Focal therapy of prostate cancer: energies and procedures

Transcription

Urologic Oncology: Seminars and Original Investigations xx (2012) xxx
Review article
Focal therapy of prostate cancer: energies and procedures
G. Bozzini, M.D.a,b,*, P. Colin, M.D.a,b, P. Nevoux, M.D.a,b, A. Villers, M.D., Ph.D.a,b,
S. Mordon, Ph.D.b, N. Betrouni, Ph.D.b
a
b
Department of Urology, Centre Hospitalier Regional Universitaire de Lille, avenue oscar lambret, Lille, France
INSERM, U703, 152 Rue du Docteur Yersin, 59,120 Loos, France. Universite Lille Nord de France, CHU Lille, F-59000 Lille, France
Received 30 March 2012; received in revised form 29 May 2012; accepted 31 May 2012
Abstract
Purpose: Over the last years, focal therapy has emerged as an intermediate management technique between radical approaches (radical
prostatectomy, external beam radiation, and brachytherapy) and watchful waiting to manage some early stage prostate cancers (CaP).
Different energy modalities are being developed. The aim of this study is to review these energy modalities and their indications.
Materials and methods: We reviewed the literature to concentrate on the practical aspects of focal therapy for CaP with the following
key words: photodynamic therapy, high intensity focused ultrasound (HIFU), cryotherapy, focal laser ablation, electroporation, radio
frequency, external beam radiation, organ-sparing approach, focal therapy, CaP, and then by cross-referencing from previously identified
studies.
Results: Prostatic tumor ablation can be achieved with different energies: freezing effect for cryotherapy, thermal effect using focalized
ultrasound for HIFU, and using thermal effect of light for focal laser ablation (FLA) and activation of a photosensitizer by light for PDT,
among others. Radio frequency and microwave therapy have been tested in this field and demonstrated their usefulness. Electroporation is
currently being developed on preclinical models. External beam radiation with microboost on neoplastic foci is under evaluation. HIFU and
cryotherapy require the use of sophisticated and expensive machines and, consequently, the procedure is expensive. Laser techniques seem
to be less onerous, with the added advantage of size.
Conclusions: Several energy modalities are being developed to achieve the trifecta of continence, potency, and oncologic efficiency.
Those techniques come with low morbidity but clinical experience is limited regarding to oncologic outcome. Comparison of the different
focal approaches is complex owing to important heterogeneity of the trials. In the future, it seems likely that each technique will have its
own selective indications. © 2012 Elsevier Inc. All rights reserved.
Keywords: Prostate cancer; Focal therapy; HIFU; Cryotherapy; Photodynamic therapy; Focal laser ablation
1. Introduction
Prostate cancer (CaP) is the most common cancer among
men over 50 years in industrialized countries in terms of
incidence. It represents the second cause of cancer-related
death [1]. At present, radical approaches, such as surgery,
external beam radiation, and brachytherapy remain the
gold standard. Those treatments, however, come with a
high incidence of morbidity, including on average: 50%
chance of impotence, 10% chance of incontinence, and
10% chance of rectal toxicity [2– 4]. Furthermore, systematic radical approaches lead to overtreatment with an
The authors declare no conflict of interest.
* Corresponding author. Tel.: ⫹⫹33612040833.
E-mail address: [email protected] (G. Bozzini).
1078-1439/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.urolonc.2012.05.011
absolute survival benefit at 15 years of only 1% among a
PSA-screened population [5]. Also, the European Screening Study revealed that 1,410 men have to be screened
and 48 diagnosed to avoid 1 CaP-related death over a
9-year interval [6]. With PSA screening, development of
new prostate biopsies protocols, and magnetic resonance
imaging (MRI), the accuracy of detection and localization has increased. As a corollary, a growing number of
small-volume and low-grade cancer foci are diagnosed in
young healthy men.
For part of these low risk localized CaP, active surveillance is another viable option of management [7]. In
the literature, the most accomplished active surveillance
study is the one reported by Klotz et al. [7] on 450
patients. The overall survival was 78.6% and specific
survival was 97.2% at 10 years. After a median follow-up
2
G. Bozzini et al. / Urologic Oncology: Seminars and Original Investigations xx (2012) xxx
of 6.8 years, only 30% of patients were treated surgically.
However, only 1 prospective randomized trial compared
radical prostatectomy and active surveillance on respective cohorts of 347 and 348 patients with a median
follow-up of 12.8 years. The results showed a gain of
6.1% specific survival at 15 years in favor of radical
prostatectomy and a relative risk of death with surgery
significant of 0.62 [8]. This result underlines the potential
shortfalls of active surveillance. Moreover, it induces
important psychological stress for patients, and it is often
difficult for clinicians to propose this management option
to young men with long life expectancies.
Focal therapy is an emerging alternative treatment option, which offers great hopes in terms of cancer control and
decreased morbidity for localized CaP. The challenge of
current focal therapy modalities is to treat only localized
tumors, sparing the rest of the prostate, especially near the
neurovascular bundles and the urethral sphincter, to minimize the potential morbidity.
