Oncologic and Functional Outcomes of Partial Gland Ablation

with High Intensity Focused Ultrasound for Localized Prostate

Cancer
Roman Bass,* Neil Fleshner, Antonio Finelli, Jack Barkin,† Liying Zhang
and Laurence Klotz
From the Division of Urology, Sunnybrook Health Sciences Centre, University of Toronto (RB, LZ, LK), Division of Urology,
Princess Margaret Hospital (NF, AF) and Humber River Hospital (JB), Toronto, Ontario, Canada

Purpose: We assessed the outcomes of high intensity focused ultrasound as

Abbreviations
primary treatment of localized prostate cancer in a retrospective series. This
and Acronyms
represents one of the largest published series of patients at intermediate and
high risk. ADT ¼ androgen deprivation
therapy
Materials and Methods: We performed a retrospective multicenter analysis of
GG ¼ Grade Group
patients who underwent partial gland ablation between January 2013 and
September 2017. Patients with biopsy proven localized disease and limited HIFU ¼ high intensity focused
multifocality based on magnetic resonance imaging who preferred minimally ultrasound
invasive outpatient therapy were treated with the SonablateÒ 500 system. LUTS ¼ lower urinary tract
Oncologic and functional outcomes were analyzed as well as risk factors for symptoms
recurrence. mpMRI ¼ multiparametric MRI
Results: A total of 166 procedures were performed in 150 patients. Grade Group MRI ¼ magnetic resonance
2 or greater was present in 89% of cases. Mean
SD followup was 24.3
14.4 imaging
months. Mean prostate specific antigen decreased 65% from 7.9
6.8 ng/ml to a PCa ¼ prostate cancer
nadir of 2.7
3.1 ng/ml. Confirmatory biopsies were performed in 87 patients PGA ¼ partial gland ablation
(52%) at high risk for recurrence. Clinically significant cancer (Grade Group 2 or PSA ¼ prostate specific antigen
greater) was detected in 37 cases (42%). Patients with a higher number of pos-
RFS ¼ recurrence-free survival
itive cores, a medial tumor location or higher prostate specific antigen had a
higher probability of recurrence. Salvage treatment was done in 37 patients RP ¼ radical prostatectomy
(24.6%), including 16 repeat partial gland ablation procedures. SRP ¼ salvage radical
prostatectomy
Conclusions: Partial gland ablation with high intensity focused ultrasound
therapy was safe and it had a minimal impact on functional outcomes. Local XRT ¼ radiotherapy
recurrence and/or failure occurred in 42% of patients at high risk for recurrence.
Medially located tumors were associated with a higher failure rate. Serious
complications were rare. Whole gland treatment was avoided in 81% of patients.

Accepted for publication July 3, 2018.

The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional
review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics
committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with gua-
rantees of confidentiality; IRB approved protocol number; animal approved project number.
No direct or indirect commercial incentive associated with publishing this article.
* Correspondence: Division of Urology, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., #S-120, Toronto,
Ontario, Canada M4N 3M5 (telephone: þ1-647-268-4517; FAX: þ1-416-480-6121; e-mail: bassroman@gmail.com).
† Financial and/or other relationship with Can-Am HIFU.

Editor’s Note: This article is the fourth of 5 published in this issue for which category 1 CME credits
can be earned. Instructions for obtaining credits are given with the questions on pages 190 and
191.

0022-5347/19/2011-0113/0 https://doi.org/10.1016/j.juro.2018.07.040
THE JOURNAL OF UROLOGY®
Ó 2019 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Vol. 201, 113-119, January 2019
Printed in U.S.A.
www.jurology.com j 113

