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1 Focal Therapy forProstate Cancer: AGuide forPatients
a
b
11
Fig. 1.3 Examples of patients receiving treatment in the (a) lithotomy position for transperineal treatment and (b)
lateral position for transrectal treatment
your treatment is performed transperineally, you
will have some small needle- prick wounds on
your perineum with short-term soreness and can
sometimes have bruising and swelling behind
your scrotum. With some focal treatment technologies, MRI or CT imaging is used for realtime monitoring of the treatment so that you may
be treated while in an MRI or CT scanner.
12
K. J. Tay et al.
What toExpect Immediately after
Treatment
Some focal therapies cause swelling of the prostate
that may make urination more difcult as a shortterm side effect after treatment. At the end of the
procedure, a urinary catheter may be temporarily
placed to allow you to urinate freely during your
recovery. This is typically left in place for several
days to allow any residual swelling caused by the
therapy to resolve. A nurse will instruct you on the
care and management of the catheter if you have
one. Occasionally, a suprapubic catheter11 may be
used instead of a urethral catheter, but the care of this
catheter is similar to a urethral catheter. Because
focal therapy is usually performed as an outpatient
procedure, you should expect to be sent home the
same day as your procedure after a short period of
observation.
Post-procedure, there is a small risk of bleeding or infection as a complication of the procedure. Supercial bruising of the skin where the
treatment was applied is common, but almost
always, this is minor and does not require any
special care. Some lightly blood-stained urine is
also commonly seen in the days after the procedure and can persist or recur to some degree for
several weeks. Light blood staining in the urine is
usually not painful and resolves on its own with
time without any special care, so it should not be
cause for alarm. On the other hand, heavy (thick
and red) bleeding in the urine can cause a blood
clot to form that can block the drainage of your
urine. You should contact your physician if you
have this degree of blood in your urine, as you
may need to be evaluated. Although infection is a
rare complication, if you have persistent and/or
high-temperature fevers, these would also be reasons to contact your physician, as these could be
signs of an infection that may need to be treated.
11
A suprapubic catheter: Suprapubic catheter is a urinary
drainage tube placed into the bladder through the skin of
the lower belly.
The urinary catheter, if you had one placed for
recovery from the procedure, is usually removed
either several days or a few weeks after the procedure. You may be observed in a physician’s
ofce after the removal of the catheter to ensure
that you can urinate without difculty. There may
be a mildly painful sensation of burning irritation
upon urinating after a catheter is removed, but
this typically decreases and resolves over the next
few days. If you have more persistent and/or
worsening urinary symptoms after the catheter is
removed, or develop the inability to urinate, you
should contact your physician so you can be
reevaluated. Persistent and/or worsening urinary
symptoms after your catheter removal could be
signs you have a urinary tract infection or that
you may need a urinary catheter for a longer
duration during your recovery.
Long-Term Functional
andOncological Outcomes after
Focal Therapy
Functional Outcomes
The recovery of erectile function after focal therapy for prostate cancer varies between individuals. Your ability to achieve and maintain erections
prior to your procedure is a strong predictor of
your ability to achieve and maintain erections
after your procedure. Because a focal therapy
treatment approach limits the treatment area to
the area of cancer and a treatment margin, there is
less risk the treatment will damage the nerves
that control erectile function. If both of your
erectile nerves can be preserved during the treatment, depending on the size and location of your
cancer, then the rate of recovery of erections is
approximately 90% at 1 year. When only one
erectile nerve is preserved, the rate of recovery is
approximately 50–70% in 1 year. During the
recovery phase for the rst several months after
your procedure, it may be helpful to undergo
1 Focal Therapy forProstate Cancer: AGuide forPatients
13
penile rehabilitation12 to help your erectile function return. This involves the stimulation of blood
ow to the penis using medications such as
Viagra (sildenal), Cialis (tadalal), or Levitra
(vardenal), the use of a vacuum pump, and/or
physical sexual stimulation. Simply stated, the
nerves and blood vessels that control your erections need to be used for you to recover erectile
function, which you can think of as similar to
how you would need to perform rehabilitation to
your leg in order to walk after a signicant injury
or surgery. In general, you will have better
chances of recovering your erectile function the
earlier you start penile rehabilitation and the
more consistently it is performed. Erectile function can continue to improve over the course of a
few years after treatment, particularly if you continue to actively participate in an erection recovery program and penile stimulation, stimulating
the erectile nerves and blood ow to the penis.