The concept of focal therapy remains controversial
among the urological community because CaP is frequently
multifocal. Multifocality was reported in 50%– 87% cases
in contemporary series of radical prostatectomy [9 –11].
However, Stanford University group showed that in case of
multifocal localizations, only the volume of the index lesion
itself (i.e., the main lesion) is predictive of progression
[10,12,13]. A threshold volume of 0.5 ml is currently held to
discuss clinically significant lesion size. This volume corresponds to a 10% risk of extraprostatic extension [14]. In
addition, CaPSURE group showed that the proportion of
patients with unilateral cancer of small volume and low risk
was increasing with a percentage of 29.8% in 1989 –1992
against 45.3% in 1999 –2001 [11]. More recently, Mouraviev et al. [15] reported unilateral and/or unifocal disease in
13%– 67% of patients.
Although the idea of focal treatment is simple, the application for CaP met some difficulties: criteria of patient’s
selection for focal therapy, precise localization, visualization, and characterization of significant cancer foci, accurate
guidance of ablative energy into the area to be targeted,
oncologic efficacy evaluation, and finally surveillance modalities.
Different energy modalities are experienced and some
preliminary results are being published. Further prospective
trials are needed to highlight the full potential of each
technique. Thus, it is still too soon to compare the efficacy
of these approaches. Practical aspects, such as length of the
procedure, cost-effectiveness, equipment size, . . . . are important factors that could, in the future, promote one technique above the others.
In this article, a description of the principles of each
energy modality as well as information on their practical use
is provided to help understanding the different techniques
and compare them.
2. Focal cryotherapy
2.1. Principles
Cryotherapy consists in cellular destruction by freezing.
The prostate cooling is obtained by introducing transrectal
ultrasound (TRUS)-guided needles using a transperineal
approach. A temperature of ⫺40°C is reached at the central
part of the prostate and the surrounding area using argon
based probes. This technique relies on pressurized gas that
can freeze (argon gas) and actively warm (helium gas)
through the Joule-Thompson effect in which different gases
undergo unique temperature changes when depressurized
according to unique gas coefficients. The introduction of
thermocouples for systematic temperature monitoring and
use of a urethral warming device have substantially contributed to a reduction in cryotherapy-associated morbidity.
Thermal control is ensured at the urethral sphincter, prostatic apex and close to the neurovascular bundles by inserting monitoring probes. A warming Foley catheter is inserted
to protect the urethra, and the rectum can be protected by
injection of a saline solution in the interprostatorectal space.
Two cycles were completed in the procedure initially described by Onik et al. [16]. The two parameters that correlate
with the likelihood of cell destruction are the cooling rate
during freezing and the lowest temperature reached. Temperatures lower than ⫺40°C are required to completely destroy
cells and a double freeze-thaw cycle results in more extensive
tissue damage and cell death than a single cycle.
Cryosurgery destroys cancer cells by brutal and repeated
freezing of the prostate. The treatment leads to cell death by
denaturing cellular proteins by dehydration, rupture of the
cell membranes by ice crystals, ischemia related to vascular
stasis, and micro thrombi [17].
Cryotherapy procedure can be monitored with TRUS by
visualization of the ice ball front. An experimental MRIcompatible robot used to insert needles into the prostate was
recently developed and should soon allow for MRI-real time
monitoring [18]. This relies on the development of MRIcompatible cryoprobes currently used for liver and kidney
cancer treatment [19].
2.2. Pros and cons
● Focal cryotherapy is not yet a validated management
option for localized CaP. Several studies have been reported with median follow-up of 12–70 months and
biopsy proven recurrence rates of 4%–23%. Regarding
functional outcome potency and continence were preserved in, respectively 65%–90% and 95%–100% [20 –
26].
● This TRUS-guided treatment mobilizes expensive and
bulky equipment, such as argon and helium gas bottles.
● The ice ball front can be monitored during treatment
using ultrasonography and allows for real-time monitoring of the procedure.
ASTRO criterion ⫽ 3 successive rises in PSA levels; BDFS ⫽ biochemical disease-free survival; GS ⫽ Gleason score; HR ⫽high risk; IR ⫽ intermediate risk; LR ⫽ low risk; NA ⫽ not available; Phoenix
criterion ⫽ PSA nadir ⫹ 2 ng/ml; Pts ⫽ patients.