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 114 ABLATION WITH HIGH INTENSITY FOCUSED ULTRASOUND FOR PROSTATE CANCER
Key Words: prostatic neoplasms; high-intensity focused ultrasound ablation; ambulatory care; treatment
outcome; neoplasm recurrence, local
MAGNETIC resonance imaging targeted prostate bi-
opsies have improved the accuracy of diagnosing
clinically significant disease.1e4 The index lesion
concept5 led to the appealing hypothesis that PGA
would provide oncologic control while avoiding the
side effects of definitive whole organ treatment.6,7
Recently focal HIFU, which aims to treat the index
lesion in patients with a solitary focus of significant
cancer, became an alternative to whole gland abla-
tion.8,9 We report the short-term and intermediate
term outcomes of PGA HIFU treatment.
MATERIALS AND METHODS
Patients at 3 medical centers who underwent primary
PGA HIFU from January 2013 to September 2017 at the
Can-Am HIFU clinic in Toronto, Ontario, Canada were
included in study. Inclusion criteria were age greater than
18 years, clinical stage T1c-T2c biopsy proven prostate
cancer, including extensive GG 1 (multiple positive cores
with more than 50% core involvement) or GG 2 or greater
disease, limited multifocality (up to 3 regions of interest
amenable to focal or hemiablation) on mpMRI and the
preference for a minimally invasive, nonradical approach
instead of established treatments such as radical prosta-
tectomy and XRT.
Procedures were done with the SonablateÒ 500 sys-
tem. Most patients received focal or hemiablation and a
few were treated with a hockey stick template covering up
to 75% of the gland. This study was deemed exempt from
International Review Board review.
Study Eligibility
Eligible patients had unilateral cT1-T2b prostate cancer
which was thought to be clinically significant. Patients
with bilateral significant cancer, cT3 disease or greater,
cN1 or Mþ disease were excluded from analysis.
Treatment Description
Cases were staged by biopsy and 3 Tesla mpMRI with an
abdominal array coil prior to the procedure. In the first 2
years of the study MRI was not widely available and 19%
of included patients did not undergo a baseline MRI.
These patients had unilateral significant cancer and
negative contralateral biopsies. After MRI became more
widely available, all patients underwent pretreatment
MRI.
All procedures were performed with the patient under
spinal anesthesia and intravenous sedation. A Foley
catheter was placed to enhance probe positioning and
identify the urethra. Co-registration with the MRI target
was performed cognitively. All known clinically signifi-
cant cancer was treated. The intent was to treat 5 to 10
times the lesion volume as identified on MRI. Treatment
was performed according to a previously described HIFU
technique. A safety margin of 3 mm was left at the apex.
In select cases of apical cancer unilateral therapy was
administered to the margin of the apex.
Copyright © 2019 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
Followup
DRE and PSA measurements were made every 3 months
in year 1 and every 6 months thereafter. Prostate biopsies
were offered to patients 1 year after treatment. Patient
resistance to compliance with followup biopsy was com-
mon in the absence of rising PSA or an indication of re-
sidual disease on MRI. Oncologic and functional outcomes
were collected and analyzed retrospectively.
Statistical Analysis
All patient data were collected in an ExcelÒ spreadsheet.
Continuous variables are expressed as the mean
SD.
Binary and categorical variables are reported as the count
and percent. We used univariate and multivariable Cox
proportional hazard models to search for significant pre-
dictive factors of RFS in PGA HIFU procedures. RFS time
was calculated in months from the date of HIFU to the
date of biopsy in patients with recurrence or to the last
followup date if there was no recurrence. Recurrence was
defined as GG 2 or higher on followup biopsy.
A Kaplan-Meier RFS curve was generated for all PGA
HIFU procedures. Natural log transformation was applied
for some covariates to normalize the distribution. The HR
and the HR 95% CI were calculated for each covariate. All
variables at p <0.10 obtained from univariate analysis
were included in the backward selection procedure to ac-
count for all potential predictive factors. In the final
multivariable model only variables at p <0.05 remained.
All analyses were done with SASÒ, version 9.4 for
WindowsÒ and R, version 3.5.0 (https://www.r-project.
org/). Statistical significance was considered at p <0.05.
RESULTS
A total of 150 patients underwent PGA HIFU of
localized prostate cancer as primary definitive
treatment between January 2013 and September
2017. Mean patient age at therapy was 64.9
7.5
years and median baseline PSA was 6.8 ng/ml (IQR
4.4e9.1). GG 2 or greater disease was present in 145
cases (89%).
Table 1 lists demographics and preoperative
data. A total of 134 patients (81%) underwent
mpMRI prior to PGA HIFU or diagnostic biopsy,
which included MRI targeted biopsies in 57 (34%)
(table 2). In 28% of cases the tumor location could
not be identified retrospectively. Table 3 lists base-
line functional characteristics.
To assess the treatment extent the prostate was
divided into 12 zones, including the anterior and
posterior base, the anterior and posterior mid gland
and the anterior and posterior apex for each lobe. A
total of 166 PGA HIFU procedures were performed
in 150 patients. Despite the small volume of cancer
(mean 1 cc) the treatment volume was approxi-
mately a third of the prostate volume. A mean of
 ABLATION WITH HIGH INTENSITY FOCUSED ULTRASOUND FOR PROSTATE CANCER 115