Similar to how erectile function prior to treatment is strongly predictive of erectile function
recovery after treatment, urinary symptoms
before treatment are also predictive of urinary
symptoms after treatment. Because a focal therapy treatment approach limits the treatment area
to the area of cancer and a treatment margin,
there is less risk the treatment will cause urinary
incontinence. Therefore, the recovery of urinary
function after focal therapy for prostate cancer is
typically quicker and more likely to be a complete recovery compared to traditional wholegland treatments. Recovery of urinary function
after your treatment will probably not require
specialized or dedicated rehabilitation, but you
may nd it benecial to strengthen your pelvic
oor and urinary sphincter muscles by performing Kegel exercises.13 Similar to penile rehabili-
12
Penile rehabilitation: The intentional practice of stimulating erections after a procedure to help with regaining
erectile function.
13
Kegel exercise: An exercise where the pelvic oor muscles are squeezed and relaxed intermittently to strengthen
the pelvic oor.
tation, the earlier you start Kegel exercises and
the more consistently you perform them, the
more benecial they will be.
Cancer Treatment Outcomes
andPost-Treatment Surveillance
Focal therapy is a relatively new treatment strategy, so there is less research on the long-term
outcomes compared to traditional whole-gland
treatment with radiation and prostatectomy.
Similar to radiation that preferentially kills prostate cancer tissue but does not necessarily kill all
prostate tissue, focal therapy has the possibility
of having cancer recur in the section of the prostate that was treated or in an untreated section of
the prostate. Depending on the size, location, and
pathologic features of any prostate cancer recurrence after treatment, these tumors could be
observed or warrant additional treatment. Prostate
cancer that appears low-risk can be observed
with continued active surveillance, similar to
patients who are on active surveillance and have
not been treated with focal therapy. Prostate cancer recurrence that is higher risk may potentially
be treated with additional focal therapy or could
warrant switching to a method of whole-gland
treatment depending on the tumor characteristics,
your preferences, and the advice of your doctor.
Since focal therapy is a new type of treatment
under development, close follow-up after focal
therapy for prostate cancer is paramount.
International consensus panels have recommended 6-month checkups with physical examination and PSA blood tests along with periodic
mpMRI imaging. Many experts recommend a
biopsy of the treated area along with any new
MRI lesions that may become apparent over
time. Some clinicians recommend periodic
biopsy of the untreated portion of the prostate, as
is typically done for active surveillance. Because
only a portion of the prostate is treated in focal
therapy, PSA is expected to remain detectable but
14
K. J. Tay et al.
signicantly reduced after treatment, in contrast
to radical prostatectomy, whereby the whole
prostate gland is removed, and the PSA should
become undetectable. On average, you can expect
the PSA level to decrease by up to 80% by the
3-month post-treatment visit. Unlike radical
prostatectomy, where PSA monitoring is much
more straightforward, PSA monitoring after focal
therapy is challenging to interpret as a sole measure. Therefore, instead of relying on just PSA
blood tests for monitoring, we recommend
planned repeat imaging with mpMRI and prostate biopsy of any suspicious lesions at 1 year
after treatment and subsequently at 2–3 year
intervals. However, if persistent elevation in PSA
is observed, an earlier or additional evaluation
with imaging and/or biopsies should be
considered.
Conclusion
Focal therapy is a cutting-edge approach to prostate cancer treatment based on a state-of-the- art
understanding of the biology of prostate cancer
as well as technologies that have made it possible
to more accurately locate and target prostate cancer. Because focal therapy is a relatively new
approach to treating prostate cancer, we still need
more longer-term data to fully understand its
long-term outcomes. Close follow-up and surveillance are important after focal therapy treatment. If you are a good t for a focal therapy
strategy to treat your prostate cancer, focal therapy offers the potential to treat and eliminate
your clinically signicant prostate cancer while
preserving your urinary and erectile function.
