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Part II
Global Perspective of Active Surveillance
(AS) and Focal Therapy (FT)
Intersection ofActive Surveillance
andRadical Therapy forProstate
Cancer: Opportunities forFocal
Therapy inNorth America
LaurenceKlotz, AndreAbreu,
andChristopherWarlick
5
Where Is theLine between Active
Surveillance andFocal Therapy
The last 20 years have witnessed a dramatic shift
in the management of low-risk prostate cancer.
CapSure data from that era (~2000–2005) indicated that approximately 90% of men newly
diagnosed with ‘low-risk’ prostate cancer (usually Gleason 3+3=6 disease) were treated radically, either with surgery or radiation [1]. This
emphasis on radical treatment was based on the
belief that low-grade prostate cancer posed a
threat to patients with long life expectancies, and
because low-risk patients were more likely to
have negative margins, it was believed that they
were the ideal cases for radical prostatectomy.
This latter view was promoted by Dr. Patrick
Walsh, who had rst described the nerve-sparing
radical prostatectomy.
L. Klotz (*)
Sunnybrook Chair of Prostate Cancer Research,
Division of Urology, Sunnybrook Health Sciences
Centre, University of Toronto, Toronto, ON, Canada
e-mail: Laurence.klotz@sunnybrook.ca
A. Abreu
Clinical Urology and Radiology, Image-Guided
Surgery, Focal Therapy and Articial Intelligence for
Prostate Cancer, USC Institute of Urology, Keck
School of Medicine, University of Southern
California, Los Angeles, CA, USA
C. Warlick
Department of Urology, University of Minnesota,
Minneapolis, MN, USA
However, major concerns existed that radical
treatment represented over treatment for this
group of patients. It had been known for 40years
that low-grade prostate cancer developed with
age in the majority of men and that very few of
these progressed to metastatic disease [2].
However, the prior experience with ‘watchful
waiting,’ which meant no treatment until metastatic disease developed, was poor, with high
prostate cancer mortality rates, particularly with
long-term follow-up [3].
Beginning in 2002, reports of an intermediate
strategy between watchful waiting and radical
treatment, eventually termed ‘active surveillance,’
began to appear [4, 5]. The concept was to follow
low-risk patients over time, with sequential
Prostate Specic Antigen (PSA) and repeat biopsies, and treat those who reclassied into a higherrisk category. This was based on the appealing
concept of using time to reveal the minority of
patients who were at risk and treat them radically
while leaving the majority of patients untreated.
This strategy generated an intense controversy
that raged for a decade. Critics believed that the
active surveillance strategy would condemn many
men to an otherwise avoidable prostate cancer
death. Ultimately, the controversy over the prin-
ciple of conservative management in low-risk
patients (as distinct from the application) was
resolved in 2012 when the US Preventive Services
Task Force published a negative recommendation
on PSA testing due mainly to concerns about
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
T. J. Polascik et al. (eds.), Imaging and Focal Therapy of Early Prostate Cancer,
https://doi.org/10.1007/978-3-031-66754-1_5
55
56
L. Klotz et al.
overtreatment [6]. The baby (early detection with
PSA) is being risked thrown out with the bathwater (aggressive treatment for all).
Over time, the active surveillance data became
more robust, with larger cohorts and longer
follow- ups. The most recent evidence is that
prostate cancer mortality using the modern
approach to surveillance incorporating MRI is
less than 1% at 15 years [7, 8]. Active surveillance is now considered the standard of care for
patients with low-risk prostate cancer and
selected patients with Grade Group (GG) 2 disease. Most patients with GG1 prostate cancer
should be managed with AS and not considered
candidates for focal or radical therapy unless they
demonstrate grade progression.
There are, however, several groups of patients
who are at higher risk for disease progression
than the typical GG1 prostate cancer patient.
