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23 Patient Selection: What Tumors Should Be Treated Based on Grade, Size, Location, Genetics and Risk…
265
true dimensions of the cancer volume [44]. In
addition to lesion size and localization, MRI can
also be used to estimate cancer aggressiveness
using ADC values [45, 46] and aid in general
treatment planning [47]. For instance, a high
B-value series improved the identication of
aggressive and index lesions [48]. Even in clinically signicant PCa patients, MRI occult cancer
presents with better long-term oncological outcomes than MRI equivocal/detectable disease
[49, 50]. A high negative predictive value of
mpMRI for clinically signicant PCa of 90% (for
PI-RADS >2) was seen, for instance, in the
PROMIS trial [51]. Therefore, MRI and MRIguided biopsy can reliably identify the index
lesion [52] and reduce the number of overseen
secondary, signicant PCa lesions. In contrast,
patient selection for FT based on an MRI-guided
pathway will leave more (small) GGG 1 lesions
untreated [53–55]. To some extent, this articial
stage migration is appreciated and reduces the
overtreatment of indolent diseases. MRI-guided
biopsy will enable the detection of single lesions
of clinically signicant PCa amenable to FT.To
conclude, the MRI-guided pathway makes patient
selection and treatment planning safer while
overtreatment is reduced.
Molecular imaging techniques such as PSMAPET/CT are less commonly used for size assessment. It can also be used for initial diagnosis [56]
and evaluation of functional properties, that is,
aggressiveness of the tumor and staging [57].
Interestingly, PSMA imaging showed better
accuracy for intraprostatic gross tumor volume
delineation than MRI in a recent trial [58].
Moreover, changes in PSMA uptake before and
after FT might help identify treatment failure,
which is often occult to MRI [59–61]. In contrast
to imaging in biochemical recurrence after radical prostatectomy, PSMA imaging for the prostate itself has high rates of false-positive ndings
comparable to or worse than conventional MRI
[62–64]. The lower specicity, especially in low-/
intermediate-risk PCa, signicantly limits the
applicability of PSMA imaging for FT.Thus, any
enthusiasm may be seen with some caution. In
fact, recent endeavors in PSMA-guided biopsy
often applied dual-labeled tracers [65] and MRI
co-registration [66] to overcome these issues.
These approaches may be applied to FT in the
future.
Third, the PSA value at diagnosis has been
historically validated in clinical risk groups [67].
PSA values, PSA density, and PSA kinetics over
time may represent surrogates for the tissue composition of the prostate and its changes over time.
While Gleason Pattern 3 and benign tissue per cc
nearly contribute equally to the serum PSA value,
Gleason Pattern 4 tissue produces sixfold-more
PSA per cc [68, 69]. While there is no consensus
concerning the threshold for PSA values, patients
with PSA <10 ng/ml are optimal candidates
for FT [25, 29]. FT may be offered selectively in
patients with PSA levels between 10 and 20 ng/
ml [23]. PSA kinetics, such as PSA doubling
time, are unreliable for the primary diagnosis
[70]. PSA density has consistently been shown to
be prognostic for assessing overall PCa risk [13].
Lower PSA density is preferable for FT because
higher PSA density is associated with higher
rates of upstaging, e.g., from unilateral to bilateral disease at RP [71, 72].
Location: Treatment Factors
• Tumor location inuences treatment success
and subsequent therapies.
• (Very) apical disease should be treated only
with caution or in special cases.
• Far distal and anterior tumors may not be
treated using HIFU.
The location of any tumor may inuence the
properties of the tumor itself and treatment
options. The inuence of tumor localization
within the prostate on its aggressiveness remains
debatable, especially if adjusted to the
GGG.Tumors in the transitional zone often present with a lower percentage of aggressive Gleason
patterns than tumors of a similar volume in the
peripheral zone [73]. In particular, in the FT
cohort, the inuence of tumor localization on
aggressiveness remained negligible because
lesions near the urethra are generally not optimal
for FT.
266
F. Falkenbach et al.
In contrast, tumor location is of utmost importance in treatment planning for both assessing
potential treatment efciency and limiting treatment toxicity. That is, the location can inuence
how reliably ablative energy can be delivered to
targets. An ideal patient has one index lesion with
sufcient security margin to critical structures
such as the urethra, bladder neck, capsule, and
neuro-vascular bundle. For instance, FT near the
urethra increases the risk of stricture formation
[74]. In contrast, such a lesion of the transitional
zone can be easily managed by cryotherapy without concerns for the rectum, the neurovascular
bundles, or extracapsular extensions. Therefore,
an individual assessment of each case and its
individual treatment modalities is necessary.
Comparative studies of different treatment
modalities of FT stratied for different lesion
regions are lacking, and some guidance by expert
reviews has been provided [28].
The “index lesion” hypothesis is one of the
fundamental paradigms of FT [75–78].
Insignicant secondary cancer deposits outside
the index lesion have recently become more
accepted [23] because they rarely contribute to
disease progression [77, 79–81]. The 2013 consensus meeting was the rst to accept not treating
lesions of GGG 1 up to a length of 5mm [21] (or
up to 1mm in a more recent consensus meeting
[23]). Nevertheless, patients with one unilat-
eral/unifocal lesion are best suited for FT.
