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348
J. Fainberg et al.
from the heart obviates any detrimental effect the
electricity may have on cardiac conduction. Once
the probes are placed and conrmed in the appropriate position, test pulses are conducted between
all active electrode pairs, and voltage is altered to
achieve an ideal current during the course of the
ablation—signaling that the energy levels are sufcient for cellular permeability- induced apoptosis. It is typical to see slight changes in tissue
conduction between probe pairs as the treatment
effect from cellular disruption can increase electrical conduction in the tissues and reduce the
measured resistance between electrodes.
The number, duration, and voltage of the pulses
red during an ablation are all factors that affect
how the ablation zone forms and functions. It is
evident in animal models that increasing the voltage increases the length and volume of the ablation
zone in a linear fashion [16]. Additionally, the
higher the number of pulses, the larger the ablation
zone, but the linear effect of pulse number appears
to dissipate above a certain number of pulses
(~200). As expected, longer needle exposures also
lead to larger ablation zones. Additionally, the distance between the electrodes can inuence the thermal effects achieved, with longer distances between
electrodes correlating with more thermal damage
during ablation. Contrarily, if there is a pause
between pulses, the thermal energy released is less
than that when there is no pause between the pulses.
After 10 or 20 test pulses are performed and currents are within accepted limits, a sequence of 80 or
90 pulses is performed between each probe pair.
Adjustments in voltage between probe pairs may
be necessary following test pulse sequences, which
may add to the number of test pulse sequences.
Clinical Trial Results forIRE
Initial in-human studies on IRE were designed to
demonstrate safety and efcacy [17]. These initial studies were “treat and resect”—patients
were treated with IRE and proceeded to prostatectomy. Histological analysis showed no residual tumor within the ablation zone and a crisp
demarcation between ablated tissue and normal
prostate glandular tissue [18].
Subsequent phase I and phase II studies demonstrated the safety, feasibility, and efcacy of IRE in
the focal treatment of prostate cancer. One study
reported on 34 patients treated with focal IRE
across multiple centers, and they reported minimal
AEs, which included hematuria, UTI, dysuria, or
prolonged catheterization. All patients were continent, and 95% of men retained potency when pretreatment was able to achieve a functional erection.
Eighteen percent of patients had residual disease,
2/3 of whom chose salvage treatment and 1/3 of
whom opted for active surveillance [19].
Subsequently, another series of 25 patients
treated with focal IRE for low- to intermediaterisk prostate cancer was reported by
MSKCC.Similarly, 16% of patients had in-eld
residual disease. Only one patient who started
with functional erections lost this ability postIRE and needed PDE5 inhibitors [20].
In the years that followed, multiple studies
reported similar efcacy and safety at short- and
medium-term follow-up intervals. Most recently,
Scheltema etal. published a follow-up series of
229 cases of focal IRE from Australia [15]. They
report a median 5-year follow-up period, making
this the most extensive series with the longest
follow-up to date. The majority (86%) had
intermediate- risk (Gleason Grade Group 2 or 3)
disease and 7% had high-risk (Gleason Grade
Group 4) disease. Seventeen percent of patients
progressed to radical treatment at a median of 35
months post-IRE. Residual prostate cancer was
found in 24% of men during follow-up biopsy.
Continence was preserved in 98% of men, and
13% of men who had erections sufcient for penetration lost this ability posttreatment.
A particular advantage of IRE compared to
other energy sources is its applicability to all areas
of the prostate, including extreme apex and anterior regions. Blazevski etal., for example, evaluated the efcacy of IRE for treating apical PCa.
With a median follow-up of 44 months, 50 patients
with PCa lesions within 3mm of the apical capsule were treated with IRE.Only one patient experienced incontinence 12 months after treatment,
and one had in-eld residual disease on repeat
biopsy. The results suggested that using IRE for
distal apex PCa is safe and feasible [21]. IRE is
29 Irreversible Electroporation forPartial Gland Ablation: Clinical Application andOutcomes
349
also not inuenced by calcication or large vessels
creating a sump effect. Finally, it has a reliable ineld clearance as evidenced by the ablate and
resect trial. The low in-eld positive biopsy rate of
2.7% [22], and the low in-eld recurrence rate in a
recent salvage prostatectomy series [23].