Table 1. Demographics and preoperative data Followup MRI data were available on 114 pa-
No. procedures 166 tients. Mean time from the procedure to followup
Age at treatment: MRI was 12.1
9 months. A positive MRI scan,
Mean
SD (range) 65.2
7.5 (45e80) defined as a PI-RADSÔ (Prostate Imaging Reporting
Median (IQR) 65.0 (60e71)
No. T stage (%): and Data System) score of 3 or greater, was identi-
T1c 132 (80) fied in 64 patients (56.1%). Lesions with a PI-RADS
T2 or greater 27 (16) score of 3, 4 and 5 were noted in 16 (25%), 28
Unknown 7 (4.2)
Baseline PSA (ng/ml): (43.7%) and 20 patients (31.3%), respectively.
Mean
SD (range) 7.7
6.8 (0.7e66) Of the 166 PGA HIFU procedures 87 (52.4%)
Median (IQR) 6.4 (4.2e9) were followed by confirmatory biopsy with a mean of
No. Gleason score sum (%):
6 19 (11.5) 14.8
7.6 months from treatment to biopsy. MRI
7 132 (79.6) targeted biopsies were performed in 36.9% of cases.
8 12 (7.2) Of the 87 confirmatory biopsies performed clinically
9 1 (0.6)
Unknown 2 (1.2) significant cancer, defined as GG greater than 1,
No. Gleason score pattern (%): was found in 37 cases (42.5%). The positive biopsy
3þ3 19 (11.5) was found in the treated area in 19 cases (51.3%). Of
3þ4 89 (53.6)
4þ3 43 (25.9) the 114 patients who underwent followup MRI 50
4þ4 12 (7.2) (43.8%) had negative MRI results, of whom 22 un-
4þ5 1 (0.6) derwent biopsy. Only 4 of those patients (8%) had
Unknown 2 (1.2)
No. diagnostic biopsy (%): clinically significant disease (table 4 and supple-
Systematic 107 (64.5) mentary table 1, http://jurology.com/).
Systematic þ targeted 26 (15.7) In the MRI negative/no biopsy cohort of 25 men
Targeted 31 (18.7)
Unknown 2 (1.2) mean PSA at the last followup visit was 2.3 ng/ml.
No. highest Gleason score pos cores: In this subgroup the mean nadir PSA was 1.4 ng/
Mean
SD (range) 2.5
1.7 (1e8) ml. In contrast, in the MRI negative, biopsy posi-
Median (IQR) 2 (1.0e4.0)
Overall No. pos cores: tive cohort of 14 patients mean PSA at the last visit
Mean
SD (range) 3.5
2.1 (1e12) was 4.6 ng/ml and the mean PSA nadir was 3.0 ng/ml.
Median (IQR) 3 (2e5) Overall favorable oncologic outcomes were achieved
in 97 of the 144 patients (67.4%) in whom followup
was based on regular digital rectal examination, PSA
4.8
1.4 zones were treated. Of the procedures 58 measurement, and/or MRI and/or confirmatory bi-
(31.9%) were unilateral hemiablation. opsy. Actuarial median RFS was 16 months (95% CI
Mean followup was 24.3
14.4 months. Mean 14e36) (fig 1).
PSA decreased 65.1% from 7.9
6.8 ng/ml before We constructed a univariate Cox proportional
treatment to a nadir of 2.7
3.1 ng/ml. The mean hazard model (supplementary table 2, http://jurol-
time from PGA HIFU to PSA nadir was 7.3
6.2 ogy.com/). Nine predictive variables were signifi-
months. Mean PSA at last followup was 4.2
4.0 cantly related to RFS. Patients with more positive
ng/ml, which was a mean 47% PSA decrease cores, bilateral, a mid gland or medial tumor loca-
compared to baseline. tion, larger lesions, or a higher PSA nadir or latest
value showed a higher probability of recurrence.
Those with lateral tumor locations had a lower prob-
Table 2. Followup biopsy results
ability of recurrence compared to those with medial
No. pts 87 locations. On multivariable analysis the proced-
HIFUdbiopsy interval (mos):
Mean
SD (range) 14.8
7.6 (6e40) ures with more positive cores (HR 1.46, p ¼ 0.010),
Median (IQR) 13 (10e16.9) a medial tumor location (HR 2.68, p ¼ 0.043) or
No. Gleason score pathology (%): higher PSA (HR 2.51, p ¼ 0.002) demonstrated a
3þ3 24 (27.6)
3þ4 23 (26.4) probability of recurrence (supplementary table 3,
4þ3 9 (10.3) http://jurology.com/, and fig. 2).
4þ4 4 (4.6)
4þ5 1 (0.7)
Neg 26 (29.9) Salvage Treatment
No. residual/recurrent prostate Ca (%): 61 (70.5) Of the 150 patients who underwent PGA HIFU 37
Not clinically significant 24 (39.3) (24.6%) proceeded through salvage treatment,
Gleason 7 or greater 37 (60.6)
No. recurrence area (%):* including repeat PGA HIFU in 16, salvage XRT in 6,
Out of field 16 (43.2) salvage ADT in 2 and salvage RP in 12. Of the 16
In field 19 (51.3) patients who underwent repeat PGA HIFU due to
Unknown 2 (5.4)
residual or recurrent disease 9 (56%) had GG 2
* In 37 patients with clinically significant prostate cancer. prostate cancer on confirmatory biopsy after the