These include those with germline mutations in
HHR genes [9], young patients with high volume
GG1 disease and high PSA density, and possibly
those with an unequivocal PIRADS 5 lesion on
MRI whose biopsy consistently showed GG1
disease. Finally, some patients are psychologically unprepared or unwilling to have no treatment. The management of these ‘low-risk’
patients overlaps with focal and denitive
therapy.
The current NCCN guidelines recommend
active surveillance as the preferred treatment for
patients with very low risk and low risk of prostate cancer, while ‘watchful waiting’ is preferred
for patients with low-risk prostate cancer and a
life expectancy of <10years [10]. The difference
between these is in the intensity and techniques
of follow-up. The strength of these recommendations derived from multiple prospective studies
of AS, and one prospective study, the ProtecT
trial [11]. Here, 1643 patients with localized
prostate cancer were randomized to active surveillance, radical prostatectomy, or radiotherapy.
After a follow-up of 15years, Hamdy etal. found
no signicant difference in prostate cancerspecic deaths between the three treatments.
Surgery and radiotherapy were associated with
lower rates of disease progression and metastases. To date, no randomized trials comparing
active surveillance with local treatments in
intermediate- risk prostate cancer patients are
available. The best available evidence for active
surveillance in intermediate-risk prostate cancer
patients stems from the prospective single-arm
study by Klotz etal. [8] Within this unique active
surveillance cohort of 993 men with favorable- or
intermediate-risk prostate cancer his group demonstrated the feasibility and safety of active surveillance in selected intermediate-risk prostate
cancer patients.
A more recent study from the VA [12] followed over 1000 patients with intermediate-risk
prostate cancer; the prostate cancer mortality at
10years in the GG2 group was 3.7%. Thus, most
patients with GG2 disease have indolent cancers
and are candidates for surveillance. However,
many patients may nd a 4% 10-year mortality
rate unacceptable and prefer intervention. This is
a fruitful area for further studies of risk stratication by imaging and/or molecular biomarkers of
this biologically heterogeneous group of patients.
Testing patients on active surveillance for
germline mutations in the HRR pathway is
becoming increasingly routine. Approximately
5% of patients with localized PCa will harbor an
HRR mutation. Clinical data with active surveillance in these patients, while limited, suggest
that, particularly with BRCA2 mutations (the
most common HRR variant in prostate cancer
patients), AS is a risky strategy. One study
showed that 80% of GG1 patients with BRCA2
had grade progression by 8years [9]. Even this
high proportion is likely an underestimate, given
the risks of under-sampling. Thus, BRCA2
patients should, in most cases, be treated denitively. One study suggested that surgery is preferred to radiation in these patients [13]. Whether
focal therapy is a sufcient treatment for BRCA2
mutated patients is unknown. It is also unclear to
what degree other HRR mutations, i.e., BRCA1
and ATM, preclude active surveillance or are candidates for focal therapy; this is an area of active
investigation.
Most young patients (under age 55) with
newly diagnosed GG1 PCa harbor small-volume
disease. Many studies have indicated that these
patients can be safely managed with active sur-
5 Intersection of Active Surveillance and Radical Therapy for Prostate Cancer: Opportunities for Focal…
57
veillance despite their young age and long life
expectancy [14]. In part, this reects the fact that
occult high-grade cancer is uncommon in young
men and increases with age. Thus, these patients
are at lower risk for metastatic disease from an
undiagnosed higher-grade cancer than the elderly.
However, a few outliers develop extensive GG1
prostate cancer at a young age. The drivers for
this are unknown. These patients are known to
have a higher chance of occult high-grade cancer
and likely are at increased risk of grade dedifferentiation over time. Focal therapy, particularly if
the disease is unilateral, is an appealing strategy.
The presence or absence of a lesion on MRI is
another powerful predictor of disease biology. In
particular, both translational and clinical studies
have demonstrated recently that MR invisible
cancers are genetically and clinically indolent
[15, 16]. The converse is that patients with a
highly suspicious (i.e., PIRADS 5) lesion, with
only GG1 on repeated biopsy, may have a more
aggressive disease than is reected in their histology. Focal therapy for these lesions may be
warranted.