Bilateral and multifocal diseases can be treated
with FT [82], but radical or whole-gland treatment may be more appropriate in many of these
cases. The size of the index tumor correlates with
multifocality [79]. While different concepts for
FT exist (such as only the lesion on MRI, lesion
+ safety margin, hemi-ablation, and sub-total
ablation), no randomized control trial has prospectively compared the optimal extent of
FT.Furthermore, it must be taken into consideration that the centerline of the prostate is no natural border for FT itself. Some lesions extend
bilaterally, and FT is still possible. Also, one can
ablate two distinct lesions which happen to be on
both sides. MRI lesions tend to underestimate the
extent and multifocality of the disease [44, 55],
and perilesional sampling of the penumbra is
important [83]. Therefore, a safety margin of
5–10mm is often recommended, at least in larger
prostates and when technically feasible. If indicated, technologies used for FT can also be used
for whole-gland ablation, with overall satisfactory long-term results [84].
In general, there is no consensus concerning
the exclusion of patients with an enlarged
prostate size (>80 cc) or lower urinary tract
symptoms (LUTS). HIFU treatment is associ-
ated with prostatic edema that can worsen preexisting obstruction and potentially displace the
target in large glands [86, 87]. Anterior lesions
are especially prone to displacement effects
because of the longer distance from the HIFU
probe to the target. Therefore, some centers prefer FT and especially HIFU in patients with prostate volume <60 or <80 cc and offer subvesical
deobstruction, such as transurethral resection of
the prostate, before FT.In contrast, cryotherapy
often improves voiding issues in men with prior
LUTS and may be offered independent of prostate volume; i.e., Wysock et al. reported an
improvement of 11 points at the International
Prostate Symptom Score in patients with severe
LUTS prior cryotherapy [88]. In conclusion, no
clear recommendations concerning prostate size
are available. Caution must be exercised in HIFU
for large glands (due to the distance length) and
in cryotherapy for small glands (due to possible
damage to the surrounding healthy tissue).
Extreme apical diseases should generally not
be treated with FT in most cases because of their
higher failure rates [89]. The anatomical proximity
to the sphincter increases the risk of treatment toxicity, such as incontinence, and makes RP as a salvage treatment option later exceedingly
challenging. In contrast, a modern series challenged this understanding. In this study, there were
no signicant differences in treatment-free survival
at 36 months according to the disease location
within each modality group (HIFU or Cryotherapy),
although the failure and recurrence rates were the
highest in the apical groups. After propensity score
matching, treatment-free survival at 36 months in
apical disease was 83% for cryotherapy versus
50% for HIFU (p = 0.18), and the authors concluded that cryotherapy might be preferable for
23 Patient Selection: What Tumors Should Be Treated Based on Grade, Size, Location, Genetics and Risk…
267
patients with apical disease [90]. In some studies,
brachytherapy showed superior continence rates
compared with thermal-based FT for apical cancers [28, 91, 92]. However, the denition of apical
disease is broad, and the authors do not advise performing any FT in patients with extreme/far distal
apical disease due to the reasons mentioned above.
Far distal or anterior lesions are generally
treatable by FT; however, the energy source
should be chosen carefully. HIFU is generally not
the best choice for anterior tumors, and ablation
across the urethra should be avoided [93].
Anterolateral lesions may be treated with HIFU
if the urethra is spared. Anterior tumors are generally more suitable for transperineal procedures
(such as cryoablation) than transrectal procedures (such as HIFU). For instance, cryoablation
as a transperineal procedure is an excellent choice
for anterior tumors and is less limited by prostate
size [94]. In contrast, HIFU is ideal for posterior
lesions in the small glands.
Especially challenging for any local treatment
remains extraprostatic extension. Generally,
(gross) extracapsular extension is a contraindication for FT in most cases. However, capsular
involvement is a gradual process, and a grading
system for the risk of extraprostatic extension has
been validated [95]. If MRI reveals capsular
involvement, ablation can be extended beyond
the capsule. Patients with unsuspicious digital
rectal examinations are preferred for FT [29].
Genetic andRisk Category: Patient
Factors
• The clinical risk categories are essential for
patient selection.
• Monogenic as well as polygenic risk factors
may contribute to a better estimation of prog-
nosis and treatment response, especially for
borderline indications. However, detailed
research on their application in FT is highly
limited.
• Owing to the low prevalence of germline
pathogenic mutations in the FT cohort, clini-
cal risk groups remain the cornerstone of
patient selection.
Risk categories aid in patient selection for FT
and rely on classical clinical risk groups (such
as NCCN or D’Amico risk groups) [21, 67,
96], multiparametric MRI ndings (targetable
lesions), and biopsy results (MRI concordant
biopsy results) [28]. Within these wide groups,
early identication of aggressive diseases requiring immediate radical treatment is limited [97,
98], and salvage FT is an option for in- and out-
eld recurrence. While in-eld recurrence can be
reduced by diligent treatment and its intensication, out-eld recurrence can be attributed to
insufcient patient selection based on the abovementioned risk groups. Somatic (i.e., tumor tissue) and germline (i.e., inherited) testing for
DNA damage response genes guide as estimates
for overall prognosis and treatment response
(i.e., Poly (ADP-ribose) polymerase inhibitors
[99, 100]). Polygenic risk scores will most likely
improve the discriminating effect even further in
the future because they co-evaluate more common variants with lower penetrance [99, 101].
