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Regarding radiotherapy methods, the importance of accurately identifying the DIL, with a
special focus on the three-dimensional location
and its proximity to the critical anatomical structures [8, 9], relies on the clinical evidence that
usually the site of recurrence, after radiotherapy,
occurs within the DIL [10]. This point is of paramount relevance. In fact, there is a clinical relationship between the dose delivered to the DIL
and the actual risk of relapse, with patients
receiving higher doses having a lower risk of
recurrence [11, 12]. In addition, it has been demonstrated that most satellite lesions do not negatively affect overall survival [13].
Radiotherapy Techniques
As mentioned before, the therapeutic radiation
dose to the DIL may be delivered either using
ERT or IRT. ERT is typically performed using
Linear Accelerators (LINACs), which irradiate
the target volume, producing photons of different
energetic levels conforming the dose by the socalled multi-leaf collimators [14]. Such technical
innovation allows the sparing of the surrounding healthy tissues by modulating the intensity
of the radiotherapy dose (intensity-modulated
radiotherapy—IMRT) [15]. In those cases where
high doses are delivered in a small number of
fractions and to a small volume, IMRT is called
stereotactic radiotherapy (SBRT) [16]. Modern
LINACs offer the possibility to deliver an adaptive and image-guided treatment; most LINACs,
in fact, are equipped with onboard imaging,
which enables the acquisition of daily cone beam
CT, thus ensuring a high level of precision [17].
More recently, hybrid machines with MRI have
been introduced in clinical practice and have
extraordinarily raised the level of precision in
the delivery [18]. Furthermore, the insertion of
a dedicated hydrogel spacer may also be considered in specic circumstances because it allows
for prostate re-irradiation, even in patients with
ulcerative colitis [19].
With regard to IRT, it is important to underline that there are two different kinds of implant,
permanent (using seeds) and temporary (using
needles); these two approaches also differ from a
radiobiological point of view because the permanent implant is associated with the low-dose rate
(LDR) IRT, whereas the temporary implant is
used with the high-dose rate (HDR) radiation
[20]. IRT uses photons that result from the natural radioactive decay of the source used (i.e.,
Iridium-192 for HDR and Iodine-125 for LDR);
due to its intrinsic physical properties, IRT
allows to deliver a higher dose to the target and
to better spare the surrounding organs at risk
thanks to the rapid fall-off of dose around the
target [21]. Several authors have underlined that
the use of image-guided IRT, using MRI registered to transrectal ultrasound, which is typically
performed during the HDR IRT implant placement, could be associated with dosimetry, radiobiological, and potentially also clinical
advantages [22, 23].
In the following paragraphs, we will present a
comprehensive review of the most up-to-date
clinical evidence about focal radiotherapy, focusing on HDR IRT, LDR IRT, and IMRT.
Clinical Evidence About High-Dose Rate Interventional Radiotherapy (HDR IRT)
In a recent paper, Peters etal. report on their
experience with 30 patients treated for primary
lesions (T-stage ≤2c, G.S. ≤7, and PSA<10) by
focal HDR IRT using 19Gy in a single fraction. All patients were staged using MRI, and
the interventional procedure was performed
under fused transrectal ultrasound/MRI guidance. The clinical outcome chosen by the
authors was biochemical disease-free survival
(biochemical recurrence dened as nadir + 2
ng/mL) and was 70% with a median follow-up
of 48 months; they also reported adverse
effects (per Common Terminology Criteria for
Adverse Events version 4.0.) as no grade >2
genitourinary, no grade >1 gastrointestinal,
and erectile dysfunction deterioration in 50%
of patients. They concluded that tumor control
was poor mostly due to suboptimal patient
selection [24].
In a larger study by Prada etal., we have data
about 50 patients (T-stage ≤2a, G.S. ≤7, and
PSA≤15) treated using 24Gy of a single fraction
with a shorter follow-up time (32 months; the
authors planned a systematic histologic follow-
up with post-implant biopsies to be performed
after biochemical relapse). In this group of
patients, the tumor-free survival (detection of
local and/or systemic tumor relapse) was 79%,
and no urinary or gastrointestinal toxicities were
recorded, with only a slight decrease in terms of
erectile function [25].
Slevin et al. collected data about the same
number of patients but using a lower dose of
19Gy in a single fraction, and they were able to
nd that PSA nadir was signicantly associated
with biochemical progression-free survival
after a median follow-up of 26 months [26].
Another clinical series by Fischbach et al.
described the use of freehand cathetersimplanted trans-gluteal using a 3T-MRI.In this
case, the total number of patients treated was
nine, and the clinical outcome provided was the
PSA level, which decreased in all cases [27].