Several series, including a series from
Australia, give support to salvage prostatectomy
when IRE focal therapy has failed [24]. These
data support the theoretical advantage of focal
therapy on oncologic and functional outcomes
versus other primary therapies should salvage
surgery be required. In the RAFT trial by Cathcart
et al. [25], good functional and oncological
results were reported in men who required radical prostatectomy after IRE was unsuccessful in
controlling their clinically signicant prostate
cancer. What is yet to be determined is how IRE
performs when compared to other focal therapy
energy sources. Should salvage prostatectomy be
needed post-ablation? However, these postablation salvage prostatectomy outcomes may
well be established over time.
Another area where IRE is utilized is in the
postradiation setting. Few studies have been conducted regarding focal therapy in this very challenging patient population; however, one recent
study from Australia reports on 37 men with
radio-recurrent prostate cancer treated with focal
IRE [26]. The median follow-up was 29 months,
and all patients had intermediate or high-risk disease. Nineteen percent of men required a secondary procedure to clear urethral sloughing
post-ablation, and at 12 months post-procedure,
93% of men were continent. Erectile function
deteriorated in the majority of men who had erections sufcient for penetration pre-IRE: 35% of
men pre-IRE were potent, and this decreased to
15% 12 months post-ablation. Seventy-eight percent of patients had local control of their disease,
11% developed a local recurrence, and 16% of
men developed metastatic disease with a median
time of 8 months to metastasis. These results
promise the possibility of expanding the indications of IRE to the salvage setting. This was further echoed in a recent review in Nature [27].
In the United States, the largest IRE multicenter trial (PRESERVE) [28] has completed
enrollment, and nalized results are awaited
(2023). This will include functional, biochemical, and MRI data in addition to the primary endpoint of posttreatment biopsy outcomes in all
patients and 5-year follow-up. We will anxiously
await these trial results as IRE seeks to be a routinely used means of focal and partial gland treatment of prostate cancer, much like other energy
sources such as HIFU and Cryoablation. In the
United Kingdom, the Cancer Guidelines (NICE)
have recently accepted IRE and Cryotherapy as
ablation modalities.
Conclusion
Irreversible electroporation is a nonthermal
option for the focal treatment of organ-conned
prostate cancer. It works by irreversibly creating
pores in the cellular membrane of prostate cells,
leading to the spillage of intracellular contents
and induction of apoptosis. Multiple phase I and
II trials have been done internationally, proving
it is safe, well tolerated, effective, and leads to
excellent preservation of urinary and sexual
function. Oncologic outcomes appear comparable to thermal energies (Laser/HIFU/CRYO)
based on the largest IRE series from Australia
that included a biopsy endpoint. It has some particular potential advantages, being applicable to
all types of prostatic tissue and all prostatic locations, less collateral damage, and a possible
immune effect. It is promising for the treatment
of radiorecurrent prostate cancer, but more data
are needed regarding this indication. The largest
Phase II trial in the US has nished enrollment
as of July 2023, and we will await the nal
results.
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ank=5.
Part VIII
Transurethral Technologies for Focal
Therapy
Role ofTransurethral Ultrasound
Ablation (TULSA) inProstate
Cancer Focal Therapy
JosephL.Chin, XiaosongMeng,
andEmilyBochner
30
Introduction oftheTULSA
Technology
Introduction
A minimally invasive ablative technology developed at Sunnybrook Health Sciences Centre
in Toronto (Profound Medical Inc., Toronto,
Canada), known as magnetic resonance imaging (MRI)-guided transurethral ultrasound ablation (TULSA-PRO), was introduced in 2013.
A “closed-loop control system” using real-time
thermal mapping (a standard MRI feature) is a
critical feature of TULSA.In essence, the amount
of energy delivered to a specic slice of tissue is
precisely and instantaneously determined by the
tissue temperature achieved during the procedure.
