Which Technology to select for Primary Focal Treatment of Prostate Cancer? – Treatment

Pathway by the European Society of Urotechnology (ESUT)

Roman Ganzer1*, Vinodh Kumar Adithyaa Arthanareeswaran1*, Hashim Ahmed2, Andrea Cestari3,

Pascal Rischmann4, Georg Salomon5, Dogu Teber6, Evangelos Liatsikos7, Jens-Uwe Stolzenburg1,

Eric Barret8

*contributed equally

1Department of Urology, University of Leipzig, Germany; 2Division of Surgery and Interventional

Science, University College of London, UK; 3Department of Urology, Advanced Urotechnology

Center, IRCCS Istituto Auxologico Italiano, Milan, Italy; 4Department of Urology, Rangueil

University Hospital, Toulouse, France; 5Martini Clinic, Prostate Cancer Center, Hamburg,

Germany; 6Department of Urology, University of Heidelberg, Germany; 7Department of Urology,

University of Patras, Greece; 8Department of Urology, Institut Montsouris, Paris, France

Corresponding author:

Roman Ganzer, MD

Department of Urology

University of Leipzig

Liebigstraße 20

D-04103 Leipzig, Germany

Phone: +49-341-9717684

Fax: +49-341-9717609

e – mail: roman.ganzer@medizin.uni-leipzig.de

Abstract:

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Purpose: there is growing interest in focal therapy (FT) of prostate cancer (PCa). The indications

for FT are continuously expanding. The current treatment armamentarium for FT includes high-

intensity focused ultrasound (HIFU), cryotherapy, focal laser ablation (FLA), irreversible

electroporation (IRE), vascular targeted photodynamic therapy (VTP), focal brachytherapy (FBT)

and external beam radiotherapy (EBRT). However, there are no clear recommendations stating

which of the available technologies might be of advantage or disadvantage with respect to

individual patient and tumour characteristics.

Methods: based on literature review, we propose a pathway for a personalised treatment plan, using

current evidence and expert opinion, to ensure optimal utilization of available technologies.

Results: posterior lesions are better amenable to FT using HIFU. Cryotherapy provides best

possible outcomes for anterior tumours. Apical lesions, when treated with FBT, may yield the least

morbidity.

Conclusion: there is still lacunae of evidence and further trials are needed to prove if the place of

FT is not only to bridge the gap between Active Surveillance and radical treatment but to act as an

alternative to radical treatment for selected patients.

{Valerio, 2016 #320}

Key words: brachytherapy - cryotherapy - focal therapy - HIFU - personalized approach - prostate

cancer

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1. Introduction

In recent years, there has been rising interest in focal therapy (FT) of prostate cancer (PCa).

Advances in imaging and improved understanding of tumour biology has led to a shift from radical

surgery to organ sparing treatment in a selected cohort of patients[1], thereby aiming at reducing

side effects of radical treatment [2]. With increasing number of patients diagnosed with low- and

intermediate risk PCa, the number of patients on active surveillance (AS) is increasing [3]. Recent

guidelines recommend AS as the standard of care for very low risk PCa [4]. However,

misclassification and uncertainty of time of progression limit AS. Certain patient-specific factors

indicate less favourable risk and some form of intervention is recommended [5]. Utilization of

better risk classification at diagnosis using novel serum and urine biomarkers, tissue-based markers

and imaging techniques such as multiparametric magnetic resonance imaging (mpMRI) may aid in

stratifying patients to either AS or appropriate intervention in the future. Although many authors

consider FT as an adjunct to AS [6], the indications for FT are expanding and can be placed

between AS and radical therapy [7-9].

The current treatment armamentarium for FT includes high-intensity focused ultrasound (HIFU),

cryotherapy, focal laser ablation (FLA), irreversible electroporation (IRE), vascular targeted

photodynamic therapy (VTP), focal brachytherapy (FBT) and external beam radiotherapy (EBRT).

Newer modalities are continuously being explored. However, there are no clear recommendations

stating which of the available technologies might be of advantage or disadvantage with respect to

individual patient and tumour characteristics. The intention of this review was to summarise current

evidence and special characteristics of different technologies used for focal treatment of PCa in

order to propose a personalised treatment plan for FT considering individual patient and tumour

characteristics.