The Story ofBreast andProstate
Cancer: Parallels andCommon
Controversies
PierPaoloAvolio, GiovanniLughezzani,
andRafaelSanchez-Salas
2
Introduction
Breast and prostate cancers (BCa; PCa) are the
most common solid tumors in women and men in
Western countries [1]. Incidence, natural history,
and screening strategies for early detection are
the main common characteristics. Focal therapy
(FT), such as lumpectomy or partial mastectomy,
and therapy tailored to the biology of the tumor
are dramatically changing the treatment landscape for early-stage BCa [2]. For instance,
radiation- based therapy (RT) and radical surgerywhole- organ resection are safely avoided in twothirds of newly diagnosed early-stage BCa [3]. In
contrast, FT is still a relatively new treatment
option for PCa management and remains limited
to select centers, and in a well-designed clinical
trial [4]. As for BCa colleagues, the effective
combinations of local and systemic therapies can
guide and inform PCa specialists in exploring
new treatment strategies aimed at minimizing the
P. P. Avolio
Department of Surgery, Division of Urology, McGill
University, Montréal, QC, Canada
Department of Biomedical Sciences, Humanitas
University, Milan, Italy
G. Lughezzani
Department of Biomedical Sciences, Humanitas
University, Milan, Italy
R. Sanchez-Salas (*)
Department of Surgery, Division of Urology, McGill
University, Montréal, QC, Canada
side effects of radical surgery while providing
optimal quality of life for patients with low- to
intermediate-risk PCa [5].
Story ofBreast Cancer Focal
Therapy
In 1894, American surgeon William Halsted
developed the radical mastectomy (RM), arguing
for the precise and complete removal of the
aficted breast, axillary lymph nodes, and pectoralis major to limit further recurrence [2, 6, 7].
Halsted’s procedure was quickly adopted as the
leading standard of care for BCa until half of the
twentieth century [6]. A shift toward less- invasive
procedures coincided with the results of a largescale prospective clinical trial comparing RM
with alternative treatments. In 1948, Patey and
Dyson published a case series of 118 women
treated with a modied mastectomy preserving
the pectoralis major muscle [8]. The study aimed
to compare their new surgical technique with the
standard Halsted mastectomy. The authors
reported similar 3-year overall survival (0S) in
patients with negative lymph nodes, 83% vs.
78%, respectively [8]. In 1954, Mustakallio S.
and colleagues published their experience of 187
women undergoing “modern” FT via partial mastectomy (sparing the pectoralis major muscle)
and breast radiation showing similar 5-year overall survival (OS) compared to the Halsted RM
© 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_2
15
16
P. P. Avolio et al.
[9]. In 1957, Kennedy and Miller reported the
rst series of simple mastectomies. The procedure involves complete removal of the mammary
gland and dissection of the pectoral fascia enbloc with the breast, preserving both pectoral
muscles and axillary lymph nodes. Reported
5-year OS was 62% in the group of tumors without local invasion [10]. This surgical excitement
was accompanied by the development of new
screening and diagnostic tools that led to the
improved management of BCa patients and a better understanding of cancer biology and progression. For instance, screening mammography,
introduced in the 1960s, contributed to doubling
the incidence of early- stage BCa from 112
cases/100,000 women in 1976 to 234/100,000in
2006 [11]. Less- aggressive surgical therapies
became more popular among women but
remained controversial among physicians.
However, randomized clinical trials in the 1980s
and 1990s showed that OS and disease-free survival (DFS) were equivalent for RM compared
with breast-conserving surgery [12–15].
Three studies should be particularly mentioned: one conducted by colleagues from Milan
between 1973 and 1980, which compared 701
patients with clinically negative axillae and
lesions <2cm in diameter, who were randomized
to either radical RM or quadrantectomy and axillary dissection followed by RT. DFS and OS
were the same between the two groups [13].
Between 1976 and 1984, a second trial began in
the United States by the National Surgical
Adjuvant Breast and Bowel Project (NSABP-B06)
[14]. In this trial, 1843 women with clinical stage
I or II cancer with lesions up to 4cm in diameter
were randomized to RM or lumpectomy with or
without RT. This trial demonstrated that either
RM or lumpectomy and RT were able to achieve
equally effective local control of the disease and
that OS at 5years of follow-up [14]. Finally, the
EORTC (European Organization for Research
and Treatment of Cancer) and Danish Breast
Cancer Cooperative Group trials conrmed no
difference in cancer-specic survival (CSS)
between conservative therapy and RM [16, 17].