It integrates quantitative image-based planning,
monitoring, and treatment control with transurethral delivery of therapeutic ultrasound to ablate
prostate tissue through thermal coagulation [1].
The entire procedure is conducted within a
3-T MRI unit (Magnetom Trio, Siemens, Munich,
Germany) with posterior and anterior multichannel phased-array coils. An ultrasound urethral
J. L. Chin
Western University, London, ON, Canada
e-mail: joseph.chin@lhsc.on.ca
X. Meng · E. Bochner (*)
University of Texas Southwestern, Dallas, TX, USA
e-mail: xiaosong.meng@utsouthwestern.edu;
emily.bochner@utsouthwestern.edu
applicator (UA), resembling a 19-F rigid cystoscope with a customized coudé tip, incorporates a
linear array of 10 independent ultrasound transducers that emit directional (planar, not focused)
high-intensity ultrasound energy directly into the
adjacent prostate (Fig. 30.1). In this conguration, the ultrasound beams expose a large volume
of tissue contemporaneously, thereby creating a
continuous region of thermal ablation. Crucial
differences between the TULSA technology and
“high intensity focused ultrasound” (“HIFU”)
include (1) TULSA delivers one large directional,
contiguous plane of ablative energy as opposed
to hundreds of discrete focused ablative “lesions”
by HIFU, (2) the heat energy of TULSA emanates from the urethra towards the prostate,
whereas for HIFU, the heat originates from a
probe in the rectum, aimed towards the prostate
from externally (Fig.30.2), and (3) image guidance is provided by real-time MRI in TULSA,
and by transrectal ultrasound in HIFU.
The UA houses ten independently controlled
5-mm ultrasound transducers that emit ultrasound energy into the adjacent prostate
(Fig.30.1). These ten transducers correspond to
ten 5-mm MRI slices, each of which is imaged
continuously throughout the procedure. The target temperature is adjustable, usually set at 55–57
°C at the peripheral boundary, to attain lethality
to epithelial cells in the target region. Ablative
treatment is tailored to patient-specic anatomy
and pathology by delineating the treatment
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
T. J. Polascik et al. (eds.), Imaging and Focal Therapy of Early Prostate Cancer,
https://doi.org/10.1007/978-3-031-66754-1_30
355
356
Fig. 30.1 TULSA
technology: A
transurethral ultrasound
device resembling a
19-F rigid cystoscope
with a customized coudé
tip, incorporates a linear
array of 10 independent
ultrasound transducers
that emit directional
high-intensity ultrasound
energy directly into the
adjacent prostate, with
urethral cooling
incorporated in the
device. Note also the
rectal cooling apparatus
J. L. Chin et al.
Fig. 30.2 Differences between TULSA and HIFU: Source and direction of heat energy; continuous heating versus
discrete heating pattern
boundaries, rotational excursion, and controlling
activation/deactivation of the individual transducers in real-time.
therapy delivery in real-time during treatment,
and implement the proprietary temperature feedback control algorithm.
A uid circuit allows water to ow through
the UA, providing 1–2 mm of urethral tissue
preservation, and a passive endorectal cooling
TULSA Procedure andWork-Flow
device (ECD) inserted per rectum provides protection for the rectal wall (Fig.30.1). The UA is
held in situ with a positioning system, which also
provides remote linear and rotational motion of
the device within the prostatic urethra. A treatment delivery console (TDC) includes customized software to outline the target prostate
boundary during planning, monitor the thermal
Patients deemed eligible for the TULSA procedure (see later section on “patient selection”) are
induced with general endotracheal anesthesia in a
room adjacent to the MRI unit. MRI-compatible
anesthesia equipment is required for ventilation
and monitoring. The patient is then transferred
onto the MRI bed, and the ECD is inserted, fol-
30 Role ofTransurethral Ultrasound Ablation (TULSA) inProstate Cancer Focal Therapy
357
lowed by a Council urethral catheter. A Nitinol
(or “Super-stiff”) guidewire via the Council catheter lumen facilitates manual insertion of the
UA.Under MRI guidance and remote operation
of the positional system, the UA is positioned
precisely within the prostatic urethra. In patients
with pertinent prior history or abnormal urethral
anatomy on imaging, cystoscopic assessment is
recommended to rule out urethral pathology,
which might pose a problem with the UA insertion. High-resolution prostate T2-weighted MR
images are then acquired for treatment planning.
