FOCAL THERAPY FOR PROSTATE CANCER: A POTENTIAL STRATEGY TO Emilie Lecornet

Special Article
Arch. Esp. Urol. 2010; 63 (10): 845-852
FOCAL THERAPY FOR PROSTATE CANCER: A POTENTIAL STRATEGY TO
ADDRESS THE PROBLEM OF OVERTREATMENT
Emilie Lecornet1,2, Hashim Uddin Ahmed1, Caroline Moore1 and Mark Emberton3.
Division of Surgery and Interventional Sciences. University College of London. London.
Service d’Urologie. Hôpital Claude Huriez. France.
3
UCLH/UCL Comprehensive Biomedical Research Centre. London.
1
2
Summary.- Focal therapy for localized prostate cancer involves destroying the cancer focus in order to offer
patients the potential of combining cancer control with
minimal side-effects. Current standard of care involves
either active surveillance or radical therapy. Neither of
these is ideal. Active surveillance carries a risk of under-treatment, with psychological morbidity as a result
of anxiety and is associated with side-effects due to repeated biopsies, although radical therapy is the gold
standard for curative treatment. With the proportion of
unifocal or unilateral disease among men with low-risk
disease rising, a focal approach could avoid both under
@
CORRESPONDENCE
Emilie Lecornet
Division of Surgery and
Interventional Sciences
University College of London, 67
Riding House Street
London W1P, 7PN (England)
[email protected]
Accepted for publication: December 27th, 2009
and over-treatment. With the advent of improved accuracy for cancer localization provided by multi-parametric MRI and new biopsy strategies such as transperineal
mapping biopsies, ablative modalities such as cryotherapy, high intensity focused ultrasound, photodynamic
therapy and radio-interstitial tumour ablation make focal
treatments a real possibility.
Keywords: Focal therapy. Cryotherapy. HIFU.
Photodynamic therapy. Prostate cancer.
Resumen.- La terapia focal entraña la destrucción del
foco cancerígeno y el tejido circundante para ofrecer a
los pacientes el potencial de combinar control oncológico y mínimos efectos colaterales. El tratamiento estándar
actual incluye vigilancia activa o tratamiento radical.
Ninguna de estas opciones es ideal. La vigilancia activa conlleva el riesgo de infratratamiento, morbilidad psicológica como resultado de la ansiedad, y no está libre
de efectos colaterales debido a las biopsias repetidas.
Aunque el tratamiento radical es el patrón oro del tratamiento curativo, conlleva riesgos de sobretratamiento
con sus numerosos efectos colaterales. Con el aumento
de la proporción de cánceres unifocales o unilaterales
entre varones de bajo riesgo, un abordaje focal podría
evitar tanto el infra como el sobretratamiento. Con la
mejora de la precisión de la localización del cáncer
proporcionada por la resonancia magnética nuclear
multiparamétrica y las nuevas estrategias de biopsia
como los mapas biópsicos transperineales, las terapias
ablativas como crioterapia, ultrasonidos focalizados de
alta intensidad (HIFU), terapia fotodinámica y ablación
radiointersticial de tumores hacen del tratamiento focal
una posibilidad real.
846
E. Lecornet, H. U. Ahmed, C. Moore, et al.
Palabras clave: Terapia focal. Crioterapia.
HIFU. Terapia fotodinámica. Cáncer de próstata.
INTRODUCTION
Focal therapy for localized prostate cancer is a new therapeutic strategy that was recently added to the armamentarium of management
approaches that could be adopted as an alternative to active surveillance and the numerous radical therapies already in practice. This article will
outline why the standard options for men are not
ideal. Secondly we discuss improvements in cancer
localization with MRI and biopsies and the current
literature base on the focal therapy treatments available (1,2). Finally, we will discuss which patient
group is best placed to receive focal therapy.
Concept of focal therapy
Management of localized prostate cancer
currently consists of two extremes: active surveillance
on the one hand and radical treatment on the other.
A greater of proportion of localized low to intermediate risk prostate cancers are now detected due to
PSA screening. Men with localized prostate cancer
are often young and have a life expectancy of more
than 15 years. The vast majority of men are not keen
on the functional and quality of life outcomes that are
traditionally associated with radical therapy but also
want to have their cancer controlled. There is a lack
of long-term data from active surveillance protocols
coupled with the inability at the moment to reassure
men that they have been accurately risk stratified and
do not have a higher risk disease which could result
in adverse outcomes. A focal treatment, destroying
the cancer focus and a small margin of normal tissue
surrounding the cancer, may be a solution for these
patients.