77/77 (100%)
No significant
difference
in IIEF
10/77 (13%); 7 in untreated areas
and 3 in treated areas
Phoenix
TRUS-guided biopsy
24 Months
5–8
6.5
Hemiablation
Phoenix
Truesdale
2010
77
1 Year
⬍6–9
795
NA
Dhar 2009
NA
4.5 Years
3–8
48
Focal ablation
Onik 2008
7.8
3.6 Years
3–8
55
Focal ablation
Onik 2007
8.3
15 Months
3–10
60
Hemiablation
7.2
28 Months
6–7
25
6
None
Rectal fistula
(0.4%)
784/795 (99%)
87/134 (65%)
36/795 (4.5%)
LR: 81%
IR: 81%
HR: 83%
LR: 64%
IR: 69%
HR: 35%
56/77 (73%)
ASTRO
None
48/48 (100%)
36/40 (90%)
5/48 (10%) in untreated areas
45/48 (94%)
52/55 (95%)
ASTRO
48/60 (80%)
ASTRO
ASTRO
None
54/55 (95%)
44/51 (85%)
53/55 (96%)
24/34 (71%)
25/25 (100%)
17/25 (71%)
3/25 (12%); 2 in untreated areas
and 1 in treated area
14/60 (23%); 13 in untreated
areas and 1 in treated area
4/55 (7%) in untreated areas
21/25 (88%)
Phoenix
None
31/31 (100%)
24/27 (89%)
1/25 (4%) in untreated area
26/28 (93%)
ASTRO
2 Sets of TRUS-guided
biopsy
1 set of TRUS-guided
biopsy
1 set of TRUS-guided
biopsy
3D-mapping transperineal
biopsy every 5 mm
3D-mapping transperineal
biopsy every 5 mm
NA
70 Months
5–7
Hemiablation
Table 2
Summary of clinical studies on focal cryotherapy
HIFU produces ultrasound waves generated by a spherical transducer. The ultrasonic energy is focused on a fixed
point. Ultrasound waves deposit energy as they travel
through tissues. During imaging and exploration modes, this
deposited energy is insignificant. By increasing the intensity
of the waves and focusing them on a single point, HIFU
allows for the deposition of a large amount of energy into
tissue, resulting in its destruction through cellular disruption
and coagulative necrosis [27]. Two mechanisms of tissue
damage are involved: thermal effect and cavitation [28].
The thermal effect relies on the absorption of ultrasound energy by the tissue and its conversion into heat. In adequate
conditions, the temperature within sonicated tissue will raise to
a sufficient level to induce irreversible damages. Damages are
classified into three groups: hyperthermia that can destroy
malignant cells in with low temperatures (41 ⬃ 49°C) during
GS
3.1. Principles
4.9
Follow-up
3. Focal HIFU
31
Pros and cons of focal cryotherapy are summarized in Table
1. Clinical results are presented in Table 2.
Hemiablation
Cancer diagnosis modality
Criterion
for BDFS
BDFS
● Intraprostatic needle insertion requires transperineal
access. This percutaneous approach is attractive but
the inability to reach the anterior part of the prostate
because of the conflict with rigid structures (such as
the pubic bone) is a major drawback.
● Clinical and radiologic follow-up after focal therapy may
be complicated from prostate morphologic modification.
● In case of treatment failure, radical prostatectomy remains a feasible option but the procedure becomes
more technically difficult because of tissue rehandling.
3
Bahn
2006
Lambert
2007
Ellis 2007
Continence
Potency
Biopsy proven recurrence
● Biopsy proven recurrence rate: 4%–
23%
● Median follow-up: 12–70 mo
● Secondary radical treatment possible
in case of failure but more difficult
● Anterior fibro-muscular stroma is a
complex region to reach
● Modification of prostate morphology:
clinical and radiological follow-up
more complex
● Preoperative hormonotherapy in 0%–
92% of cases
● Procedure cost:
€2,500 for 5 needles, 1 urethral
warming catheter, and 2 thermal
monitoring probes
€160 for argon gas bottle per
procedure
● Overcrowding of the operating room
Mean preoperative
PSA (ng/ml)
● Real time monitoring with
trans rectal
ultrasonography
(visualization of the ice
ball)
● Perspective of real time
monitoring with MRI
● Possibility of secondary
radical treatment in case of
failure
● Short hospital stay (2–3 d)
● Less morbidity than radical
approaches:
- Potency: 65%–90%
- Continence: 95–100%
N°
pts
Cons
Ablative
template
Pros
Adverse
events
Table 1
Advantages and disadvantages of focal cryotherapy
Retention
(n ⫽ 1)
None
4
Fig. 1. Classification of heat-induced damages. (Color version of figure is available online.)
an extended period (⬎10 min), coagulation which consists in
necrosis of tumor tissue without immediate ablation (level of
protein denaturation 57 ⬃ 60°C) and vaporization inducing
tissue necrosis and charring (temperature ⬎100°C) (Fig. 1).
Cavitation is the result of the interaction of ultrasound and
microbubbles of water. This interaction may lead to oscillation
of these microbubbles, violent collapses and dispersion of
energy enhancing tissue ablation.
This technique provides the advantage of a transrectal
treatment with prostate destruction while sparing the rectum
itself. By combining precise control over the position of the
transducer within the rectum and active cooling of the rectal
mucosa, the risk of rectal injury is minimized. Two devices
are available for the treatment of CaP with HIFU: Sonablate
and Ablatherm.
3.2. Pros and cons
● Focal HIFU is not yet a validated management option for
localized CaP. Several studies have been reported with
median follow-up of 12–120 months and biopsy proven
recurrence rate of 8%–23%. Regarding functional outcome, data were inconsistently reported but potency and
continence were preserved, respectively in 89%–95%
and 90 –100% [29,30 –33].
● It is the least invasive technique requiring only intrarectal probe insertion.
● It relies on bulky, expensive, and difficult to transport
equipment. This treatment modality is not available in
every institution.