Using the treatment delivery console, the treating
physician(s) (often a urologist and MR radiologist) jointly traces the outer prostate boundary on
axial images acquired transverse to the UA and
aligned with each transducer element. Treatment
begins with high-intensity ultrasound energy
delivered to the prostate through rotational movement of the UA under active MRI thermometry
feedback control. Real-time MRI thermometry
images are acquired every 5.9 s, providing continuous assessment of a three-dimensional temperature volume during treatment. Maximum
prostate temperatures are maintained at <100 °C
by the feedback controller to avoid tissue carbonization and boiling, both undesirable during
ultrasound therapy. After treatment, contrastenhanced MRI is acquired after a weight-adjusted
intravenous injection of a gadolinium-based contrast agent to assess for any targeted but nonperfused volume.
Early Studies
The development of this technology began
around 2000, with comprehensive in silico studies followed by tissue-mimicking gel phantom
testing [2]. An invivo canine model (n = 40 subjects) included acute “treat and resect” and
chronic longitudinal studies, which demonstrated
the feasibility and safety of TULSA in the preclinical setting.
A proof-of-concept clinical rst-in-man study
ensued in 15 patients who were scheduled for
radical prostatectomy, whereby a dened
MR-visible region of the prostate was treated
immediately prior to radical prostatectomy [3].
The canine and initial human studies demonstrated that the accuracy of targeting was ±1.5
mm, and the distance between ablated and
healthy unaffected tissue was 1.3mm. Acute cell
kill with coagulative necrosis was documented to
the designated treatment boundary [2, 3].
Phase 1 Clinical Trial (“Subtotal” Ablation)
A Phase 1 trial of 30 low-risk patients was then
conducted in three centers (in Canada, Germany,
and the U.S., respectively) [4]. The intent was
subtotal ablation with a clinical safety endpoint.
As mandated by the regulatory authorities, ablation volume was contoured on intra-procedural
MR images, intentionally sparing a 3-mm rim of
prostate tissue, thus leaving about 10% of the
prostate volume untreated. Based on preclinical
data, delayed cell kill was anticipated to migrate
an additional 1.3 ± 0.5 mm (maximum: 3 mm)
toward the prostate capsule [5].
The baseline characteristics of the 30 participants included mean pretreatment PSA of 6.0 ng/
ml, with 24 (80%) and 6 (20%) participants having low- and intermediate-risk prostate cancer,
respectively. TULSA was successful and well
tolerated by all study participants, with an average prostate volume of 48ml (range: 21–95 ml).
There was no intraoperative complication, no
rectal injury or stula, and no severe urinary
incontinence. The most attributable events were
acute Clavien-Dindo Grade (G)1 and G2, with
one G3 (epididymitis) and no G4 or higher
adverse events.
Exploratory outcomes included quality of life
parameters (International Prostate Symptom
Score, IPSS, and International Index of Erectile
Function, IIEF) and serum prostate-specic antigen (PSA) response. Median IPSS was 8 (IQR:
5–13) pretreatment and 6 (IQR: 4–10) at 3 months.
Median pretreatment IIEF was 13 (IQR: 6–28),
decreased transiently but recovered to 13 at 12
months. Median PSA decreased 87% at 1 month
and was stable at 0.8 ng/ml at 1-year follow- up.
Positive biopsies showed a 61% reduction in total
358
J. L. Chin et al.
cancer length, clinically signicant disease in 9 of
29 patients (31%; 95% CI, 15–51), and any disease in 16 of 29 patients (55%; 95% CI, 36–74).