2. Materials and methods

PubMed was searched until November 2016 to identify preclinical studies, clinical trials, original

articles, reviews, editorials and letters to the editor, addressing FT in PCa. In addition, abstracts

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from the European Association of Urology, European Society of Medical Oncology, American

Urological Association and American Society of Medical Oncology meetings were also searched

for relevant abstracts. Search terms included focal therapy, clinical trial, PCa, high-intensity focused

ultrasound, HIFU, cryotherapy, irreversible electroporation, IRE, laser ablation, photodynamic

therapy, VTP and brachytherapy. A list of articles determined to be relevant was circulated among

the authors, and final consensus was reached on both structure and the literature. For all treatment

technologies, the current literature on FT was especially screened for the following factors:

Morbidity, repeatability, tumour risk category, tumour location, tumour size and prostate volume,

MRI/TRUS fusion and anatomical issues.

3. Results

Although FT is gaining popularity both among physicians and patients [10], a clear discordance

exists between the number of review articles and original studies published. PubMed search

revealed over 144 reviews and only 28 clinical trials. This lacuna resulted in numerous consensus

meetings to be convened in recent years [11-13]. Key features of potential lesions that can be

treated by FT was described in a report of a consensus meeting by Donaldson et al [14]. An expert

panel from 2012 gave recommendations for optimal approach in designing, developing and

delivering randomised controlled trials evaluating the role of FT in men with localized PCa [15,16].

A very recent meeting addressed the need for standardization of definitions used in FT of PCa [17].

Description of Available Technologies

High Intensity Focused Ultrasound (HIFU):

HIFU uses the principle of a convex lens [18]. Using a spherical transducer ultrasound waves are

focused to a target area in order to create coagulation necrosis by a thermal and mechanical effect.

Two systems have received FDA approval in 2015: the French Ablatherm system (EDAP-TMS,

Vaulx en Velin, France) and the American Sonablate 450 system (SonaCare, Charlotte, North

Carolina, USA). FocalOne (EDAP-TMS) is the latest HIFU generation device for the treatment of

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PCa specifically designed for focal treatment. ExAblate2100 (InSightec Ltd., Haifa, Israel) is a

commercially available system that utilizes MRI to accurately guide and monitor temperature

during treatment [19]. Detailed anatomical MR images facilitate identification of target zones, help

in endorectal ultrasound array placement and orientation and real time MR temperature monitoring.

Previous studies on focal HIFU showed positive control biopsy rates varying from 11% at two years

[20] to 23% at six month [21] follow up. Initial results of FocalOne by Crouzet et al. showed

negative biopsies after one month of therapy in ten patients studied; with no difference in

continence and International Index of Erectile Function (IIEF) score [22].

Cryotherapy:

Cryotherapy uses a nadir temperature averaging -40o C for effective cryo-destruction of tissue using

“freeze rupture” [23] i.e. cytolysis through extracellular and intracellular mechanisms. The

combined effect of cellular, physical and biochemical insults results in adequate ablation of tumour

tissue. Newer devices have been introduced where pressurized gas is used to both freeze (argon gas)

and then actively thaw (helium gas) tumour tissue, thereby allowing usage of smaller probes (17-

gauge), enabling more precise treatment and reduction in damage to surrounding structures such as

the urethral sphincter. Previous studies have shown recurrence-free survival rates ranging from 72%

[24] to 94% [25] with acceptable continence and potency rates. Detailed results of focal HIFU and

cryotherapy studies are summarised in table 1.

Focal Laser Ablation (FLA):

FLA, also referred to as laser interstitial thermotherapy, is a thermo-ablation technique which

utilizes high-energy laser light to generate coagulation through rapid heating of targeted tissue.

Energy is delivered to the prostate using laser fibres inserted by a transperineal approach through

needles. Studies have shown that wavelengths between 800 and 1100 nm have comparable effects

[35-38].

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Vascular Targeted Photodynamic Therapy (VTP):

VTP is based on the interaction between light brought by transperineally inserted intraprostatic laser

fibres, a photosensitive agent (PS) administrated orally (aminolevulinic acid (ALA) or motexafin

lutetium) or intravenously (TOOKAD or WST-11), and oxygen present in tissues. It is a form of

nonthermal ablative technique.