● Tumor location is also an important parameter. To avoid
urethral lesions, tumor located near the prostatic apex or
near the midline should not be treated using this energy
modality. Also, HIFU cannot reach anterior tumors, located too far away from the energy source.
● This treatment can be repeated in case of primary
failure but with an increased risk of side effects [34].
As with focal cryotherapy, radical prostatectomy remains a potential option in case of failure but is to be
more difficult than usual because of tissue rehandling.
Also, follow-up might be more complicated than after
radical treatment.
● Prostate size is a limiting factor and preoperative
transurethral resection of the prostate (TURP) is frequently proposed to reduce the size of the gland.
Pros and cons of focal high intensity focused ultrasound
(HIFU) are summarized in Table 3. Clinical results are
presented in Table 4.
4. Focal photodynamic therapy (PDT)
4.1. Principles
Raab [35] and Tappeiner et al. [36] initially described
PDT at the beginning of the 20th century. PDT is based on
the interaction between light brought by a laser fiber, a
photosensitive agent (PS) administrated orally or intravenously, and oxygen present in tissues: the absorption of a
luminescent photon by the PS leads to a chain reaction
inducing the release of singlet oxygen and antioxidant enzymes. This singlet oxygen can directly kill tumor cells by
the induction of necrosis and/or apoptosis, or cause destruc-
Table 3
Advantages and disadvantages of focal HIFU
Pros
Cons
● Noninvasive treatment (no
intraprostatic needle)
● Possibility of repeated
procedure
radical treatment
● Short hospital stay
● Limited morbidity:
- Potency: 95%
- Continence: 90%–100%
● Median follow-up: 12–120 months
● Biopsy proven recurrence rate:
8%–23%
● Possibility of rectal lesions (US
probe introduction)
● Not applicable for all prostatic
tumors
● Secondary radical treatment
possible in case of failure but more
difficult
● Modification of prostate
morphology: clinical and
radiological follow-up more
complex
● Preoperative TURP and/or
hormonotherapy
● Length of procedure: 3–4 h
● Overcrowding of the operating
room
tion of tumor vasculature, producing an acute inflammatory
response that attracts leukocytes, such as dendritic cells and
neutrophils [37].
When administrated systemically, PS accumulates preferentially in malignant cells [38,39]. PS are mainly administrated intravenously like WST-11 but some of them like
5-ALA or its esters can be given topically or orally. In its
basic state, the PS is pharmacologically inactive and stable.
When light is delivered at an appropriate wavelength, (specific to each PS [40]), the drug goes into an excited phase
and the excess of energy is restored in three ways:
● Release of heat
● Emission of fluorescent photons (used for photodiagnosis)
● Change-over in an intermediate state called “triplet
state”
It is in this “triplet” state that the cytotoxic action of the PS
appears: simultaneously, oxydoreduction reactions leading
to the formation of radical intermediates (type 1 reaction)
and reactions leading to the formation of the highly cytotoxic singlet oxygen by energy transfer from the photoexcited sensitizer (type 2 reaction) [41] are produced. This
type 2 reaction is usually dominating and leads to apoptosis
and necrosis. PS is then destroyed by the singlet oxygen and
the radical intermediates. This decrease of efficiency
through time corresponds to the decrease of induced-fluorescence called “photobleaching.” Cell destruction induces
the decrease of fluorescence [42], making this a corollary to
the efficacy of the treatment.
Accomplishment of PDT requires intraprostatic laser fibers placement. This is achieved through transperineal approach using a brachytherapy template under TRUS-guidance. After fibers placement, interstitial illumination must
5
be conducted in a darkened room to prevent cutaneous
photosensitization.
4.2. Pros and cons
● Focal PDT is another technique requiring transperineal needle insertion. Its particularity relies on the
administration of a photosensitizer that can be activated by light in the vasculature or in the tissue. Some
photosensitizers have the advantage of being selective
of neoplastic cells [43,44] but they can also induce
side effects. Trials are very heterogeneous, using different photosensitizers and different ablative templates. Recently, 2 phase II trials using WST 11 were
completed and oncologic results are expected. From a
functional outcome standpoint, no change from baseline was observed when using IPSS and IIEF scores
[45,46].
● This modality uses diode lasers as the energy source
with all the advantages cited above.
● This treatment also alters prostate morphology and
follow-up may be more challenging than usual. In case
of a primary failure, a repeat treatment and radical
approaches are 2 feasible options. (Azzouzi A-R, Emberton M: Results of Tookad soluble vascular targeted
photodynamic therapy (VTP) for low risk localized
CaP (PCM203), presented at the AUA 2011, Washington DC).
● Reliable treatment planning is still lacking and its
elaboration relies on the integration of 3 variables:
light distribution, photosensitizer distribution and oxygen present in tissues. This issue is still being investigated and a 2-mm precision can be achieved for
Jankun et al. [47], while Betrouni et al. [48] reported
an 84.89% correlation between simulated volumes and
MRI-obtained volumes after swelling correction.