More recently, Ménard etal. focused on the use
of focal HDR IRT for radio-recurrent prostate
cancer. The authors provide data on 73 patients
with a median 29-month follow-up, and they
found a failure- free survival of 67%, with no
grade-3 or higher toxicity events attributable to
IRT [28]. A summary of the main ndings of
studies analyzed in this paragraph is provided
in Table27.1.
Median
follow-up
48 months
No grade >1 GI
ED deterioration in
50% of patients
32 months
and GI
Slight decrease EF
Only one late G3 GU 26 months
24 months
29 months
and GI
No grade ≥3 GU and
GI
bDFS 70% No grade >2 GU
single fraction
Clinical
setting Schedule Outcomes Side effects
Imaging used for
implant
Number of
patients
TFS 79% No acute or late GU
bPFS at 1, 2 and 3 years were
95.2%, 70.6%, and 41.8%
PSA decreased in all patients No acute or late GU
single fraction
single fraction
Primary 20Gy in
43 Ultrasound Recurrent 19Gy in
Kingdom
single fraction
resonance
FFS 67%
fractions
Author Year Country
Table 27.1 Summary of recently published papers about focal HDR interventional radiotherapy for prostate cancer
Peters etal. 2019 Netherlands 30 Ultrasound Primary 19Gy in
Prada etal. 2020 Spain 50 Ultrasound Primary 24Gy in
Slevin etal. 2020 United
2020 Germany 9 Magnetic
2022 Canada 73 Ultrasound Recurrent 22-26in two
Fischbach
etal.
Ménard
etal.
bDFS biochemical disease-free survival, bPFS biochemical progression-free survival, GU genitourinary, GI gastrointestinal, ED erectile dysfunction, EF erectile function, TFS
tumor-free survival, FFS failure-free survival
Clinical Evidence About Low-Dose Rate Interventional Radiotherapy (LDR IRT)
In a small series, Mahdavi etal. reported 2-year
outcomes of focal LDR IRT, and the authors
noted a marked PSA reduction with basically no
grade-3 side effects (per LENT/SOMA scale)
[29]. With a similar follow-up time but enrolling
a larger series of patients, Srougi etal. focused on
the different outcomes in terms of international
prostate symptom score (IPSS) according to the
primary location of the DIL to the apex or to the
base. The interesting nding of the researchers
was that signicantly less urinary toxicity is
found in DILs located at the apex compared to
those at the base [30].
In a phase II feasibility study by Graff etal.,
the international index of erectile function
(IIEF- 5) was specically addressed, and the
result after 12 months of follow-up showed that
the erectile function in their series who underwent focal LDR IRT was not signicantly
affected [31]. A somewhat surprising result
comes from the study of Langley et al., who
compared the toxicities in 362 patients receiving whole-gland (WG) therapy with LDR IRT to
30 patients receiving hemi- gland therapy; the
authors interestingly reported that international
prostate symptom score (IPSS) and quality of
life questionnaire prostate-specic 25-item
(QoLB) were not signicantly different between
the two groups of patients with a median followup of 50 months [32]. Slightly different results
were found by Kim et al., who compared 30
patients receiving WG therapy to other 30
patients receiving focal/partial therapy with a
median follow-up of 45 months; the genitourinary toxicity was found to be signicantly
reduced in the focal therapy group compared to
the WG, whereas the incidence of rectal toxicity
was similar between the two groups [33].
Anderson et al. retrospectively investigated
the role of focal LDR IRT for low- to intermediaterisk disease in 26 patients and found that the
mean focal planning target volume as a percentage of the prostate volume was 24.5%; the
authors concluded that LDR IRT has a favorable
toxicity prole and a high rate of control and
therefore decided to launch the LIBERATE prospective registry to further investigate this topic
[34]. The impact of focal therapy using LDR IRT
on continence and ejaculation was explored by
Matsuoka et al. in a large series of 51 patients
with a considerable follow-up time of 5.7 years;
the authors report that pad-free continence rate
was 100%, and ejaculation was preserved in 67%
of the patients [35]. A summary of the main ndings of studies analyzed in this paragraph is provided in Table27.2.
Table 27.2 Summary of recently published papers about focal LDR interventional radiotherapy for prostate cancer
Imaging
used for
implant
Clinical
setting
Prescription
dose Outcomes Side effects
decrease
recurrence
No G3
≥toxicity
for apex
than for
base
No G1
>toxicity
IIEF-5 not
affected
Median
follow-up
24
months
24
months
12
months
(continued)
Author Year Country
Mahdavi
etal.
Srougi
etal.
Graff
etal.
2017 Canada 5 Ultrasound Primary 144Gy PSA
2017 France 41 Ultrasound Primary 145Gy n.a. IPSS worse
2018 France 17 Ultrasound Primary 160Gy No MRI
Number
of
patients
Table 27.2 conituned
Number
of
Author Year Country
Langley
etal.