Where Is theLine between Focal
Therapy andRadical Treatment?
Men considered candidates for denitive therapy
include those with signicant amounts of GG2 or
higher due to the more aggressive behavior of
Gleason patterns 4 and 5. Gleason pattern 4
shows more abnormal expression of genes
involved in cellular proliferation [17, 18], cellular invasion, and metastasis, and demonstrates
higher frequencies of TMPRSS2-ERG fusions
[19–21] and PTEN deletions [22] than Gleason
pattern 3. Furthermore, radical prostatectomy
series demonstrate worse pathologic outcomes
and disease progression in men with GG2 vs 1
disease [23]. Thus, men harboring substantial
amounts of pattern 4 usually warrant some form
of treatment.
Data from the SPCG4 [24] and the PIVOT
[25] randomized trials demonstrated a survival
advantage to denitive therapy over observation
for men with intermediate-risk or higher disease
and no benet in terms of survival for men with
lower-risk disease or older men at roughly
20years of follow-up. The ProtecT randomized
trial of active monitoring compared to surgery or
radiation demonstrated no difference in survival
between the three arms but did note a roughly
10% risk of developing metastases in the active
monitoring group compared to a 5% risk in the
denitive treatment arms [11]. Focal therapy was
not an option in the ProtecT trial. Taken together,
this group of studies suggests that denitive therapy provides a moderate survival benet to men
with intermediate or higher-risk disease, but a
less clear benet to many men with low and
favorable intermediate-risk disease, though the
risk of metastases is decreased. These studies
provide the justication for denitive treatment,
and none of them incorporated a focal therapy
option. However, given the moderate benet and
the long time frame required to recognize the
benet of denitive therapy, many men may prefer the option of an intermediate form of treatment to reduce the risk of adverse quality of life
effects of denitive therapy.
Men with isolated GG2 cancers may be the
ideal candidates for focal therapy. They harbor
Gleason pattern 4, which confers sufcient biologic aggressiveness to justify therapy, but are
amenable to local control with treatment of the
index lesion. About 25–40% of men with GG1
disease who start out on active surveillance will
be reclassied on surveillance biopsy at 10years,
most to GG2 [7, 8]. These men have historically
been offered denitive therapy. However, these
are patients for whom focal therapy may be
attractive. These patients require long-term follow- up, particularly of the untreated areas of the
prostate. In this sense, focal therapy becomes an
extension of active surveillance instead of a lesser
version of denitive therapy; men who undergo
focal therapy will still require surveillance afterward at a frequency similar to those on active surveillance, with a possible decrease in intensity in
men who remain stable on surveillance over time.
Men with small isolated GG3 cancers may also
be good candidates for focal therapy. Classifying
cancer as a GG2 or GG3 is subject to sampling
error when based on biopsy. In the SPCG4 trial,
58
L. Klotz et al.
men who underwent prostatectomy and had conrmed Gleason 4+3=7 had a 5 times higher risk
of death compared to men with Gleason 3+4=7,
suggesting a real increased biologic risk in men
with predominant Gleason pattern 4 [24]. This
emphasizes the need for multilevel risk stratication in these patients beyond what is currently
recommended by NCC guidelines.
Men with high-risk prostate cancer should be
offered denitive therapy. Most are not candidates for focal therapy. The term ‘high-risk’
refers to GG4 or higher, locally advanced disease, and patients with very high PSA.There are
three exceptions to the mandate for denitive
therapy (surgery or high-dose radiation) for highrisk patients. These are (a) men with limited life
expectancy, (b) those with low-stage isolated
high-risk lesions that, based upon location and
extent of disease within the prostate, have a high
likelihood of successful local control with focal
therapy, and (c) PSA>20 with a low PSA density, as their only high-risk feature. Men with
PSA>20 are classied as high-risk by denition.
However, this number is arbitrary and has considerably less prognostic value than grade and stage.