In recent years, different techniques of focal
treatment have been evaluated and developed. This
has largely been possible through improvements in
prostate cancer localization, using imaging as well
as prostate mapping biopsy techniques, as well as
development of ablative techniques.
Problems of standard care
Active surveillance
Patients who fulfil current active surveillance criteria represent a very low-risk group. Criteria
commonly used are PSA<10ng/ml, PSA doubling
time>3years, Stage T1c to T2a, Gleason<7, percentage of positive number of cores and tumor presence
<50% of a single biopsy core (3-8). However, these
criteria may not be strict enough as the diagnostic test
that they are based on has significant random and
systematic errors. It is not surprising therefore, that 1
in 4 to 1 in 3 men initially suitable for active surveillance were found to have higher Gleason grade or
burden of cancer on repeated biopsies (9).
In addition, although active surveillance is
thought to have no side-effects, as there is no treatment until progression, this assertion should be somewhat moderated. Active surveillance can involve
deterioration of quality of life as shown by health
questionnaires (10-13). We should also take into
consideration the psychological burden of living with
an untreated cancer with the uncertainty of disease
progression and anxiety as well as healthcare and
financial burdens associated with an intense surveillance programme. Some groups have tried to show
the psychological consequences of active surveillance
(14-16), finding higher anxiety levels due to surveillance. However, others did not find this (17).
Can we determine whether patients under
this regimen will develop a non-curable cancer during
the period of surveillance? Cases have been reported
of patients who were thought to be suitable for active
surveillance, but at radical prostatectomy were found
to have more aggressive and in some instances incurable disease (i.e., extracapsular extension or lymph
node metastases) (13,18). Many have argued that
because we have a limited ability to predict which
cancers can be safely observed without disease progression (19), surveillance should not be carried out
in any men with prostate cancer (20).
Radical therapy
Once a localized prostate cancer is diagnosed, radical therapy remains the gold standard
treatment with a curative intent. However, radical
whole-gland therapies can give rise to significant
side-effects with adjoining structures suffering damage and injury, such as bladder (especially bladder
neck), neurovascular bundles, external rhabdosphincter and rectum. These can lead to reduced
bladder capacity, urge incontinence, or bladder
neck strictures, urethral strictures, stress incontinence, impotence and bowel toxicity (diarrhoea,
bleeding, pain). The frequency of these effects dependent on the modality employed. Living with the
side-effects of treatment could be worse than living
with the disease itself, which may never progress
or progress at such a slow rate that many men die
FOCAL THERAPY FOR PROSTATE CANCER: A POTENTIAL STRATEGY TO ADDRESS THE PROBLEM OF OVERTREATMENT
of other causes (9). Despite surgery and radiotherapy showing improvements in their delivery, for
example with laparoscopy and robotic surgery, or
intensity modulated radiotherapy, the benefits of
these over traditional surgical and radiotherapeutic approaches are limited with no significant improvements in quality of life after radical treatment
(21,22).
Focal therapy techniques
High intensity focused ultrasound (HIFU)
High energy density is generated by the tight focusing of ultrasound waves. Therapeutic HIFU
is usually delivered using low frequencies (3.5-4.5
MHz), causing heat and “inertial cavitation” and then
tissue destruction. When temperatures rise to 56°C
and this temperature is held for at least 1 second,
tissue damage can occur, with resultant coagulative
necrosis and an inflammatory response. In HIFU, the
temperature achieved is typically above 80°C. Two
transrectal devices currently exist: the Ablatherm®
device (Edap-Technomed, Lyon, France) and the Sonablate® 500 (Focus Surgery, Indianapolis, IN).
847
size allows the surgeon to make a relatively precise
treatment, so the damage to surrounding structures
can be minimized. However, the lack of real-time feedback is problematic as all the user visualises is a
hypoechoic ice-ball front which does not represent the
temperature gradient accurately.