Early experience from Taneja et al. [39] and Azzouzi et al. [40] highlighted that the intervention is

safe, teachable and repeatable. The challenges of TOOKAD Soluble are limited to the accurate

placement of needles within the prostate using a grid. A study conducted by Moore et al. [41]

showed that the optimal drug dose, light dose and light density index (LDI) for prostate ablation

using TOOKAD Soluble are 4 mg/kg WST11 activated by 753 nm light at a dose of 200 J/cm and a

LDI of ≥1. These parameters applied in a group of 12 men resulted in treatment effect in 95% of the

planned treatment volume and an 83% negative biopsy rate at 6 months. The first multicentre phase

III pivotal randomised study conducted by Azzouzi et al. [42] showed significant reduction in

cancer progression and need for radical surgery in TOOKAD VTP when compared to patients in

AS. The results of previous studies with FLA and VTP are summarised in table 2.

Focal Brachytherapy (FBT):

Brachytherapy for PCa involves implantation of ‘‘free’’ radioactive isoseeds 125 and usage of

dynamic dose calculations with continuous feedback as per the actual position of each seed. The

volume of prostate to be treated is based on the site of the positive biopsies and on the MRI images.

Cosset et al [43] treated 21 patients with FBT using a mean focal dose of 145 Gy with an average

D90 of 183.2 Gy, and a mean V100 of 99.3%. The mean initial prostate specific antigen (PSA) was

6.9 ng/mL which dropped to 2.6 ng/mL at 12 months. There was a borderline improvement in

international prostate symptom score at 6 months and a significant better International Index of

Erectile Function score compared with comparative historical results for total prostate implants. A

study by Barret et al. [28] on 12 patients revealed a drop in mean PSA from 6.2 to 2.8 ng/mL with

no significant change in potency and continence at 12 month follow up. Dosimetric calculations by

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Kamrava et al. [44] revealed that FBT yielded a statistically significant decreased radiation dose to

organs at risk and provided complete target coverage with a catheter array designed for whole gland

coverage.

External Focal Beam Radiotherapy (EBRT):

The possibility of using EBRT as a FT modality is being explored with newer devices like

CyberKnife (Accuray Inc., California, USA) which delivers high dose hypofractionated stereotactic

body radiation using a robotic arm in combination with intrafractional prostate motion tracking

[45]. Typical treatment includes 80–200 beams of radiation to focal regions of prostate that are

delivered from up to 100 or more positions around the patient. Each beam can be targeted at a

unique position within the target volume. The smallest reasonable target volume is around 2cm3.

The target volume consisted of a 5-mm expansion zone antero-laterally and 3mm posteriorly in a

study conducted by King et al. [46]. A recent study by MacDougall et al. [47] highlighted that

CyberKnife maintained better accuracy and precision when compared to Rapidarc system (Varian

Medical Systems, Palo Alto, California, USA) due to its real-time fiducial motion tracking system.

Irreversible Electroporation (IRE) :

The treatment effect in IRE is secondary to permanent nanopore formation in the cell membrane

leading to apoptosis. With apoptosis, cells are phagocytized by immune cells and then replaced by

innate cellular regeneration. Because the mechanism of cell death in IRE is non-thermal, this

technique is not limited by the disadvantages of tissue heating or freezing as in other thermal

ablative techniques.

The first to report on the use of IRE in PCa were Onik et al. [48], who treated 16 patients with

localized cancer. Patients who were potent before remained so after IRE treatment. However, two

patients who received bilateral IRE treatment required 6 months for full return of potency. Van den

Bos et al. [49] performed an ablate-and-resect study, performing IRE in 16 prostate cancer patients

4 weeks prior to radical prostatectomy. In this study, IRE ablation zones were found to extend

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beyond the IRE needles, with three needle ablations being up to 2.9 times larger than the needle

configuration. A recent study by Valerio et al.[50] revealed in field residual disease in 38.9% of

patients following IRE. Interestingly, 85.7% of these patients had clinically significant disease.

4. Discussion

Special characteristics of FT technologies:

Morbidity:

Except for one study by Azzouzi et al. [51] randomising VTP (TOOKAD soluble) against AS, there

are there are no prospective randomised trials comparing morbidity outcomes of any of the FT

modality with each other or with standard treatment options. There was higher incidence of grade I

and II morbidity in VTP when compared to AS in this study. The other published non-comparative

reports however indicate a low morbidity profile with FT. It is prudent to note that most studies

used heterogeneous methods of assessment of continence and potency [52]. A retrospective study

by Barret et al [28] comparing adverse effects of the four FT modalities HIFU, cryotherapy, VTP

and FBT indicated that focal cryotherapy was responsible for most of the complications. However,

the authors conclude that the complication rates decreased with increase in expertise. None of the

studies and case reports have reported grade IV or severe morbidity.