The accumulation of evidence from randomized
clinical trials gradually led to more acceptance
by the medical community, patients, and guideline panels. Indeed, in 1990, the National
Institutes of Health consensus recognized the
equivalency of medical outcomes for these procedures and recommended breast- conservation
therapy as the appropriate method of primary
therapy for the majority of women with stages I
and II BCa [18]. Breast-conserving surgery was
dened as a combination of conservative surgery
for the resection of the primary tumor with (or
even without) surgical staging of the axilla, followed by RT for the eradication of residual
microscopic disease of the breast with or without
adjuvant systemic therapy. The goal of this technique was to provide satisfactory cosmetic results
without compromising local tumor control or
survival compared with radical RM. Given the
scientic community efforts, rates of breast conservation rose, from 23% in 1985 to 53% in the
1990s and up to 70% in select populations by
early 2000, and contemporary trends continue to
decrease rates of adjuvant therapy [19]. For
instance, in 2005, two randomized trials with
12years of follow-up showed that in postmenopausal women with hormone-receptor-positive
cancer, RT did not improve OS or salvage RM
rates, although it had a small effect on reducing
local recurrence [20, 21]. These ndings were
conrmed by a third study published in 2015,
ultimately helping to drive the adoption of
lumpectomy and adjuvant hormone therapy alone
in women over 65 [22].
Story ofProstate Cancer Focal
Therapy
Similar to BCa in the second half of the twentieth
century, FT for PCa is mostly supported by retrospective or case-report studies in the absence of
large multicenter randomized trials. Furthermore,
many urologists are still skeptical about this type
of treatment, and international guidelines consider it feasible only in the setting of experimental and well-designed clinical trials [23]. The
introduction of prostate-specic antigen (PSA)
screening led to a reduction in advanced PCa
diagnosis, similar to the introduction of mam-
2 The Story ofBreast andProstate Cancer: Parallels andCommon Controversies
17
mography in BCa diagnosis. However, new
results from several large PSA-based screening
trials have only been published in the last 5years.
The randomized Prostate, Lung, Colorectal, and
Ovarian (PLCO) screening trial, reporting data at
16 years, and the Cluster Randomized Trial of
PSA Testing for PCa, reporting data at 10years,
showed no reduction in mortality in screened
men, but they did show an increase in the detection of low-risk PCa [24, 25]. The increase in
PCa diagnoses has been accompanied by an
exponential increase in the radical treatments
performed (both RT and radical prostatectomy
[RP]), considered the only tools capable of lowering the progression of local disease. However,
similar to the RM, RP is associated with signicant morbidity, most notably erectile dysfunction
and urinary incontinence. Despite the advances
in surgical techniques and the introduction of
robotic surgery, the 12-month urinary incontinence rates ranged from 4% to 31% [26], and the
12-month potency rates ranged from 54% to 90%
[27]. Concerns about overtreatment and the inevitable side effects of radical treatment have led to
the introduction of new therapies aimed at preserving patients’ quality of life and providing
excellent oncologic and quality-of-life outcomes.
Several energy modalities are available and have
been used for the purposes of FT: irreversible
electroporation, high-intensity focused ultrasound (HIFU), cryotherapy, focal laser ablation,
photodynamic therapy (PDT), brachytherapy,
and radiofrequency ablation [4]. However, early
FT series lacked uniformity in post-ablation follow-up protocols due to the lack of long-term
follow-up data and consensus opinion.
Guillaumier S. and colleagues reported a 5-year
follow-up of 625 men undergoing focal HIFU for
clinically signicant PCa [28]. DFS was 99% at
1-year, 92% at 3-year, and 88% at 5-year followups [28]. Metastasis- free survival (MFS), CSS,
and OS in 5 years was 98%, 100%, and 99%,
respectively [28]. Oishi M. etal. reported similar
results for 160 consecutive men who underwent
hemigland cryoablation of localized PCa. After
5 years, the treatment failure-free survival rate
was 85%. Similar to early descriptions of BCa
conservation therapy, these case series have been
appropriately criticized for patients’ inclusion
criteria and adopted follow-up strategies [29].