Therefore, as a sole parameter, a PSA>20 does
not preclude focal therapy. All of the relevant
parameters (disease-related and patient-related)
must be integrated in making an informed decision about focal vs denitive therapy.
Given the risk of poor outcomes in men with
high-risk disease, focal therapy in these patients
should be considered with caution and offered on
an individual case basis. An important area of
future research is to dene selected men with
high-risk diseases for whom this approach is
likely to be safe and effective.
Why Select Focal Therapy Rather
Than ASor Radical Treatment?
With active surveillance, there is a slight but nonzero (1–2%) risk of distant spread and a 25–35%
risk of eventually requiring treatment. Radical
therapy is usually but not always effective, has
increased morbidity when compared to active
surveillance, and can adversely affect patients’
function and quality of life. For many men with
intermediate-risk cancer, neither of these pathways seems optimal. Hence, there has been an
unmet need for a treatment option that provides
oncologic control, preserves normal urinary,
bowel, and sexual function, and avoids the morbidity related to radical therapy. Focal therapy
has emerged as a promising middle option for
these patients, balancing out oncologic control
and quality of life preservation.
The number of patients who are eligible for
focal therapy is a function of the eligibility criteria used to select patients, which varies between
clinicians, centers, and regions. Few studies have
estimated the number of potential candidates. In
a cohort of 454 men who underwent multiparametric MRI and correlated target biopsy with
whole-mount histology after radical prostatectomy, 38% would have been eligible for focal
therapy based on NCCN histologic criteria for
intermediate risk, meaning GG≤ 3in the target
region [26]. The single-center and retrospective
nature of this study limits the generalizability of
its ndings. In contrast, a large multicenter cohort
study in Europe, which included 2371 patients
with Prostate Imaging Reporting and Data
System (PI-RADS) ≥3 lesions and biopsy-proven
prostate cancer, found that based on consensus
criteria, 13% were eligible for focal ablation and
16% for hemiablation [27]. Of the 13% eligible
for focal ablation, 6.2% were GG1 and 6.5%
GG2. However, unlike the previous study, this
study did not correlate its ndings with wholemount histology. These studies are also limited
by reliance on histology rather than natural history, and likely underestimate the actual proportion of eligible patients.
Advancements in the diagnostic pathway,
including MRI-informed prostate biopsies and
articial intelligence models, have rened treatment planning, tailoring it to individual patients.
For instance, an AI model has been developed to
produce treatment margins for focal therapy, evidencing superiority to conventional margins [28].
With enhanced imaging, precise targeting of suspicious lesions, and accurate treatment planning
tools, oncologic outcomes for focal therapy
patients are likely to be further improved.
5 Intersection of Active Surveillance and Radical Therapy for Prostate Cancer: Opportunities for Focal…
59
Patients with intermediate-risk prostate cancer
diagnosed from a targeted biopsy of a solitary,
unilateral lesion on MRI, with either a negative
systematic biopsy or low-volume GG1, are ideal
candidates for focal therapy. As shown by the
SPCG-4 trial [24], which followed patients over
29 years, no survival benets were observed in
GG2 patients treated with radical prostatectomy.
There were many limitations to the SPCG-4 trial,
and this important observation should not be
interpreted as indicating that treatment of GG2
has no value at all, but it does suggest that the
impact of treatment is modest. Focal therapy,
based on the concept of ‘less is more,’ is therefore an appealing option for these patients [29].
Additionally, focal ablation preserves the option
of salvage therapy in those who have local recurrence, such as further focal therapy, radical prostatectomy, or radiation therapy [30].
Focal therapy provides medium- to long-term
oncologic control in most patients without substantially affecting quality of life. For instance, a
multi-institutional study of 1379 patients undergoing high-intensity focused ultrasound showed
failure-free survival rates of 93%, 83%, and 68%
at 3, 5, and 7years for intermediate-risk patients
[31]. Another multicenter, open-label, phase 2
study evaluating MR-guided focused ultrasound
in patients with localized GG2 or GG3 intermediate- or high-risk prostate cancer reported that,
at a 2-year follow-up, 88% of patients did not
have GG≥2 cancer in the ablated zone.