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 116 ABLATION WITH HIGH INTENSITY FOCUSED ULTRASOUND FOR PROSTATE CANCER

Table 3. Multivariate Cox proportional hazard model of recurrence predictors (R2 ¼ 44.9%)
Final Multivariable Model Coefficient
SE p Value HR (95% CI)
Overall No. Gleason score pos cores 0.38111
0.14718 0.0096 1.464 (1.097e1.953)
Medial tumor location (yes vs no) 0.98693
0.48748 0.0429 2.683 (1.032e6.975)
Latest log PSA 0.91815
0.30278 0.0024 2.505 (1.384e4.534)

first PGA HIFU treatment, 5 (31.2%) had GG 3
disease and 1 (6.2%) had GG 4 cancer. Eight of the
16 patients (50%) patients had a positive lesion on
followup MRI after salvage HIFU, 4 (25%) had a
negative MRI and 4 (25%) had no known MRI re-
sults. Information on post second PGA HIFU fol-
lowup biopsies was available in 5 patients, including
2 with negative biopsies and 3 with GG 2 or greater
cancer.
SRP was performed in 12 men. No perioperative
complications were reported except 1 case of intra-
operative bladder neck reconstruction due to locally
advanced disease. Final pathology revealed stage
pT3 in 7 cases. Positive surgical margins were pre-
sent in 25% of the final pathology specimens, all in
cases of stage pT3 disease. Nine patients (75%)
treated with SRP had undetectable PSA at last fol-
lowup with an overall mean PSA of 0.09 ng/ml in all
12 who underwent SRP.
At a median followup of 9.6 months (range 3 to
27) full continence was achieved in 7 of the 12 pa-
tients (58%) while 5 more recent patients still
needed 1 pad per day. Mean PSA in the salvage
XRT/ADT cohort was 0.8 ng/ml at the last visit.
Patients in the salvage RP and XRT/ADT subgroups
showed a durable response to salvage therapy with
no evidence of disease progression, although this
was at short-term followup. Overall whole gland
treatment was avoided in 111 of the 137 patients
who were receiving regular followup (81%).
reported improved LUTS after treatment (supple-
mentary table 4, http://jurology.com/).
Safety and Side Effects
No intraoperative complications were reported.
Data on treatment side effects were available for
153 of the 166 PGA HIFU procedures. A total of 51
adverse events (33.3%) were documented in 39 pa-
tients. Grade I complications based on the Clavien-
Dindo classification were reported in 35 cases
(22.9%) after PGA HIFU. The most common grade I
complication was acute urinary retention in 20 pa-
tients (13.1%) (supplementary table 5, http://jurol-
ogy.com/). A total of 12 patients (7.8%) experienced
grade II complications and 4 (2.6%) underwent
surgical intervention and were classified with a
grade III complication.
In 4 men (2.6%) a urethrorectal fistula developed
after PGA HIFU therapy. Mean time to fistula
development was 5.5
1.9 weeks. All patients were
treated successfully with an indwelling Foley cath-
eter for a mean of 5.5 weeks (range 3 to 8). No pa-
tient with a fistula required surgical intervention.