Cryotherapy is the most studied ablative therapy technique. Ahmed et al identified 13 cryotherapy series reporting extractable data, and found that,
according to ASTRO criteria, cryosurgery has good
biochemical control (25) using a whole-gland treatment. Using Phoenix criteria, it was found that there
was 80.5% 10 year biochemical disease free survival for low-risk groups. The 5-year rate was 91.1%.
10-year rates for negative biopsy status was 73.8%
(26).
Data from focal cryotherapy studies, although more recent and therefore limited by short
follow-up, found biochemical disease free rates varying between 80% to 96% (9, 27 - 31) with disease-free survival of 84% at 3 years (26). However,
comparison between studies is difficult since there is
no agreed or validated measure of success or failure
after focal therapy.
Recent review data regarding HIFU in the
use of whole-gland ablation demonstrate five yearnegative biopsy rates from 87% to 97% (1) (23, 24)
with five-year disease free survival rates, according to
ASTRO criteria, varying from 66% to 78% (1) (24).
Reported side-effects using the whole-gland approach are incontinence (0.5%-15.4%), urethral stricture
(24%), fistula (0-2%) and impotence (13-53%) (25)
However, these side-effects are poorly reported (1).
HIFU is promising because it allows precision in targeting lesions and it seems to have a low morbidity.
In addition, MRI thermography could be coupled to
the energy in order to permit temperature monitoring
during the treatment.
Morbidity seems to be diminished by focal cryotherapy, with a higher health related quality of life,
due to lower rates of incontinence, fistula, or erectile
dysfunction (32). A multicenter study of 106 patients,
using 3rd generation devices, report morbidity rates
in whole-gland cryotherapy of 5% urethral sloughing,
3% incontinence with pad usage, 5% urge incontinence without pads, 3.3% of transient urinary retention,
and 2.6% rectal pain. Contemporary results for potency after focal cryotherapy are about 80-90% (26).
Nevertheless, long-term data are still needed. We will
soon be able to improve the evaluation of focal cryotherapy, as a result of large multicenter databases
such as the COLD (Cryo On-Line Data) registry.
Cryotherapy
Photodynamic therapy (PDT)
Cryotherapy involves freezing and waving to
destroy cancer. Tissue destruction is caused by vascular injury, direct cytolysis, ice crystal formation, intracellular dehydration, pH changes, cryoactivation of
immune responses and induction of apoptosis. It also
causes endothelial damage leading to platelet aggregation and micro-thrombosis. 3 minutes of freezing at
a temperature of -0°C can ablate tissue effectively. 3rd
generation devices for cryotherapy perform prostate
cancer ablation with trans-rectal ultrasound guidance
and urethral warmers. Small probes use pressurized
gas that freeze, and then thaw the tissue. The probe
This uses a photosensitising drug that accumulates preferentially in tissue. The drug is then activated by light of a specific wavelength in the tissue or
in the vasculature. Tissue oxygen is also required for
the treatment effect. The activated drugs, create tissue
damage. This technique is based on a transperineal
approach, using a brachytherapy template to insert
optical fibers that deliver low power laser light to activate an intravenously administered photosensitizer.
A few studies have been reported. Ahmed et
al. found seven studies recently (25). Efficacy related
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E. Lecornet, H. U. Ahmed, C. Moore, et al.
to this technique seems to be promising, but these are
only preliminary results on PSA levels after treatment.
In most of the published studies, there are no biopsy
results. Trials are currently under way to evaluate this
technique further. Preliminary results are encouraging,
but improvements are to be made (33), and cancer
control has yet to be confirmed (1).
TRUS biopsies the retention rate is higher with groups
finding 5-10% rates of acute urinary retention even
when alpha-blockers are used peri-procedure (35).
Many groups have concluded that mapping biopsies
should be recommended for selection of focal therapy patients (9,41,35,36). Some also point out that
dissection difficulties can occur if a radical prostatectomy is then performed (19,37,35).
Radiofrequency interstitial tumour ablation (RITA)
Adding colour Doppler seems not to improve
the detection rate for small tumours although its role
in significant tumours may be useful (42). Recently,
contrast-enhanced TRUS (CE-TRUS) has shown some
promise higher sensitivity for detection of cancer foci.