● PDT can be considered as an oxygen-dependent therapy like external beam radiation. Following this example, several teams reported that fractionated treatment might be more effective [49,50]. However, this
raises the question of PDT efficacy for hypovascular
or hypoxic prostate tumors [51–53].
Pros and cons of focal PDT are summarized in Table 5.
Clinical results are presented in Table 6.
5. Focal laser ablation (FLA)
5.1. Principles
FLA was initiated in the 1970s [54]. Its applications typically uses neodymium-yttrium-aluminum-garnet (NdYAG)
lasers at 1,064 nm or diode lasers at 830 nm. The Nd-YAG
laser has deeper penetrating abilities, but it is bulkier and
more expensive. The technologically more advanced
980-nm diode lasers are increasingly used.
6
Ablative template
N°
pts
Mean
preoperative
PSA (ng/ml)
GS
Follow-up
Cancer diagnosis
modality
BDFS or RFS
RP specimen
analysis
Biopsy
proven
recurrence
Potency
Continence
Adverse events
Madersbacher
1995
True focal
10
24.5
NA
NA
Unilateral echoic
lesion and
histology
proven
NA
NA
NA
NA
No rectal wall
lesion during
surgery; no
NVB lesion on
histology
Muto 2008
Posterior hockey
stick
29
5.4
5–10
32 Months
MRI and TRUSguided biopsy
At 6 mo:
3/28 (11%)
At 12 mo:
4/17 (23%)
NA
29/29 (100%)
None
Ahmed 2011
Hemiablation
20
7.3
4 ⫹ 3 or
less
12 Months
NA
At 6 mo:
2/19 (11%) in
the treated
lobe
19/20 (95%)
18/20 (90%)
El Fegoun
2011
Hemiablation
12
7.3
3 ⫹ 4 or
less
10 Years
MRI and 3Dmapping
transperineal
biopsy every 5
mm
TRUS-guided
biopsy
ASTRO
2 years BDFS:
LR: 83%
IR: 54%
HR: 0%
NA
3 Complete
destruction
of the
tumor and
7 partial
destructions
(mean
53%)
NA
NA
At 1 year:
1/12 (8%)
NA
12/12 (100%)
Hematuria (65%);
dysuria (30%);
urethral
stricture
(n ⫽ 1)
2 UTI
1 retention
Ahmed 2012
Hemiablation or
midline
ablation or
bilateral 2areas ablation
41
6.6
4 ⫹ 3 or
less
12 Months
NA
At 6 months:
9/39 (23%) of
which 3/
39 (8%)
had
significant
cancer
31/35 (89%)
38/38 (100%)
MRI and 3Dmapping
transperineal
biopsy every 5
mm
RFS:
90% at 5 years
38% at 10 years
NA
Dysuria (22%);
urinary debris
(34%); UTI
(17%); 1
retention
ASTRO criterion ⫽ 3 successive rises in PSA level; BDFS ⫽ biochemical disease-free survival; GS ⫽ Gleason score; NA ⫽ not available; NVB ⫽ neurovascular bundle; Pts ⫽ patients; RFS ⫽
recurrence-free survival; RP ⫽ radical prostatectomy; UTI ⫽ urinary tract infection; HR ⫽ high risk; IR ⫽ intermediate risk; LR ⫽ low risk; MRI ⫽ magnetic resonance imaging.
Table 4
Summary of clinical studies on focal HIFU
Table 5
Advantages and disadvantages of focal PDT
Pros
Cons
● Possibility of repeated treatment
● Possibility of secondary radical
treatment
● Limited clinical experience
● Transperineal needle insertion
is difficult for anterior tumors
possible in case of failure but
more difficult
● Lack of reliable treatment
planning
● Limited morbidity: no
modification in IPSS and IIEF-5
scores
● Cost: €200 per fiber
€15,000–60,000 for a laser source
● Potential photosensitizer side
effects
● Treatment modality oxygendependent: efficacy on
hypoxic tumors?
● Use of diode laser with very long
life expectancy
● No overcrowding of the operating
room (laser source weight ⫽ 2–5
kg)
● Photosensitizer selectivity for
neoplastic cells
7
● This treatment modality requires transperineal access
for needles insertion. Reaching the anterior part of the
prostate can be an issue.
● Medical laser sources are becoming small devices
(laptop size) and thus suitable for operating room
conditions. Their costs are also limited compared with
the devices used for cryotherapy or HIFU (between
€15,000 and 60,000).
● Laser fibers are MRI-compatible allowing treatment
monitoring using MR-thermometry. It can also be
achieved using fluoroptic thermometry that consists in
inserting a probe in region of interest of the prostate.
● Current lack of reliable treatment planning is a major
drawback and is still being investigated [62].
● As for other techniques, follow-up might be more
complicated than after radical approaches but radical
prostatectomy remains feasible in case of primary
failure [61]. Pros and cons of focal laser ablation
(FLA) are summarized in Table 7.
6. Other focal therapy modalities
Energy is delivered to the prostate using laser fibers
inserted using a transperineal approach through needles.