However, these represent audacious efforts by a
part of the urologic scientic community toward
new treatment techniques for localized PCa. In
2017, Gill and colleagues published the rst and
only randomized controlled trial evaluating the
efcacy of FT [30]. The authors randomized 413
men with low-risk PCa to partial gland ablation
with PDT (n=207) or active surveillance (AS)
(n= 206) [30]. At 4years, conversion to radical
therapy was less likely in the ablation cohort than
the surveillance cohort, 53% versus 24%, respectively [30]. CSS rates overall and by grade were
signicantly lower in the ablation cohort (HR
0.42, CI=0.29–0.59) [30]. Finally, biopsy results
were negative throughout the prostate in 50%
after ablation versus 14% after surveillance (risk
difference 36%, CI 28%, 44%) [30]. Despite the
small sample size, this study showed similar
results to the NSABP-B06 or the Milan Trial for
BCa. Furthermore, similar to BCa FT, inclusion
criteria for PCa FT patients have changed.
Recently, clinical trials on PCa FT only enrolled
patients with the International Society of
Urological Pathology (ISUP) 2 and very wellselected patients with ISUP 3 cancers, with
patients having ISUP 1 cancer allocated to AS
programs [5]. Of note, PCa FT is a good option
for patients not eligible for up-front AS, providing the chance to undergo an AS regimen following successful ablation. For instance, a recent
single- arm, multicenter study enrolled only
patients with ISUP grade 2 or 3 to evaluate
whether magnetic resonance imaging (MRI)guided HIFU can safely reduce treatment burden.
At 24months, 78 (88% [95% CI 79–94]) of 89
men had no evidence of grade 2 or higher PCa in
the treated area, demonstrating that FT is feasible
when patients are carefully selected [31]. In addition, no serious adverse events associated with
MRI-guided HIFU were reported, showing the
safety of the procedure as a minimally invasive
approach to selectively treat cancer within the
prostate gland and preserve adjacent structures
crucial for urinary and bowel continence and
erectile function [31]. Recently, literature
research yielded 103 listed clinical trials, with at
18
P. P. Avolio et al.
least three randomized trials comparing focal to
whole-gland therapy with primary outcomes of
treatment failure (need for further therapies) and/
or co-primary endpoints measuring the qualityof-life domains of erectile function and urinary
continence [32]. We strongly believe that the
future of FT will depend on the favorable reports
of long-term functional and oncologic outcomes
using standardized denitions that allow for
comparison across trials using various ablation
technologies and treatment templates.
Trends inMetastatic Progression
ofBreast andProstate Cancer
An improved understanding of BCa metastatic
progression was essential to the adoption of
FT. Halsted’s theory that cancer begins in one
place, grows there, and eventually migrates to
local lymph nodes and then to more distant
organs rationalized the demolitive approach of
surgery he proposed [33]. If the Halstedian paradigm is correct, effective screening, such as
mammography, should allow cancers destined to
metastasize to be identied at an earlier stage and
reduce the incidence of cancers that rst present
as metastatic disease. However, the incidence of
metastatic BCa has been stable since 1975, supporting the hypothesis that BCa is a systemic disease by the time it is detectable, a paradigm
typically attributed to Bernard Fisher [33]. The
introduction of systematic therapy, such as chemotherapy (L-phenylalanine mustard) and later
endocrine therapy (tamoxifen), and their validated efcacy in combination with conservative
surgery further conrms the Fisher paradigm of
BCa progression [32, 33]. In contrast, the steep
decline in the incidence of metastatic PCa is most
likely the result of PSA screening [24]. Thus,
PCa destined to become metastatic appears to t
the Halstedian paradigm: a steadily progressing
disease that allows time for screening to nd it at
an earlier stage. However, many men who are
diagnosed with localized PCa have disease recurrence despite screening programs and early inter-
ventions [34]. This nding suggests that
microscopic metastases may develop very early
in the course of the disease and is more consistent
with Fisher’s paradigm than with Halsted’s [33].
Additionally, data from autopsy studies show
indolent intermediate-risk PCa can be found in
the prostate decades before any recommended
screening programs. Samuel Hellman proposed a
third paradigm: that for each type of cancer, there
are multiple paths to metastasis [35]. Aggressive,
poorly differentiated cancers tend toward the
Fisher paradigm; localized, well-differentiated
cancers tend toward that of Halsted [35]. Earlier
diagnosis may be possible for women with cancers that would ultimately become metastatic but
not for some women presenting with metastasis
because the two groups have different disease
dynamics. Although PCa may generally be considered a slowly progressing disease that allows
ample time for early detection, there is also evidence of variability. These ndings suggest a
similarity between the two diseases: both appear
to include a subgroup of cases that rst present
as a systemic disease. A better understanding of
the biology and genetics behind PCa and BCa
will be critical for the new generation of physicians. For instance, molecular proling reveals
the heterogeneity of BCa, with tumors that
range from aggressive to those with ultra-low
risk of progression [36]. Similarly, in PCa,
genomic panels can identify metastatic risk
independent of the clinical risk category [37].
