A Multi-Center Randomized Single-Blind Two Arm Intervention Study Evaluating Irreversible Electroporation for the Ablation of Prostate Cancer

Current surgical and ablative treatment options for prostate cancer have a high
incidence of (temporary) incontinence, erectile dysfunction and/or bowel
damage. These side effects impair the quality of life of prostate cancer
patients and impact on patients* decision to undergo early, potentially
curative interventional treatments. These side effects are due to procedure
related damage of the blood vessels, bowel, urethra and/or neurovascular
bundle. New treatments that limit damage to these structures have the potential
to improve patient outcomes. Ablation with Irreversible Electroporation (IRE)
has shown to be effective and safe in destroying tumour cells and to have the
potential advantage of sparing surrounding tissue and vital structures such as
blood vessels and nerves.

Primary:
- To evaluate differences in side effect profile of patients treated with focal
or extended ablation performed with image-guided IRE for the ablation of
prostate carcinoma.
- To evaluate differences in quality of life of patients treated with focal or
extended ablation performed with image-guided IRE for the ablation of prostate
carcinoma.

Secondary:
- To evaluate the oncological efficacy of image guided IRE for the focal and
extended ablation of prostate carcinoma.

- To evaluate the efficacy of MRI in the imaging of ablation success, extend of
the ablation zone, 3 months, 6 months and 1, 2, 3, 4 and 5 years post IRE
ablation.

Multi-centre Randomized Clinical Trial: 106 patients with confirmed unilateral
(T1c-T2a) low risk (Gleason sum score 6) or intermediate risk prostate cancer
(Gleason sum score 7) will be offered to have the IRE treatment. These patients
will be randomized into one of the two arms of the study.

Arm 1: Focal ablation of the prostate at the location of positive biopsies.

Arm 2: Extended ablation of the prostate at the side of the positive biopsies.

The imaging data (MRI and ultrasound) will be entered into the Planning
Software system of the IRE-device. The volume of the prostate is measured and a
specified ablation zone will be determined. The patients will be admitted for
overnight stay in the hospital on the morning of the scheduled IRE procedure.
The IRE will be performed under general anaesthesia following the
anesthesiological protocol and the specified zone identified in the planning
stage will be ablated. IRE electrode needles will be placed into the prostate
under ultrasound image guidance with a transperineal approach using a grid.
When the needles are in place, electric pulses of one to two minutes duration
are used to ablate the specified zone. The total procedure time will be
approximately 1.5 hour.

Data will be collected and patients will be followed up at 1 day
post-operatively, 2 weeks, 1 month, 3 months, 6 months, 12 months and
thereafter annually until 5 years post-IRE.

Arm 1: Focal IRE ablation of the prostate at the location of positive biopsies.

Arm 2: Extended IRE ablation of the prostate at the side of the positive
biopsies.

A variety of ablation techniques have been used in the treatment of localised
prostate cancer. These techniques include cryoablation, high-intensity focused
US (HIFU), RFA, microwave coagulation, Vascular Targeted Photodynamic Therapy
(VTPT) and Interstitial Laser Thermotherapy (ILT)40 . These focal techniques
have been receiving increasing interest, and show significant potential in the
management of prostate cancer due to the higher detection rate of localised
prostate cancer due to the PSA test, and to the improved technology available
41-43. They are gaining increasing popularity because they are minimally
invasive, require only a short hospital stay, and may have a better side effect
profile, lower morbidity and less impact on the quality of life 40. Most
current techniques however, have been shown to have limitations.

Cryoablation involves freezing undesirable tissue by direct contact with a
cryogen-cooled probe. Cryotherapy has a higher morbidity than other minimally
invasive techniques, in particular a high rate of erectile dysfunction of
80%.29 Other disadvantages are the thick probes that are difficult to use,
tissue damage at the margins of treatment, and injury to adjacent structures.

HIFU has had good short to medium results in low to intermediate risk prostate
cancer and larger trials are being conducted. This is a non-invasive technique
utilising hyperthermia to cause coagulative necrosis of the targeted area29. It
shows potential as a therapy in both whole gland ablation and focal ablation44.
Erectile dysfunction is theoretically a likely side effect but has not been
adequately documented. Swelling of the prostate post-procedure is a more common
side effect, and causes frequently urinary retention. This technique is limited
by difficulty in treating the entire prostate gland, in particular the anterior
prostate45. In 1999 HIFU was validated in a study in which one side of the
prostate was ablated. After two weeks the efficacy of the ablation was compared
with the histopathological results after radical prostatectomy46. 9 patients
were treated in this study with in all patients complete necrosis of the
ablated tissue. However in 2 patients a small residual tumour was seen. There
were no fistulae reported in this series.

Advantages of minimally invasive techniques / Focal therapy
The recent downward migration of prostate cancer stage on diagnosis, most
likely due to the increased use of PSA tests. This has opened the door to focal
strategies tailored to the management of organ-confined, early stage prostate
cancer 45+47.

With the obvious advantage of avoiding a major invasive surgical procedure,
minimally invasive techniques have the potential for diminished side effects,
and thus may provide a more desirable treatment option. While prostate cancer
may be slow growing and classified as low risk, it is difficult to distinguish
which cancers require treatment from those that do not 29. Focal techniques may
provide a more definitive treatment option than active surveillance, and may be
better tolerated by older patients with comorbidities, with the potential for
fewer side effects. Recently published long-term survival rates of patients
undergoing primary or salvage cryotherapy for prostate cancer are also
promising. Results indicated an 87% overall 10-year prostate-cancer-specific
survival, despite early cryotherapy technology and the majority of patients
being high risk 48.

While solid tumours in other organs such as the breast, skin and kidney, were
initially treated with radical surgery, focal, organ-sparing therapies are now
common and result in lower morbidity and disfigurement with equivalent rates of
cancer control 29.

The major disadvantage with these techniques may be that they may not control
the cancer as well as the established techniques 40. Another disadvantage of
some conventional ablation techniques is potential damage to surrounding
structures, which can cause symptomatic problems, in many cases as the result
of thermal damage.

Expected advantages of IRE compared to current treatment options
IRE has a number of advantages compared to thermal ablation and radical
surgery, these include:

• Small needle electrodes with radiology guidance
• Very short high voltage pulses create permanent pores in cell membranes
• Fast - around 5-10 minutes per treatment
• Rapid disappearance of targeted cells
• No residual cavity or distortion
• Almost no post-operative pain
• Sparing of supporting and vital structures and consequently offers an
alternative when thermal ablation and surgery are precluded.

Risks
Hazard
General anesthesia (procedural)
Muscle Blockade (procedural)
Cardiac Arrhythmia (both procedural and device, unlikely from device due to
distance)
Multiple Prostate Biopsies (procedural)
IRE electrode needles placed in or through sensitive structures. (Foreseeable
misuse)
Insufficient Muscle Blockade (procedural)
Vascular Dissection (device)
Perforation (device)
Hemorrhage (device)
Lack of Sterile Technique/Breach of Sterile Field (procedural)

ECG (EKG) Disruption after pulsing (2-3 sec)
Tumour Recurrence (device)
Tumour Seeding (procedural)
Nerve Damage (device)
Acute or Sub-acute Vascular Damage (device)

Injury to Prostatic Urethra or External Sphincter (device)
Urethro-rectal Fistula (Both procedural or device)
Rectal Tear/ Perforation (from TRUS guided biopsy or Endorectal MRI coil)
(procedural)
Postoperative Hemorrhage (device)