Repeatability:

Repeatability of a FT modality may be advantageous for patients who develop local recurrence by

avoiding the need for radical treatment and possibly reduce morbidity. Studies have shown that FT

performed with different modalities like HIFU [53] and cryotherapy [54] is repeatable. Out of nine

patients who had positive biopsy following FT, four men (9.7%) underwent repeat focal HIFU in a

study conducted by Ahmed et al [21] with a reduction in PSA from a median of 3.9 ng/mL (IQR

3.7–4.5) at 6 months (before retreatment) to 2·9 ng/mL (1.8–3.6) at 12 months. No further data was

provided on the remaining five patients who opted for AS and post repeat treatment morbidity and

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changes in quality of life. Cryotherapy was repeated in numerous studies in the past [25,34,33,9,31].

The number of cycles that can be repeated is being explored. After evaluating the magnitude of

‘‘spill’’ from a hemigland FBT treatment, Kamrava et al. [44] concluded that retreatment for a

central lesion could be difficult in brachytherapy and other salvage options.

In summary, FT was described to be repeatable in HIFU, cryotherapy and FBT, but none of the

studies measured changes in morbidity following retreatment. Future studies looking at this aspect

may provide valuable information on the repeatability of FT modalities.

Tumour risk category:

Current guidelines do not recommend FT for very low risk disease. Most of the FT modalities have

initially been focused on treating low risk disease. The feasibility of primary FT using HIFU and

cryotherapy has also been studied in intermediate risk PCa patients with acceptable results

[52,55,54]. A study by Muto et al. [30] revealed that 2-year biochemical disease-free survival rates

after HIFU in patients at high risk were significantly inferior than those in patients at low risk. High

risk patients were also included in cryotherapy studies conducted by Ward et al. [31], Trusedale et

al.[28], Onik et al.[29] and Ellis et al.[33] with poor outcomes in this category of patients. However,

there is no evidence from comparative studies showing superiority of any FT modality in treating

higher risk disease.

Tumour location:

Location of tumour foci is important for choosing the FT modality [56]. Posterior tumours, even in

large prostates, are well accessible by a transrectal modality such as HIFU. However, thermal

technologies such as HIFU and cryotherapy might not be first option in apically located tumours, as

urethral sphincter damage might occur. Further trials are warranted comparing different FT

modalities with respect to location. Cryotherapy is not first choice in posterior lesions since it has

been shown that temperatures lower than -20°C are required to destroy tumour cells but collateral

cellular damage can occur in normal tissue at -15°C, and in neurovascular tissue, a decrease in

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autonomic nerve function is seen at +3° C, becoming irreversible at temperatures below -20° C

[18].

Anterior lesions may be more easily ablated by transperineal needle-based energy such as

cryotherapy, FLA and VTP when compared to HIFU [57]. Apical lesions can be more safely

targeted by FBT, minimising damage to the urethral sphincter. A recent study by Cosset et al. [43]

in 21 patients showed extremely low urethral toxicity even while treating apical lesions with FBT.

Post-cryotherapy failures were observed in the exact area where surgeons attempted to protect the

urethral wall from deep freezing, using a urethral warming catheter with 43°C irrigation. [10]. In

summary, treatment of apical tumours with thermal energy options like HIFU and cryotherapy are

associated with an increased risk of urethral sphincter damage.

Tumour Size and prostate volume:

Older generation HIFU devices were limited to prostate glands with volume >40 cc due to the

limitations in focal distance length [28]. The 3.0 MHz probe in newer devices like Ablatherm

creates lesions that are adjustable from 19 to 26mm in height. It is of disadvantage that the focus

point might be outside the prostate in smaller glands, especially in the peripheral zone. The

Sonablate probe is comprised of two different crystals with focal length 3.0 cm 4.0 cm respectively.

The discrete ablation volume of both these crystals is 10 mm in height. The FocalOne probe has a

dynamic focusing transducer that can move the focal point of the transducer to a maximum of eight

different points producing a treated zone from 5 up to 40 mm in height. At the end of the treatment

contrast enhanced ultrasound image can be acquired to indicate devascularized ablated areas.