Advances in the understanding of BCa biology,
rst through recognition of early metastasis and
now through molecular proling of BCa, have
shifted BCa therapy toward local control and
systemic treatment [33]. PCa has generally been
considered to have a localized Halstedian
growth pattern that is amenable to radical local
control. Modern genomic proling, by identifying tumor- specic metastatic risk, can now provide the same basis for physicians to explore
focal therapies in combination with systemic
therapy, with the unlimited goal of preserving
good quality of life while achieving optimal
oncologic outcomes.
2 The Story ofBreast andProstate Cancer: Parallels andCommon Controversies
19
Focal Therapy Candidates
Although PSA screening has led to a drop in metastatic PCa, it has also led to a signicant increase
in low and very low-risk metastatic PCa diagnoses. Anderson et al. demonstrated that among
2502 men with pure ISUP 1 at RP, 0.28% had
focal extracapsular extension, and none had seminal vesicle invasion [38]. Additionally, Ross
et al. identied no lymph node metastases in a
cohort of around 14,000 men who underwent RP
with ISUP 1 PCa in the surgical pathology [39].
These ndings provide an important pathophysiologic context to previous reports that AS for
ISUP 1 PCa is highly effective and safe [40]. For
instance, in a cohort of 1.300 men at the Johns
Hopkins Hospital, men with low-risk PCa had
excellent outcomes on AS, with 15-year MFS
and CSS rates of 99.4% and 99.9%, respectively
[41]. FT may be the watershed between AS programs, offered to patients with disease at low and
very low risk of metastasis, and radical therapies,
offered to patients with disease at high risk of
metastasis or locally advanced disease. Thus, the
“ideal” candidate likely represents an individual
with greater than 10years in PCa life expectancy,
a single or multiple well-delineated multiparametric (mp) MRI-visible, biopsy- proven ISUP 2
cancer(s) in a location(s) amenable to ablation
with a treatment margin not likely to injure the
neurovascular bundle, urethra, or sphincter [4].
As with PSA screening, the introduction of mammography led to increased diagnoses of indolent
disease [11]. For instance, excision and adjuvant
radiation were traditionally used to treat ductal
carcinoma in situ (DCIS) of the BCa. However,
in a randomized trial of 636 patients with low- or
intermediate-grade DCIS, the local failure rate
was 0.9% in the RT arm versus 6.7% in the observation arm (HR 0.11; 95% CI [0.03–0.47];
P<0.001) at 7years [42]. Thus, similar to ISUP
1 PCa, there is disagreement about whether treatment for DCIS is necessary also using focal therapy procedures.
The Index Lesion Theory
A common criticism of both BCa and PCa FT
argues that tumors are typically multifocal; thus,
FT leads to incomplete treatment. Indeed, pathologic studies of RM specimens have shown that
BCa is usually a multi-focal disease [43]. Satellite
tumors (invasive carcinoma or DCIS) have been
incidentally detected in 63% of consecutive RM,
and half the patients are present in quadrants
other than the index quadrant [43]. However,
large randomized and prospective trials with
long-term follow-up demonstrated that surgical
excision of only the clinically detected tumor did
not adversely impact MFS or OS rates [44]. In
addition, adjuvant whole RT and endocrine therapy (tamoxifen) decrease local recurrence rate
and improve long-term OS may address untreated
foci [20]. Furthermore, the resection of additional
lesions based on pre- operative MRI ndings does
not improve either local or distant recurrence
[45]. Although also the majority of PCa is multifocal, the index lesion drives the biology of the
disease. The index lesion is considered the largest, highest-grade tumor and/or the tumor with
extraprostatic extension [4]. In multiple RP
series, most patients harbor multifocal disease,
but in these same studies, secondary lesions were
very small (average 0.3–0.63 cm3) and potentially insignicant [4]. Additionally, Noguchi and
colleagues found that secondary lesions less than
0.5cc had little impact on PSA failure after RP
[46]. Still, a recent study showed that cancers
invisible on mpMRI are at lower risk of progressing than mpMRI-positive cancers [47]. Thus,
treating only visible tumors seems to reduce
overtreatment while preserving oncologic outcomes. From a biogenetic perspective, low-risk
lesions do not appear to share genetic mutations
with high-risk lesions, such as TP53 or
TMPRSS2-ERG fusion [4]. In addition, lowgrade tumors adjacent to neighboring high-grade