Kim etal. 2020 Korea 30 Ultrasound Primary 145Gy bRFS
Anderson
etal.
Matsuoka
etal.
n.a. not available, IIEF-5 international index of erectile function, IPSS international prostate symptom score, MRI magnetic resonance imaging, GI gastrointestinal, QoLB quality of life questionnaire prostate-specic 25-item, WG whole
gland, bRFS biochemical recurrence-free survival, GU genitourinary, BF biochemical failure, FBBF free from biochemical failure
2020 UK 30 Ultrasound Primary 153Gy Only 1
2021 Australia 26 Ultrasound Primary 145Gy FFBF
2022 Japan 51 Ultrasound Primary 160Gy BF 24% Continence
patients
Imaging
used for
implant
Clinical
setting
Prescription
dose Outcomes Side effects
recurrence
91.8%
96.2%
IPSS and
QoLB
reduction
similar to
WG
Sexual
potency
preserved
in 73%
GU
toxicity
better than
WG
GI similar
to WG
No grade
≥3 GU or
erectile
toxicities
or grade
≥2 GI
100%
Ejaculation
preserved
in 67%
Median
follow-up
50
months
45
months
24
months
68
months
Clinical Evidence About Focal External Beam Radiotherapy (ERT)
There are different ERT techniques that can be
used in the focal treatment of prostate cancer,
allowing to obtain partial organ dose-escalation
in the treatment delivery. However, there are only
a few initial clinical experiences about the use of
focal ERT with specic regard to radio-recurrent
prostate cancer. The rst series reported the clinical results of 44 patients who had already received
a full course of ERT.All patients received 35Gy
in 7 fractions to the intraprostatic site of recurrence identied through MRI and PET-CT (histological conrmation was not obtained in all
cases). The median follow-up time was 25.4
months, with 2-year biochemical failure and clinical relapse-free survival of 58.3% and 67.9%,
respectively. No acute grade-3 or higher toxic
events were reported, with two late grade-3 genitourinary toxicities [36].
More recently, a phase 1 study was published, and it included data about eight patients
treated by focal (maximum tolerated dose
40Gy in 5 fractions) to the histologically conrmed intraprostatic site of recurrence after a
previous full course of ERT.The median biochemical recurrence interval was 9.1 years,
and the median prior ERT dose was 76.5 Gy.
The median follow-up was 35 months; only
one patient experienced biochemical recurrence, and the most common adverse effect
observed was a grade ≥2 genitourinary toxicities [37]. A summary of the main ndings of
studies analyzed in this paragraph is provided
in Table27.3.
Table 27.3 Summary of recently published papers about focal external beam radiotherapy for prostate cancer
Number of
Author Year Country
Matrone
etal.
Patel
etal.
LC local control, bFFS biochemical failure-free survival, CRFS clinical relapse-free survival, GU genitourinary, GI
gastrointestinal
2021 Italy 44 Recurrent 35Gy in 7
2023 USA 8 Recurrent 40Gy in 5
patients
Clinical
setting Schedule Outcomes Side Effects
fractions
fractions
2-yr LC
90.1%
2-yr bFFS
58.3%
2-yr CRFS
679%
1
biochemical
failure
No acute G3
≥toxicity
2 cases of late
G3 GU
Several G2
≥GU toxicity
Only 1 G2 GI
toxicity
Median
follow-up
24 months
35 months
[42]. The latest GEC-ESTRO guidelines, with
Discussion
endorsement by the European Association of
Urology, recommend the use of focal IRT only
Regarding the available clinical evidence about
the use of focal radiotherapy in prostate cancer, a
recent systematic review on the topic highlighted
that in recent years, prostate focal therapies,
including focal radiotherapy, have been extensively investigated; However, more high-quality
studies are desirable before becoming standard
treatment [38]. Level 1 research comparing salvage focal therapies to existing whole gland strategies is needed to further establish the role of
these promising treatments [39]. The available
data at present allow us to say that in the case of
focal therapy, including focal radiotherapy, most
complications are mild, usually happen within
the rst month of follow-up, affecting mainly the
genitourinary system, and can be managed with
routine medications. Information about erectile
function is less detailed; however, it is much
lower compared to whole gland treatments [40].
In addition, current evidence supports the use
of focal therapy in highly selected patients. In
fact, when comparing functional outcomes and
complications in the case of salvage treatment
after focal therapy with the same treatment in the
primary setting, no signicant differences have
been highlighted so far. This nding suggests that
focal therapy could have little impact in terms of
additional side effects when a salvage treatment
is required [41]. However, universally accepted
guidelines for focal radiotherapy planning, technique, and follow-up are still to be determined
within the context of clinical trials, in line with
recommendations of other national multidisciplinary guidelines [43, 44]. Additional points of
debate within the scientic community about the
use of focal therapy for prostate cancer encompass the need for longer follow-up time, the lack
of consensus as to what denes the concept of
oncological control (presence of cancer in the
untreated prostate), and the PSA kinetics [45].
