on Focal abla6on: mpmri necessary for treatment planning and FU Short and mid term outcomes seem promising Longer FU and prospec6ve trials are necessary Salvage abla6on: PSA nadir associated with brfs and PFS: Techniques to minimize side effects needed