Continence is well preserved in patients
undergoing focal therapy. Studies demonstrate
95–100% no-pad continency post-ablation [32,
33]. In comparison, urinary incontinence rates
post-radical prostatectomy range from 4% to
31% at 1-year follow-up, depending on the denitions used and whether the outcome was patient
or surgeon reported [34]. About 85% of patients
recover to baseline levels of erectile function
after focal therapy [35, 36]. There is an initial
decline within the rst 3 months, followed by
improvements at 6 and 12months. No signicant
differences have been demonstrated between
energy modalities [37]. One study observed no
difference in erectile function 4years post-focal
therapy compared to untreated patients on active
surveillance [38]. In contrast, post-prostatectomy
potency ranges from 54% to 94%, with an overall
erectile function recovery rate of 58% [39].
Several studies of Patient Reported Outcomes
(PROs) report considerably lower rates of recovery [40]. With radiotherapy, 6–69% of patients
develop erectile dysfunction post-treatment, with
a median rate of erectile dysfunction of 24%
[41].
Focal therapy is a safe procedure with a low
incidence of serious adverse events [42].
Rectourethral stulas, one of the most feared
adverse events, occur in 0.3% to 1% of cases
[42]. Less severe adverse events include hema-
turia, urinary tract infections, and urinary retention, which can all be effectively managed.
Focal therapy is benecial for intermediate-risk
patients (GG2–3) who wish to maintain potency,
continence, and overall quality of life, and is an
important middle ground between active surveillance and radical treatment. It also has a role
in selected patients with GG1 cancer who, due
to anxiety or other unusual features of their cancer, prefer to have intervention; and selected
high-risk patients with small, focal GG4 lesions
and otherwise favorable parameters or with
PSA>20 as their sole high-risk parameter, who
prioritize QOL.
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Focal Therapy andActive
Surveillance ofProstate Cancer:
AEuropean Perspective
RiccardoLeni, MarcoMoschini, ArmandoStabile,
AlbertoBriganti, andGiorgioGandaglia
6
Introduction
The widespread use of prostate-specic antigen
(PSA) testing in the last century led to an
increase in the incidence of indolent prostate
cancer (PCa) diagnoses, and to the treatment of
many of them with curative-intent modalities
such as radical prostatectomy (RP) and radiation therapy (RT) [1]. The diagnosis, and treatment of cancers that would not cause any
symptoms, and ultimately would not be the
patient’s cause of death, is known as overdiagnosis and overtreatment [2]. At the end of the
last century, three large, randomized trials questioned whether RP would result in a survival
benet, compared to observation, in men with
localized PCa [3–5]. The most recent results
from the ProtecT trial, which compared active
monitoring to RP and RT, in men with screening-detected localized PCa, demonstrated that
although the long-term risk of metastases is
slightly higher for men initially monitored,
there is no difference in PCa mortality [5].
These results pose serious questions on whether
aggressive upfront treatment modalities are justied in men who would die of the disease at
similar rates if initially observed. Active surveillance (AS) and focal therapy (FT) have emerged
as treatment options, for men with localized,
Grade group (GG) 1 (Gleason 3 + 3) and 2
(Gleason 3+4) PCa. Their aim is to obtain cancer control, without exposing the patients to