The thermal effects produced by the laser energy spread
from the absorption zone and cause an increase in the
temperature of surrounding tissues. Damages can be classified as described in Fig 1. Studies have shown that wavelengths between 800 and 1,100 nm have comparable effects
[55,56]. The results obtained in vivo on canine model and
cadavers demonstrated a good penetrating power and easy
handling [56 –58]. Penetration of the laser beam also varies
according to optical and thermal properties of the target
tissues. Monitoring of the procedure can be achieved by
using fluoroptic thermometry next to critical structures,
such as the prostate apex or near the rectum or by using
MR-thermometry [58,59].
5.2. Pros and cons
● FLA is not yet a validated management option for localized CaP. Lindner et al. [60] performed a radical prostatectomy 1 week after a targeted-FLA procedure on 4
patients. They reported complete ablation of the targeted area with no viable cell remaining and good
correlation between necrosis volume predicted on
MRI and histologic necrosis volume with CK8 staining (vital stain ablation volume).
● A phase I trial has been reported with 50% of patients
free of cancer and 67% of patients free of cancer in the
treated lobe. From a functional standpoint, potency
and continence were not altered [61].
● It is among the youngest techniques of focal therapy
and few data are available regarding oncologic and
functional outcome.
6.1. Interstitial microwave thermal therapy
Microwave antennas launch electromagnetic waves in
the frequency range of 300 MHz to 2,450 MHz into the
surrounding tissue. The waves cause small electric currents
propagating through tissue, causing it to heat up. Microwaves applicators are inserted in the prostate through the
perineum and each one is housed within a water-cooling
jacket. Rectum and urethra are protected using thermocouples and cooling Foley catheter.
To the best of our knowledge, microwave thermal therapy has mainly been performed for recurrent cancer after
external beam radiation, and no attempt of focal therapy is
available in the PubMed database.
Sherar et al. [63] reported the feasibility and safety of
this modality for radio-recurrent CaP.
Lancaster et al. [64] reported a whole-gland microwave
thermal therapy on 1 patient with a localized CaP. At 18
months, PSA was still undetectable and no complication
arose.
Recently, Cheng et al. monitored successfully a procedure on a preclinical dog model using MRI and contrastenhanced ultrasound [65].
Development of medical imaging and biopsy strategies
makes possible the realization of focal microwave thermal
therapy.
6.2. Radiofrequency interstitial tumor ablation (RITA)
The energy is produced by a radiofrequency (rf) generator that can reach 50 W with a frequency of 460 kHz. It is
administered through a 15-gauge needle with monopolar
triple-hook electrodes separated by a 120° angle, describing
8
Ablative
template
PS
N° pts
Light delivery
path
GS
PSA
MRI results
PSA response
Remaining
cancer on
biopsy
Incontinence
Potency
Adverse effects
Windahl 1990
Post TURP
remnant
2
Transurethral
Post TURP
NA
6 and 10
NA
NA
NA
None
Variable
6
5–8
4.9–10.6
NA
NA
None
NA
None
Moore 2006
Hemi-ablation
Temoporfin
6 (10 procedures)
- transperineal (2)
- transurethral (3)
- during RP (1)
Transperineal free
hand insertion
Reduction from
10 to 2.5 and
from 6 to 0.2
Reduction of
20%–70%
0/2
Zaak 2003
Hematoporphyrin
derivative and
photofrin
5-ALA
3⫹3
1.9–15
Visible necrosis
areas
Reduction in
8/10
procedures
(14%–67%)
10/10
NA
23
Arumainayagan
2010
Hemi-ablation
and near
whole gland
Hemi-ablation
Padeliporfin
(WST 11)
40
Transperineal
NA
NA
Visible necrosis
areas
NA
NA
None
NA
Padeliporfin
(WST 11)
85
Transperineal
NA
NA
87% necrosis in
the treated
lobe
NA
NA
NA
NA
Azzouzi 2011
GS ⫽ Gleason score; MRI ⫽ magnetic resonance imaging; PS ⫽ photosensitizer; pts ⫽ patients; RP ⫽ radical prostatectomy; TURP ⫽ transurethral resection of prostate.
⁄
- Sepsis (n ⫽ 1)
- irritative voiding
symptoms
- recatheterisation
(n ⫽ 2)
- recatheterization
(2)
- prostatitis (2)
- hematuria (1)
- orchi-epidymitis
(1)
- optic neuropathy
(1)
- prostatic urethral
stricture treated
by TURP (1)
Table 6
Summary of clinical studies on focal PDT
Table 7
Advantages and disadvantages of FLA
Pros
Cons
● Possible real-time monitoring
by MR-thermometry and/or
fluoroptic thermometry
● Possibility of repeated
treatment
radical treatment
● Limited morbidity: preserved
continence and potency
● Laser cost: €15,000–60,000
● fibers cost: €400
● Use of diode laser with very
long life expectancy
● No overcrowding of the
operating room (laser source
weight ⫽ 2–5 kg)
● No use of photosensitizer
● Limited clinical experience
● Biopsy proven recurrence rate: 50%
overall, 33% in the treated lobe
● Transperineal needle insertion is
difficult for anterior tumors
possible in case of failure but more
difficult
● Lack of reliable treatment planning
a 2 cm volume sphere when they are deployed. These
electrodes are introduced into the prostate using transperineal approach under TRUS guidance. Urethra can be cooled
using saline serum irrigation. RITA permits an irreversible
destruction of live tissue by generating temperatures around
100°C that induce a coagulative necrosis in the tumoral
area, without any evidence of venous thrombosis or significant hemorrhages at the tumoral borders [66].