lesions have similar transcriptomic proles to
low-grade tumors in patients without high-grade
20
P. P. Avolio et al.
tumors [48]. This supports a polyclonal evolution
of PCa. Thus, nonindex lesions may be small,
low grade, and have low metastatic potential,
reinforcing the value of FT in PCa.
Untreated Clinically Signicant
Cancer
Suitable selection of intermediate-risk PCa
patients for FT relies on good-quality mpMRI
imaging that not only allows image-targeted
biopsy but also creates a similar pathway to perform image-targeted PCa ablation. Targeted
mpMRI biopsy increased the detection of highrisk PCa with improved sensitivity (77% vs 53%)
for the detection of intermediate and high-risk
cancers at RP [4, 49]. Two clinical trials supported these results. The PROMIS trial showed
that mpMRI had improved sensitivity to detect
ISUP 2 cancer (87% vs 60%) compared to systematic biopsy [50]. The PRECISION trial
showed the targeted biopsy alone preferentially
increases the detection of ISUP 2 cancer when
compared to systematic biopsies alone [51].
Despite the ability of targeted biopsy to increase
the detection of clinically signicant PCa over
standard systematic biopsies, mpMRI has several
limitations, the most important of which include
the underestimation of lesion size at nal pathology by up to 10 mm and under staging since
mpMRI may miss anywhere from 5% to 28% of
“invisible” clinically signicant PCa [52]. For
this reason, systematic biopsies are still needed to
better characterize tumor extension and multifocality in the setting of FT. Similar to the PCa
diagnosis, in the NSABP-B06 trial, the authors
reported that 15% of mastectomy specimens contained cancer outside the index quadrant [14].
Nevertheless, in BCa, systemic therapy is used
routinely, which impacts both distant and local
recurrence. Urologists interested in minimally
invasive prostate cancer treatments should learn
from the evolution of BCa treatment and the
work of our surgical oncologist colleagues that a
better understanding of the disease biology will
lead to effective combinations of local and sys-
temic therapies for PCa, and this will be the key
to preventing, detecting, and treating the recurrence in FT.Although mpMRI is a valuable diagnostic tool to reduce missed clinically signicant
PCa, a comprehensive, biological- based, and
multimodal approach to FT will help to improve
progression-free survival and patient quality of
life.
Further Prospective
Prostate FT trials have been criticized for the
adopted inclusion criteria, the short follow-up,
the lack of randomization, and especially the
non-negligible rate of high-grade recurrence in
the index lesion after treatment. However, with a
longer follow-up, the breast FT trials may shed
light on the oncologic outcomes to be considered
when referring to FTs. Interestingly, a trial with
20years of follow-up showed that recurrence in
the ipsilateral breast was nearly 40% after FT, but
CSS and OS were similar to patients who underwent RM [44]. In July 2018, the U.S.Food and
Drug Administration stated that delaying time to
whole gland therapy or reducing the need for
such therapy could serve as new regulatory endpoints given the known risks of urinary, sexual,
and bowel toxicity [4]. New prostate FT trials
should consider progression-free survival as the
primary endpoint, rather than MFS or CSS, given
the long natural history of localized PCa. Focal
therapy outcomes, as known today, could be
improved with a combination of energies and a
systemic treatment option like androgen deprivation therapy [5]. The results of ongoing prospective studies (CHRONOS Trial and ENHANCE
trial) are awaited to conrm these ndings [53].
Furthermore, novel approaches like the one
explored in the RTIRE trial (NCT 05345444) will
shed light on the potential combination of energy
(IRE) and a lower dose of radiotherapy (32.5
Gray in 5 fractions). Additionally, improved
assessment and intervention of tumor microenvironment are critical to the development of effective FTs to consolidate cancer control without
affecting functional outcomes.