Prospective ongoing follow-up data on this
cohort are available at 3 and 5 years [6]. There
have been no new serious or severe adverse
events. By 1 year, PSA had decreased 90% from
5.8 to a nadir of 0.6 ng/ml, with 88% (range
83–95%) prostate volume reduction. Biopsy at 1
year identied a 61% reduction in cancer length,
signicant cancer in 9 of 29 men (31%), and any
cancer in 16 of 29 (55%). At 3 years, 3 of 22 men
had refused biopsy, and 7 of 22 were positive (2
clinically signicant). By 5 years, 16 men had
completed protocol follow-up, 3 had withdrawn
with PSA <0.4 ng/ml, 10 patients had had salvage
therapy without complications (6 prostatectomy,
3 radiation, 1 laser), and 1 died of unrelated cause.
Of the 16 men at 5 years, the median (Interquartile
range) PSA remained at 0.55 (0.4–1.2) ng/ml, and
IPSS of 6 (5–13) returned to 5 (4–10) by 3 months
and 6.5 (6–9) at 5 years. At baseline, 9 of 16 had
erections sufcient for penetration, 11 of 16 at 1
year, and 7 of 16 at 5 years. All 16 had leak-free,
pad-free continence at 1 year and 5 years.
Predictors of the need for salvage therapy included
lower ablation coverage and higher PSA nadir.
Phase II (“TACT”) Clinical Trial (“Whole Gland” Ablation)
A Phase II study was subsequently conducted in
North America and Europe involving 13 centers.
A total of 115 patients with low- or intermediaterisk disease were treated with whole gland ablation with urethral and apical sphincter sparing
[7]. The co-primary 12-month endpoints were
safety and efcacy. Treatment planning was
modied from the prior Phase 1 trial, sparing a
2 mm outer rim of prostatic tissue instead of a
3 mm rim, and the target temperature at the
boundary was raised to 57° from 55 °C.Seventytwo (63%) had grade group 2, and 77 (67%) had
NCCN intermediate-risk disease. There was 98%
(IQR 95–99) thermal coverage of the target volume, and a spatial ablation precision of 1.4mm
was achieved on MR thermometry. Grade 3
adverse events occurred in 8% of men. The primary endpoint (mandated by the U.S.Food and
Drug Administration) of prostate-specic antigen
reduction of 75% was achieved in 110 of 115
patients (96%) with median prostate-specic
antigen reduction of 95% and nadir of 0.34 ng/
ml. Among 68 men with pretreatment grade
group 2 disease, 52 (79%) were free of grade
group 2 disease on 12-month biopsy. From the
entire cohort of 115 men, 111 underwent follow up biopsy 12-month, of which 72 (65%) had no
evidence of cancer. Multivariate predictors of
persistent grade group 2 at 12 months included
intraprostatic calcications at screening, suboptimal magnetic resonance imaging thermal coverage of target volume, and a PI-RADS >3 lesion at
12-month MR imaging (p < 0.05).
There was no rectal injury or Grade ≥4
adverse event in the TACT trial. Grade 3 adverse
events occurred in 9 men (8%), including urinary
and epididymal infection, retention, perineal
pain, urinoma, and urethral stricture; all were
resolved before 1 year. Erectile function (based
on IIEF Question 2 score >2) was maintained or
regained in 69 of 92 patients (75%) by the 1-year
mark. Pad-free urinary continence was reported
in 102 of 111 patients (92%) and social continence was preserved in 110/111 (99%) at 1 year,
and the bowel function remained stable from
early on. As an incidental observation, the treatment was accompanied by a 90% volume reduction as measured by pre- and post-procedure
MRI, from a median of 40–4ml posttreatment.
The 4-year oncologic and functional follow- up
data showed maintenance of response trends [8].
By 4 years, 18 men (16%) had undergone salvage
treatment (8 radical prostatectomy, 8 radiation therapy, 1 androgen deprivation therapy, 1 surgery plus
radiation) without unexpected complications. At 4
years, the median (IQR) PSA was 0.9 (0.4–1.6) ng/
mL, a reduction of 86% (75–95%) from baseline
and of 96% to the nadir (n = 76). Median IPSS
decreased from 7 at baseline to 5 at 4 years (n =
73). Erections sufcient for penetration (IIEFQ2 ≥
2) were reported in 46/57 (81%) at 4 years. Padfree urinary continence and social continence were
both preserved at 4 years in 68/72 patients (94%)
and 71/72 men (99%), respectively.