Regarding the concerns about survival outcomes for focal therapy, some insights may come
from studies addressing the use of partial therapy,
which consists of treating only the peripheral
zones sparing the urethra. A large cohort of 354
patients treated between 1997 and 2007 using
partial LDR interventional radiotherapy and a
median follow-up of 11 years was recently
published; it included both low-risk and favorable intermediate-risk patients and authors found
that both distant metastasis and prostate cancerspecic mortality were signicantly higher only
in the favorable intermediate group. However,
this study was performed in the pre-MRI era and
cannot be easily applied to modern practice
where MRI, along with subsequent targeted
biopsy, can clearly dene lesion location [46,
47].
Much work needs to be done, especially in
terms of patient selection, not only using standard classication systems such as PSA, TNM
stage, and Gleason score, but also looking for
further biomarkers that may allow to determine
the real biological aggressiveness and allow for
more accurate risk stratication [48]—and following mature trial design recommendations of
expert groups [7].
Further support is expected in the near future
from the “omic” sciences. For instance, a recent
dosiomic-based machine learning model was
developed to predict the local failure after partial
prostate re-irradiation with ERT [49].
Furthermore, articial intelligence (AI) will soon
play a major role in prostate treatments [50].
Additionally, patients’ empowerment is another
crucial point of debate in this clinical setting,
especially in the light of a recent and interesting
survey that was performed on 20 patients affected
by prostate cancer following an active surveillance protocol; the results of this study highlighted that almost half of the sample showed a
potential interest in focal therapy [51]. Taking
into account the treatment costs, it would be an
advantage to address the economic point in all
future investigations, and it would be important
to foster new multidisciplinary consensus strategies [52].
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Focal Cryotherapy
KaeJackTay, SriramDeivasigamani, AaronKatz,
andThomasJ.Polascik
28
Introduction
Prostate cancer (PCa) is the second most common male non-skin cancer worldwide, accounting for 14% of cancers diagnosed in men [1].
Radical prostatectomy (RP) and whole-gland
irradiation (RT) are considered traditional gold
standards for cure. However, these modalities are
often associated with signicant posttreatment
functional impairment due to the intimate relationship between the prostate, the urethral sphincter mechanism, and the periprostatic nerve plexus
affecting erection [2]. The widespread use of
these therapies has led to concerns regarding
overtreatment and unnecessary exposure of men
to functional impairment. Studies of the natural
K. J. Tay
Department of Urology, NUS-Duke Health,
Singapore, Singapore
S. Deivasigamani (*)
Department of Urologic Surgery, Duke University
Medical Center, Durham, NC, USA
e-mail: Sriram.deivasigamani@duke.edu
A. Katz
Department of Urology, NYU-Langone Long Island
School of Medicine, New York, NY, USA
e-mail: Aaron.katz@nyulangone.org
T. J. Polascik
Department of Urologic Surgery, Duke University
Medical Center, Durham, NC, USA
Department of Radiology, Duke University Medical
Center, Durham, NC, USA
e-mail: thomas.polascik@duke.edu
history of untreated prostate cancer have shown
risk of cancer progression and mortality are inuenced by the index lesion, mainly the Gleason
grade of the cancer [3, 4]. Focal therapy was initially conceived as a minimally invasive treatment with low morbidity for men with less
aggressive PCa, such as those with Gleason 3 + 3.
In the last decade, there has been increasing
evidence that low-grade PCa of (Gleason 3 + 3 or
prognostic grade group, GG 1) variety is slowgrowing and unlikely to result in prostate cancer
mortality if left untreated [5]. Current surveillance cohorts show a metastatic cancer rate of
0.4–2.8% and a cancer mortality rate of
0.15–1.5% at 10–15-year follow-up [6, 7].
However, up to half of these men do eventually
undergo treatment due to cancer progression [8].
The 12–18-month re-biopsy cancer upgrading
rate can be as high as 21%, suggesting that many
of these men were undergraded, which is likely
due to under-sampling of the prostate gland with
random, 12-core transrectal ultrasound (TRUS)
biopsy as the diagnostic test [9, 10].
Multiparametric magnetic resonance imaging, or
mpMRI, with its ability to detect clinically signicant, or GG >2 cancer irrespective of location
within the prostate gland, has transformed patient
selection for active surveillance (AS) [11]. The
large-scale adoption of mpMRI in early PCa has
also allowed urologists to detect the index lesion
that could potentially be focally treated. If these
lesions could be successfully ablated, the remain-
© 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_28
327