Studies have shown that TRUS-guided RITA treatment
is feasible, safe, and reproducible for the treatment of previously untreated patients with clinically localized CaP,
yielding predictable lesion sizes [66,67].
Shariat et al. [68] reported the RITA procedure on 11
patients (8 after radiation failure and 3 primary treatments).
Before the RITA treatment, systematic sextant and 6 laterally directed biopsies were used to map the local extent of
the disease. Only areas of biopsy-proven cancer were focally ablated.
Overall, 90% of the patients experienced a decrease in
serum PSA superior to 50%, and PSA doubling time after
RITA was longer than that before RITA (mean 37 ⫾ 22 vs.
14 ⫾ 13 months). At 1-year biopsies, 55% of patients were
free of cancer. Minor adverse effects occurred with hematuria (n ⫽ 2), bladder spasms (n ⫽ 1), and burning sensation
during urination (n ⫽ 1). Continence and erectile function
are not mentioned. Two procedures had to be interrupted
because of increase of temperature measured by the rectal
probe.
RITA is a suitable modality for organ-sparing treatment.
Further studies are needed to evaluate its full potential.
6.3. External beam radiation, brachytherapy, cyberknife,
proton therapy
Radiotherapy techniques using photons are widely used
in the management of CaP [69,70]. Several pilot studies in
9
which a microboost is delivered to the dominant tumor
region have been conducted with external beam radiation
[71–73] and brachytherapy [74]. The highest dose was delivered in a feasibility study by Singh et al. [75] who treated
3 patients with an ablative dose of 95 Gy to the macroscopic
tumor within the prostate with no severe toxicity. Tumor
localization was performed by using MRI [71–73], sextant
biopsies [74], or both [75].
In these trials, no severe toxicity was observed, and
Mirabel et al. reported 98% of 5-year biochemical diseasefree survival.
A single blind randomized clinical trial comparing standard external beam radiation to standard external beam
radiation associated to an additional integrated microboost
to the macroscopic tumor of 95 Gy has recently begun with
already 50 patients included [76]. Proton therapy appears to
be another viable option for the focal treatment of CaP but
the cost-effectiveness ratio is currently not favorable to that
method [77].
Cyberknife is a promising technique offering equivalent
oncologic control and less morbidity than standard external
beam radiation or brachytherapy. To the best of our knowledge, no clinical trial is available on the PubMed database.
However, some trials are presently recruiting.
6.4. Electroporation
Irreversible electroporation (IRE) is a new nonthermal
ablation modality that uses short pulses of DC electric
current to create irreversible pores in the cell membrane,
thus, causing cell death.
In a preclinical canine model, Onik and colleagues [78]
reported the feasibility and efficiency of this procedure for
the treatment of CaP. One of the disadvantages of this
technique is the risk of reflex movements induced by the
electrical impulse that could induce needle displacement
and thus cause damage to healthy structures.
6.5. Nanoparticle thermotherapy
It is a novel method of interstitial heating of tumors
following direct injection of magnetic nanoparticles. Its
feasibility and good tolerability was shown in 2 phase I
clinical trials for whole-gland treatment of localized CaP.
However, this new approach is limited by patient discomfort at high magnetic field strengths and irregular intratumoral heat distribution [79].
7. Discussion
Focal therapy for CaP remains to become a validated
management option for localized CaP owing to a lack of
evidence regarding oncologic efficacy [80]. This assessment
is applicable to all energy modalities. More data with longer
follow-up are available for HIFU and cryotherapy but it
10
remains insufficient to recommend those treatment modalities outside of a clinical trial. For FLA and PDT, data are
more recent with short follow-up and phases II and III
clinical trials are ongoing.
For all these therapies, clinical studies involved a small
sample with short follow-up. Preliminary data on oncologic
outcomes is encouraging but lasting cancer control can only
be demonstrated with extended follow-up of larger patient
cohorts. Furthermore, there is still no consensus on what
patient eligibility criteria for focal therapy should be.
Though focal therapy is now understood to be indicated
for low risk localized CaP [81], different diagnosis strategies are being used to adequately map cancer foci among
the prostate. The aim is to adequately identify and localize
clinically significant tumor inside the prostate.
For some authors, only transperineal saturation biopsies
can now enable an accurate mapping of the locations, dimensions, and uni- or multifocal tumor lesions [82– 84].
However, this technique comes with high cost and possible
biopsy-related complications. For others, the couple MRI/
TRUS-guided biopsy would allow for detection of the index
lesion. Villers et al. have shown that it is possible to detect
tumor sites ⬎0.33 ml using multiparametric MRI [85].