Three patients were in year 1 of therapy. The
remaining patient was receiving salvage treatment.
The PGA therapy technique was altered after this
initial experience to increase the cooling time be-
tween treatment pulses in the mid zone. Since
making that technical alteration, no further fistulas
have developed.

DISCUSSION
Functional Outcomes
PGA HIFU therapy, which addresses the gap be-
During followup no change in continence, LUTS and
tween active surveillance and whole gland therapy,
erectile dysfunction was reported by 94.9%, 84.1%
usually focuses on patients with intermediate risk,
and 86.5% of patients, respectively. Six men (4.3%)
clinically localized prostate cancer and aims to
achieve a higher rate of the trifecta (cancer control,
Table 4. Functional outcomes erectile function preservation and continence) as
No. Pts (%) traditional therapy.10e13 In this study 89% of pa-
tients had GG 2 or greater disease. This distin-
Continence:
No change 131 (94.9) guishes our series from most known PGA HIFU
Insignificant deterioration 5 (3.6) published studies, in which the proportion of pa-
Significant deterioration 2 (1.4) tients with Gleason score 6 has ranged from 32% to
Lower urinary tract symptoms:
No changes 116 (84.1) 86.6%.7,14e20
Mild deterioration 10 (7.2) We support routine post-HIFU biopsy. While
Significant deterioration 6 (4.3) routine posttreatment biopsy was promoted, pa-
Symptom improvement 6 (4.3)
Erectile dysfunction: tients with an excellent biochemical response with
No change 115 (86.5) MRI indicating complete resolution of cancer tended
Mild deterioration 15 (11.3) to resist undergoing this biopsy. Thus, patients who
Significant deterioration 3 (2.2)
underwent posttreatment biopsy in our study were

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 ABLATION WITH HIGH INTENSITY FOCUSED ULTRASOUND FOR PROSTATE CANCER 117

Figure 1. Kaplan-Meier RFS curve

at higher risk for recurrence (eg higher PSA or
positive MRI). Of those patients at high risk for
recurrence 57.5% were clear of significant cancer at
the followup biopsy. Multivariable Cox analysis
showed that patients with more positive cores at the
initial biopsy (HR 1.46, p ¼ 0.01), those with a
medial tumor location (HR 2.68, p ¼ 0.043) and
those with higher PSA during followup (HR 2.51,
p ¼ 0.002) were at increased risk for recurrence.
The observation that medial tumors were more
likely to recur probably reflects well-meaning efforts
to spare the urethra during PGA HIFU.
The recurrence rate of significant cancer was
24.6%, which is relatively high. Many reasons may
explain this finding, including patient selection,
limitations of the Sonoblate technology, the learning

Figure 2. Kaplan-Meier RFS curves by procedure with or without medial tumor location (log rank test p ¼ 0.0320). Solid curve represents
not medial tumor location. Dashed curve represents medial tumor location.