The detection rate of clinically significant prostate
cancers was improved in a number of studies (43-46)
with the ability to provide real-time targeted biopsies
(42). Prostate Histoscanning has also shown promise
with a higher sensitivity and specificity for significant
lesions as defined by a volume of 0.5cc but studies
have been small and non-blinded. The results of a
multicentre European blinded study currently under
way are awaited (47, 48).
This new technology is performed by the
transperineal approach, using percutaneous needles
inserted under ultrasound guidance. Low-level radiofrequency energy heats and ablates tissue by coagulative necrosis. There are no studies on RITA for
prostate cancer treatment and only a few historical
reports on the use of this ablative technique in benign
prostatic hyperplasia.
The need for accurate localization of the lesion
For many years, imaging of the prostate was
by B-mode transrectal ultrasound imaging (TRUS).
However, TRUS has a low sensitivity and specificity
for prostate cancer with other prostatic pathologies
like benign prostatic hyperplasia or prostatitis being
hypoechoic as well. TRUS biopsies can only predict
unilaterality of cancer in 27.6% of cases and this was
not improved by adding other biopsy characteristics
such as percentage tumour involved or number of positive biopsies (34). The number of necessary cores
to correctly localize cancer is uncertain. A number of
groups have stated that TRUS biopsies are not sufficient for tumour localization, or accurate staging or
grading, in the case of selecting patients for a focal
treatment (35-38).
Transperineal ultrasound guided (TPUS) biopsies can now be performed. Using a brachytherapy
template, taking one core every 5mm, the extent and
location of cancer can be mapped within the prostate. Different studies have shown that TPUS biopsies
accurately demonstrate clinically significant prostate
cancer with a high degree of sensitivity (37). Cancer
detection rates increase from 29% - 34% for traditional techniques to 47-70% for TPUS biopsies (39,40),
particularly in the anterior part of the gland that is
inherently under-sampled by TRUS guided transrectal
biopsies (35,37). TPUS also allows accurate Gleason
grade to be determined (9, 37, 40). On simulation
models, TPUS biopsies performed every 5mm could
detect 95% of significant cancers defined by volume
of 0.5cm3 (39). The toxicity and healthcare burden
are the main disadvantages of TPUS biopsies. Although TPUS biopsies have a lower infection rate than
Multi-parametric MRI protocols are now
showing encouraging results in detecting significant
lesions, with a volume cut-off of 0.5cm3 or 0.2cm3,
and in accurate localization of the cancer as well as
cancer characterization (grade, extraprostatic extension) (49,43,50).
Image-guided treatment is also under development, with CE ultrasound (51,52) or MRI (53-56).
Nevertheless, MRI-guided treatment is not currently
ideal because of the magnetic environment, the problem of access to MRI, cost and patient discomfort
(43). Combining imaging and histopathological data
from prostate mapping biopsies appears possible to
create the most accurate localisation of lesions to deliver focal therapy at the present moment.
Patients suitable for Focal Therapy
For the moment, there is no consensus about
which criteria should be used to select men for focal
therapy. With current trends of PSA screening and
the lowered PSA threshold for biopsy, 45% to 85% of
patients fall in the category of low-risk (PSA< 10 μg/
L, Gleason grade 3 + 3, cT1c–cT2a). It is estimated
that between 25% and 84% of men currently being
treated would not succumb to their disease should
their disease be left untreated representing significant
overdiagnosis (13).
Prostate cancer is usually regarded as a multifocal disease. However, several studies, based on
FOCAL THERAPY FOR PROSTATE CANCER: A POTENTIAL STRATEGY TO ADDRESS THE PROBLEM OF OVERTREATMENT
radical prostatectomy specimens, found a significant
proportion of men having either unifocal or unilateral
disease. It has been reported that prostate cancer is
unilateral in 16% to 63% (9, 21, 38, 57-60) and unifocal in 13% to 26% (9, 35, 61). This argument leads
to the proposition that a substantial number of men
could have a hemiablation approach to their disease.
Interestingly, a recent study has found that unifocal
cancers have a more aggressive behaviour than multifocal disease. In a series of 1159 radical prostatectomies, pathological examination found 18.7% versus
10.1% of Gleason 8 to 10 for unifocal and multifocal
cancers, respectively. Furthermore, biochemical recurrence rates were 38,5% for unifocal disease versus
24,2% for multifocal disease.