30 Role ofTransurethral Ultrasound Ablation (TULSA) inProstate Cancer Focal Therapy
359
Conclusions drawn from the TACT trial are
that effective disease control is durable to 4 years,
with continued recovery of quality of life and a
favorable safety prole after whole-gland ablation
with TULSA.Moreover, most patients with intermediate-risk disease appear to be candidates for
TULSA.Contraindications include tight urethral
strictures (preventing insertion of the 19-F urethral applicator); prostatic calcications >3mm in
the area of the index cancer; and a distance from
the urethra to the target margin of >3cm.
Other Global Experience withTULSA
The ALTA Klinik in Germany reported their
single- center retrospective experience on 52 consecutive patients who underwent either primary
(n = 47) or salvage (n = 5) “customized” TULSA,
of which 67% had intermediate-risk and 19% had
high-risk disease. Eighty percent of the procedures were “partial gland ablation” and 75%
were nerve-sparing [9]. The planned ablation was
dependent on individual tumor parameters, the
presence or absence of clinically signicant
benign prostatic hyperplasia as well as patient
preferences. The median follow-up was 16
months (maximum 36 months). “Early treatment
success” was dened by a negative multiparametric MRI and lack of PSA recurrence. Baseline
PSA was 8.0 ng/ml (range 5.2–13); median PSA
nadir after primary treatment was 1.1 ng/ml
(0.5–2.1). Based on the authors’ denition, 88%
attained “early treatment success,” which
included 9 patients who had undergone a single
repeat TULSA treatment. One patient had worsened urinary symptoms, requiring 1 pad/day
postoperatively. All 37 patients who had erectile
function prior to TULSA retained their potency.
Of those with concomitant clinically signicant
lower urinary tract symptoms, 83% reported
symptomatic improvement.
TULSA has also been utilized in the salvage
setting for patients with localized prostate cancer
recurrence/persistence following radiation. The
earliest report originated in Finland on postirradiation TULSA, as a Phase I/II prospective study
in 11 patients [10]. No adverse events occurred,
and eradication of disease in the treated zone
occurred in 10/11 patients. There were two outof- eld positive biopsies. Minimal changes were
seen in quality-of-life parameters (IPSS, IIEF,
and EPIC scores). Accrual for this trial has been
extended to 40 patients.
The ALTA Klinik group has expanded their
“real-world” experience to 180 patients (150 primary and 30 radio-recurrent cases) with targeted
ablation. The treatment response rates have been
similar to their initial experience [11].
In a Phase 1 prospective study from Finland,
27 men with lower urinary tract symptoms due to
bladder/prostatic outlet obstruction, previously
scheduled for primary surgical intervention,
received TULSA [12]. The median follow-up was
16 months. Median values for measured parameter changes included prostate volume reduction
from 53 to 32.5 ml, PSA decline from 3.0 to 1.45
ug/L, and post-void residual volume decrease
from 71 to 54ml. There was clinical improvement
in average ow rate, Qmax, voided volume, IPSS
and IPSS QoL score, IIEF-5, as well as EPIC-26
urinary incontinence and irritative domains.
Relief of urinary symptoms in men with
locally advanced prostate cancer was assessed in
one study, with the primary goal of care being the
palliation of symptoms [13]. All subjects (n = 10)
were catheter-dependent at baseline with urinary
retention, and 9 of the 10 men suffered gross
hematuria. At the last follow-up (up to 1 year), all
patients were free from gross hematuria, and
70% were voiding spontaneously catheter-free.
Ongoing Clinical Trials onTotal
andLesion-Targeted TULSA
A randomized controlled trial is underway in
North America between customized TULSA and
radical prostatectomy in patients with the clinically localized intermediate-risk disease
(NCT05027477), with two co-primary endpoints:
(1) superiority safety endpoint at 1 year, and (2)
non-inferiority efcacy endpoint at 3 years. The
safety endpoint is dened as the proportion of
patients who maintain both pad-free urinary continence and erectile potency. The efcacy end-