Cryotherapy must be used carefully in tumours located in smaller glands [52] since the “ice ball”

may extend into adjacent neurovascular bundle (NVB) or urethra in small prostates increasing risk

of collateral damage [58]. This can be avoided by choosing smaller needles thereby reducing the

size of the ice ball. Other modalities like IRE, FLA and FBT do not seem to be restricted by

prostate volume for FT approaches.

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MRI/TRUS fusion:

MRI/TRUS real time fusion during FT procedure is currently possible with the FocalOne [22] and

Sonafuse platform [59] of the Sonablate device. These systems have the ability to import images

such as mpMRI for treatment planning. Although this option is promising it has some technical

limitations: prostate deformation during treatment might impair the accuracy of image fusion. For

instance, Shoji et al. [60] showed significant swelling and shift of about 13% for the entire prostate

during HIFU treatment. Difficulties arise when more that one MRI zone is fused for treatment

planning. Only limited data is currently available on the biopsy outcomes following this modality

[22].

In-bore MRI interventions:

Usage of mpMRI for real time intraoperative guidance is being explored in HIFU, Cryotherapy,

FLA, and brachytherapy [61]. In-bore visualization of tumour enables accurate targeting of lesions.

Magnetic resonance thermometry provides real time temperature feedback indicating selective and

adequate tumour ablation as well as monitored preservation of sensitive surrounding structures like

urethral sphincter and NVB [61].

Anatomical issues:

Rectal abnormality like congenital defects, post anorectal resection or post radiation strictures make

transrectal modalities like HIFU and transrectal MR-guided focal laser therapy unusable. Newer

platforms using transperineal route without TRUS control but with in-bore MRI guidance like

cryotherapy, FLA and brachytherapy may be useful in this situation.

Personalized treatment strategy:

Given the numerous primary FT options and its unique advantages, there is now increasing interest

in developing patient individualised treatment recommendations [56]. We propose a pathway for a

personalised treatment plan to ensure optimal utilization of available technologies. The pathway

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was developed based on tumour location within the prostate. Posterior lesions are better amenable

to FT using HIFU. Cryotherapy provides best possible outcomes for anterior tumours and apical

lesions, when treated with FBT, may yield the least morbidity. Recommendations of the

personalised approach strategy considering first and secondary choice options are shown in Figure

1.

5. Conclusions

FT of PCa is still considered experimental and should not be offered outside clinical trials. Recent

studies were able to prove feasibility, low morbidity profile and satisfying short and medium term

oncologic results, mainly based on imaging and re-biopsy. Inclusion criteria of recent study

protocols were mainly based on risk category and number and extension of positive biopsies. Based

on current literature and expert opinion the intention of the ESUT ablative group was to evaluate if

the selection of different FT technologies can be facilitated based on several tumour and patient

characteristics. Although the scientific base is weak it might help in designing future FT trials.

6. Legends:

Figure 1:

Schematic representation of the personalised FT approach. FBT = focal brachytherapy; FLA = focal laser

ablation; HIFU= high-intensity focused ultrasound; IRE = irreversible electroporation; PDT = photodynamic

therapy

Table 1 : Summary of HIFU and cryotherapy studies

BRFS – Biochemical recurrence free survival; IIEF-5 = International Index of Erectile Function; ; LUTS =

Lower urinary tract symptoms; MRI= Magnetic resonance imaging; NA = not available; TRUS = Trans

rectal ultrasound; UTI = urinary tract infection.

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Table 2: Summary of Focal laser ablation and VTP studies. CEUS = Contrast Enhanced Ultra

Sound; IIEF = International Index of Erectile Function; MRI= Magnetic resonance imaging; NA =

not available; PDE5 = Phosphodiesterase Type 5 Inhibitor.

Statement about the author’s contribution to the manuscript:

Ganzer: protocol development, data collection and management, manuscript writing/editing

Arthanareeswaran: protocol development, data collection and management, manuscript

writing/editing

Ahmed: data collection and management

Cestari: data collection and management

Rischmann: data collection and management

Salomon: data collection and management

Teber: data collection and management

Liatsikos: data collection and management

Stolzenburg: data collection and management

Barret: protocol development, data collection and management, manuscript writing/editing

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