treatment side effects. The rationale of AS is to
monitor men with GG 1 and selected patients
with GG 2 disease and to treat them once cancer
shows signs of progression [2]. Over the last
R. Leni · M. Moschini · A. Stabile · A. Briganti ·
G. Gandaglia (*)
Division of Oncology/Unit of Urology, Soldera
Prostate Cancer Lab, URI, IRCCS Ospedale San
Raffaele, Milan, Italy
Vita-Salute San Raffaele University, Milan, Italy
e-mail: gandaglia.giorgio@hsr.it
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
T. J. Polascik et al. (eds.), Imaging and Focal Therapy of Early Prostate Cancer,
https://doi.org/10.1007/978-3-031-66754-1_6
63
64
R. Leni et al.
few years, the uptake of AS for low-risk PCa has
increased in Europe, with the highest proportion
of men managed with AS observed in Sweden
[6, 7]. The Prostate Cancer Research
International Active Surveillance (PRIAS) project is the largest European AS registry, including data from more than 5000 patients managed
with AS [8]. With the introduction of multiparametric magnetic resonance imaging (MRI) of
the prostate in the PCa diagnostic pathway, a
transition to imaging-based surveillance protocols has been observed and is being adopted in
many European countries [9, 10]. Indeed, up to
50% of patients initially managed with AS
undergo denitive treatment during follow-up,
and the use of MRI after a diagnosis of low-risk
PCa at systematic biopsy only is associated with
disease reclassication (i.e., nding higher
grade cancer at subsequent biopsies) [8, 10].
Considering the excellent long-term oncologic
outcome of AS, this represents, to date, the management of choice for early-stage PCa, as recommended by the European Association of
Urology (EAU) guidelines [2]. However,
whether treatments involving the complete
removal of the prostate or its total irradiation are
associated with improved and clinically meaningful long-term cancer control, either after disease reclassication on AS or for newly
diagnosed favorable intermediate-risk PCa, is a
matter of debate [5, 11]. FT has emerged as an
alternative form of treatment with respect to RP
and RT in patients with localized PCa [5, 12].
The use of standardization of reporting systems,
namely, the Prostate Imaging Reporting and
Data System (PI-RADS), led to high interobserver reproducibility in determining the size
and position of the index lesion [13]. There are
hypotheses that the index lesion, usually the
largest suspicious area within the prostate,
drives the clonal evolution of PCa cells capable
of metastasizing and ultimately determines
mortality [14]. It became appealing to investigate whether the ablation of such foci could be
enough to cure or at least prolong patient survival [12]. The aim of the FT is to achieve longterm local cancer control while avoiding the
side effects of RP and RT [12]. While the natu-
ral history of terminating AS encompassed
either RP, RT, or transition to watchful waiting
(WW) [15], FT is emerging as a potential option
with the aim of reducing the side effects of
radical- intent treatments.
Active Surveillance: Available
Protocols inEurope andtheEAU
Guidelines Position
The long-term oncologic outcomes of AS are
supported by strong evidence, with an incidence
of PCa mortality close to zero, and an incidence
of metastases of about 2% at 10years [16]. The
mainstay of surveillance strategies is the repetition of sequential assessments, namely, MRI and
biopsies, to rule out higher-grade cancer in a
timely manner. In Europe, the Prostate Cancer
Research Active Surveillance (PRIAS) protocol
is the most widely used, as shown in Table 6.1
[8]. Although there are many inter-institution
variations of inclusion criteria and monitoring
schedules, the PRIAS protocol is the backbone
for a widely adopted common strategy for AS in
Europe. The PRIAS protocol was established
almost two decades ago as a set of recommendations to follow men with low-volume grade
group 1 PCa (namely, one or two positive systematic biopsy cores). More recently, inclusion
criteria were expanded to accommodate the use
of MRI, and patients with a small amount of
grade group 2 were allowed on AS.Indeed, many
institutions allow for the inclusion of patients
who do not meet individual PRIAS inclusion criteria [17]. The contemporary PRIAS protocol
mandates the execution of MRI and biopsies
1year after diagnosis and every 3years thereafter. Visits are performed annually, and PSA tests
semi-annually. Discontinuation usually takes
place when a surveillance biopsy shows highergrade cancer. In the most recent report of the
PRIAS study, among 5302 patients, eight developed metastases and only one died of PCa [8].
Concordant to worldwide reports, approximately
50% of men remain on AS at 5-year follow-up,
with 30% leaving AS due to protocol-based reasons for discontinuation [8].