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 118 ABLATION WITH HIGH INTENSITY FOCUSED ULTRASOUND FOR PROSTATE CANCER

curve of matching the extent of therapy to the
extent of disease and other parameters which are
difficult to quantify.
Significant cancer outside the treatment zone
was found in 16 patients (11%). This may reflect the
identification of cancer which was not identified on
pretreatment MRI or else disease progression in the
untreated prostate.
Of the patients 80% were at intermediate risk
(GG 2 or 3), 12 (8%) had GG 4 disease and 1 had GG
5 disease. Although they were at high risk, these
patients had a small volume of high grade disease
on biopsy and solitary lesions less than 1.5 cm on
MRI. They actively sought minimally invasive
intervention and were aware that this approach
was less likely to be successful than surgery or
radiation. We acknowledge that PGA carries a
significant risk of under treatment in these men at
high risk.
The positive surgical margin rate was 25% in our
salvage prostatectomy series. This is comparable to
the 15% overall positive surgical margin rate of
primary surgery and specifically in pT3 stage cases
it was reported to be up to 37%.21 Patients in the
salvage RP and XRT/ADT subgroups showed a du-
rable response to salvage therapy with no evidence
of disease progression or spread.
LUTS and erectile dysfunction rates were
reportedly unchanged after PGA HIFU in 84% and
86% of patients, respectively. These values compare
favorably to patient reported outcomes after surgery
or radiation.
The rate of adverse effects and complications was
substantially lower than that associated with whole
gland HIFU.10,11,13 In our series most complications
were Clavien-Dindo grade I. Only 2.6% of patients
required surgical intervention. Our main concern
was related to the development of urethrorectal
fistulas in year 1 of PGA HIFU implementation.
Four patients (2.6%) experienced a transient pros-
tate rectal fistula related to the early technique. All
patients responded successfully to catheter
drainage. Since changing the technique to decrease
the temporal intensity of treatment, no fistulas have
developed.
There are a number of limitations to the current
study. It was a retrospective study with no control
arm and limited followup. Low patient motivation to
comply with followup biopsy was common in those
with dramatic PSA response and/or negative MRI.
Of the patients 19% did not undergo pretreatment
MRI, reflecting limited access to prostate MRI in
Canada during the first few years that this treat-
ment was offered. The cohort was heterogeneous in
terms of the initial diagnostic strategy and followup.
CONCLUSIONS
PGA HIFU for localized prostate cancer is safe with
a minimal long-term effect on quality of life.
Persistent, clinically significant cancer was identi-
fied on biopsy in 42% of patients, of whom most had
clinical features associated with a higher risk of
recurrence. Failure was more common in cases of
medial lesions, likely due to urethral sparing stra-
tegies. Whole gland treatment was avoided in 81%
of patients. Complications beyond Clavien-Dindo
grade 2 were rare.

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EDITORIAL COMMENT

The authors describe a solid experience with HIFU the cohort. They offered salvage treatment with
deployed to treat localized PCa. It features a rather HIFU, XRT/ADT or surgery with these patients
detailed presentation of outcomes with the tech- showing adequate results with no evidence of dis-
nique applied for PGA, one of the most dynamic ease progression.
fields in localized PCa therapy.1 Beyond cohort After PGA one should be able to safely identify
heterogeneity, and the selection and followup limi- recurrence to provide radical cancer control if
tations acknowledged by the investigators 2 as- needed.3 This information is motivating to further
pects are of the utmost importance. First, most refine current experiences with PGA on accurate
treated patients had intermediate and high risk selection (with genetic information), treatment
PCa with close to 80% harboring Gleason 7 disease (hopefully with actions taken in the prostatic
(most of the initial PGA series treated low risk microenvironment), and solid imaging and biopsy
PCa). Although a rather high recurrence rate of based followup.
greater than 40% is described, 81% of patients
avoided whole gland treatment. The latter is an
Xavier Cathelineau and Rafael Sanchez-Salas
essential and unique characteristic of PGA: to
Department of Urology
control disease and rationalize therapy aiming for L’Institut Mutualiste Montsouris
the so-called trifecta.2 Second, the authors provide  Paris Descartes
Universite
interesting information on salvage treatment in Paris, France

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