Furthermore, real-time MR-guided intervention has recently
become available for prostate biopsy, supported by integrated technology that utilizes a robotic-assisted needle delivery system [86]. MRI may also enable guidance of transrectal biopsy to increase the sensitivity and specificity of
detection (especially for anterior fibromuscular stroma cancers). Emerging TRUS technologies, including contrastenhanced ultrasound, Doppler ultrasound, elastography, and
fusion MR-ultrasound imaging should further enhance diagnostic accuracy.
In the presented trials, patient selection was heterogeneous between studies. Gleason score and mean preoperative PSA were not comparable. Some authors proceeded to
the tumoral mapping using TRUS-guided biopsies while
others used only transperineal saturation biopsies. Ablative
templates were different from 1 study to another.
Defining treatment success or failure often relies on PSA
level. Biochemical standards for defining treatment success
or failure have not been established for focal therapy. Astro
(3 successive PSA rises) or Phoenix criteria (PSA nadir ⫹
2 ng/ml) are usually used but their validation applies only to
external beam radiation, and no evaluation has been made
regarding their pertinence for FT. Once again, there is no
standardization between studies in the use of these criteria.
Moreover, using PSA nadir after FT is difficult because this
treatment leaves in place a variable portion of the prostate
that can still produce PSA.
Relying on PSA levels alone to assess the efficiency of
FT seems insufficient because there is no hard proof that
biochemical disease-free survival is related to overall or
specific mortality.
As for TRUS-guided biopsy or imaging methods on their
own, they are at present unreliable due to lack of sensitivity.
Once again, emerging TRUS technologies (contrast-enhanced ultrasound, Doppler ultrasound, elastography, and
fusion MR-ultrasound imaging) should be evaluated in this
indication.
In the presented trials, assessment of oncologic efficacy
was performed using random TRUS-guided biopsies and
multiparametric MRI in the most recent studies. Follow-up
of FT procedures was mainly performed using PSA levels.
As previously discussed, these modalities lack sensitivity.
Retargeting devices allowing to rebiopsy the previously
identified tumoral area (Urostation System - Koelis, La
Tronche, France) should be able to increase detection rate of
treatment failure [86].
However, all clinical data available on focal therapy
regarding functional outcome are promising, with better
continence and potency rate than with radical approaches.
However, functional data were inconsistently reported in
the different series, leading to a potential bias.
In the hypothesis of oncologic control equivalence and
comparable morbidity of each energy modality, the potential advantages and disadvantages of these different organsparing approaches should be reported.
Repeatability of FT procedure and possibility of secondary radical treatment in the case of failure are advantages
shared by all energy modalities. However, clinical and radiologic follow-up can be more complex and less reliable
due to the modification of prostate morphology after treatment. Another advantage of all FT procedures is the shorter
hospital stay than with radical approaches leading to decreased economic impact.
Real-time monitoring is an important parameter allowing
control of adequate progress of the procedure and precise
delivery of the energy on cancer foci. Currently, MR-thermometry can be used to monitor tissue temperature during
FLA. Transrectal ultrasound can be used to monitor focal
cryotherapy by revealing the ice ball front [87].
Also, MRI is a valuable asset, allowing real-time guidance of needle insertion but it remains a complex procedure
requiring expensive compatible equipment [86].
HIFU relies on a bulky device, difficult to transport as
cryotherapy relies on argon and helium gas bottles leading
to an overcrowding of the operating room. Technological
improvement of diode laser sources now led to the development of very light lasers (between 2 and 5 kilos) that are
easily transportable and with a very long life expectancy,
reduced maintenance requirements, and storage cost. HIFU
appears to be a less invasive procedure but risks of rectal
lesions cannot be excluded.
Transperineal insertion of the needles is used for FLA,
PDT, and cryotherapy. This approach makes access to anterior tumors difficult from the conflict with the pubic arch.
Robotics development permitting automated mechanical delivery of the intervention needle through different angles
may provide a solution.
Prostate volume is another limitation of HIFU frequently
requiring transurethral resection of prostate (TURP) before
HIFU. By contrast, FLA and PDT can be performed initially.
Currently, energy modalities available for FT have different advantages and disadvantages and none can be preferred based on practical aspect. In the future, it is likely that
each technique will have its specific indications based on
tumor and patient characteristics. Prospective trials are still
lacking to confirm the oncologic efficacy of focal therapy.
8. Conclusions
Focal therapy is emerging as an intermediate option
between radical approaches and watchful waiting in the
management of low-risk CaP in carefully selected patients.
As it remains to be validated by scientific societies, its
application must be confined to clinical research.
Several energy modalities are being developed to
achieve the trifecta of continence, potency, and oncologic
efficacy. Those techniques carry a low morbidity but clinical experience is limited to define the oncologic outcome.
Comparison of the different focal approaches is complex
owing to important heterogeneity of the trials. Each energy
modality has its own advantages and disadvantages, and
currently none has proven to be superior to the others.
Selection of the most suited organ-sparing approach must be
decided with the patient, depending on the tumor characteristics.
9. Acknowledgments
The authors thank Eric Barret for the information regarding cryotherapy and Pascal Servell for the English editing.
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Focal therapy of prostate cancer: energies and procedures

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