Multifocal disease need not necessarily be
excluded from focal therapy. Evidence points to men
with multifocal prostate cancer being eligible for a
form of focal therapy if ablation is targeted towards
the index or significant lesions alone. A cut-off at
0.5cm3 (less than a diameter of 10mm) can be used
to predict lifetime risk of mortality (62). 80% of secondary non-index lesions are less than 0.5 cm3
(21, 35, 63, 64). Moreover, secondary cancer foci
were found to have on average a cumulative volume less of 0.3cm3. 90% of extracapsular extension
comes from the index lesion, and this index lesion
represents 80% of the total tumor volume (13, 27,
35,30,52-56,65,66). Presence and volume of the
secondary cancer foci has no influence on biochemical recurrence after a radical prostatectomy (35). An
important and interesting research question therefore
involves focal therapy to treat the index lesion alone
and surveillance of the secondary non-significant lesions (provided they are small and have Gleason 6
or less) (67). Indeed, one such trial is underway at the
authors centre (National Cancer Institute registration
protocol number: NCT00988130).
A number of consensus groups have met to
discuss recommendations for focal therapy. In 2006,
first criteria appeared in the Consensus Conference
on Focal Treatment: expectancy life >5 years, stage
T1 to T3, PSA<15ng/ml, no M1 disease. They considered lymph node disease as a relative contraindication. They believe that PSA density, PSA doubling
time, Gleason score and ploidy status should not be
taken into account (36). Eggener et al, in the TASK
Force group, proposed criteria to determine which
patients should have focal therapy. They proposed
criteria reflected those used in active surveillance. The
very population, which argue, should not have any
treatment. In other words, clinical stage T1–T2a, PSA
less than 10 ng/ml, PSA density less than 0.15 ng/
ml, PSA velocity less than 2ng/ml yearly, no Gleason
4 or 5, no evidence of extra-prostatic extension and
849
a single lesion (68). Sartor et al add that a lesion
with largest dimension of <15 mm in any plane by
imaging with the lesion not exceeding 5mm of capsular contact on axial images should be used to define lesions on MRI. Furthermore, the regional nodes
should not be suspicious for metastatic disease. In
other words, they should measure <7mm in the short
axis and have a smooth border, and there should not
be an asymmetric cluster of nodes) (35).
CONCLUSIONS
Focal therapy for prostate cancer represents
a paradigm shift that may provide the middle way
between under-treatment and over-treatment offering
ablation of the cancer and preservation of non-malignant tissue and surrounding vital structure in order to
lower side-effects.
Recent advances in cancer localization using
imaging (multi-parametric MRI, tissue ultrasound
characterisation, contrast-enhanced ultrasound) have
shown encouraging accuracy rates in detection as
well as localization of prostate cancer. TPUS biopsies,
which map the prostate every 5mm, arguably
provide the ideal accuracy in cancer localization and
characterisation for delivering focal therapy but carry
a healthcare burden. Trials are needed to assess
feasibility, efficacy and safety of focal therapy. Many
of these trials are currently in process and if the early
signs of lower toxicity are verified then planning for
larger long term studies is needed either using cohort
designs or comparative pragmatic designs to assess
focal therapy against active surveillance and radical
therapies.
Authors’ disclosure statement
Hashim Ahmed is funded by the Medical Research Council from the Research Fellowship scheme.
Hashim Ahmed and Mark Emberton receive funding
from Pelican Cancer Foundation, UK, The Prostate
Research Campaign UK, St Peters Trust, UK and the
Prostate Cancer Research Centre for work in focal
therapy. Mark Emberton also receives funding from
UCLH/UCL Comprehensive Biomedical Research
Centre. In addition, Mark Emberton receives research
funding from Steba Biotech, France (manufacturers
of TOOKAD, a photodynamic agent used in prostate
cancer therapy) for trials in focal therapy. He is also
a Medical Advisor for Focus Surgery/Misonix/USHIFU/UKHIFU(manufacturers and distributors of the
Sonablate® 500 HIFU device). Mark Emberton is a
Director of Mediwatch PLC and Prostate Mapping Ltd.
Caroline Moore is a consultant for Steba Biotech.
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E. Lecornet, H. U. Ahmed, C. Moore, et al.
None of the funding sources had any role in
the writing of this article.
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