Despite promising results, current guidelines do
not incorporate these markers as a standard of care
for risk stratication [13, 14, 96]. Studies focusing on cancer genome research have established
that PCa has a relatively low mutational burden
[102]. Due to the high overall disease prevalence,
even this low burden of somatic mutations in
patients suitable for FT by conventional means
can be useful for patient stratication. For this
purpose, RNA expression genomic classiers
can help in treatment decisions, that is, borderline indications like high-volume GGG 1 disease
[99, 103]. Prolaris (Myriad, Salt Lake City, UT),
Genomic Prostate Score (MDxHealth (former:
Oncotype), Irvine, CA), and Decipher (Veracyte,
San Diego, CA) are commercially available gene
expression proles used to improve patient risk
stratication [104–107]. Currently, none of these
biomarkers has been investigated independently
for FT.In AS cohorts, these tests could somewhat
predict the risk of progression [99, 105, 106, 108,
109]. The extrapolation to FT cohorts appears
reasonable for the reasons mentioned above but
needs to be validated.
In general, germline mutations are identied
in 1–17% of prostate cancer patients depending
268
F. Falkenbach et al.
on the stage (localized vs. metastatic) and personal/family history of cancer, including not only
prostate but also breast, ovarian, and pancreatic
cancers [110–112]. Germline mutations are associated with a higher risk of PCa, earlier age at
diagnosis, aggressive PCa phenotype, and worse
oncological outcomes [113–115]. Germline
mutations in the DNA damage response (such as
BRCA1, BRCA2, and ATM) as an underlying
driver of the disease are rare among localized diseases suitable for FT (<1%) [112]; i.e., carriers of
germline BRCA mutations are more likely to
have higher Gleason grades with intraductal/cribriform morphology [116, 117]. Therefore, these
patients are more often unsuitable for FT even
when they t in regard to conventional risk
groups. While FT in these patients has not been
investigated, AS has been. Halstuch etal. reported
on outcomes of AS in 18 PCa patients with germline mutation. At a median follow-up of 28
months, 80% of patients continued AS with no
upgrading or radical treatment. The authors concluded that AS may be feasible in careers of
germline mutations with low-risk PCa [118]. In
contrast, Carter etal. showed that patients with
germline mutations (BRCA1, BRCA2, and ATM)
are at a signicantly higher risk of grade reclassication and upgrading than patients with wildtype phenotypes [119]. In general, BRCA
mutations are independent predictors of shorter
cancer-specic survival for localized PCa, even
after adjustment for common clinical risk parameters [113]. BRCA2-decient localized cancer
shares many molecular hallmarks with castration-resistant PCa (see WNT-pathway) [99, 120].
From this notion, patients with known BRCA
mutations are offered FT rarely or only if they
agree to an intensied follow-up scheme.
In summary, at the time of this writing (October
2023), the role of genetic analyses and genomic
biomarkers in FT candidates was yet to be clearly
dened. While genetic analyses and genomic biomarkers should not be routinely considered prior
to FT, in a subgroup of patients who do not fully
satisfy FT selection criteria (high volume GGG1,
GGG2 with cribriform pattern or selected group
GGG3), these tools may help identify patients at
high risk of failure and disease progression. If
high-risk mutations are known, FT should be
carefully considered (Fig.23.1).
Fig. 23.1 Patient selection for focal therapy as continuous risk function
23 Patient Selection: What Tumors Should Be Treated Based on Grade, Size, Location, Genetics and Risk…
269
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Prostate Focal Therapy: Denitions
andCommon Terminology
JohnF.Ward
24
Introduction
The term “focal therapy” (FT), as applied to the
treatment of localized prostate cancer (PCa), is a
blanket term that encompasses any treatment of
the prostate with the intent to preserve some portion of the prostate gland. This concept of partial
gland ablation (PGA) is intended to provide a
very personalized treatment of the prostate gland,
based upon the location and extent of the PCa
within the gland of the specic man, rather than
the brute, one-size-ts-all approach that has been
the standard approach to prostate cancer for
decades. Therefore, there is no one “focal therapy” as the location and volume of cancer will
vary with each patient. The ability to deliver
destructive energy to different volumes of the
prostate tissue and in different regions of the
prostate gland (apex, base, lateral, anterior, posterior) may inuence the energy source employed,
the oncologic success, and the collateral
morbidity.
FT, as it was initially performed, was essentially a “blind” procedure. It was based upon the
interpretation of a biopsy template and then
applying that information to a region(s) of the
J. F. Ward (*)
Department of Urology, University of Texas, M.D.
Anderson Cancer Center, Houston, TX, USA
e-mail: jfward@mdanderson.org
prostate that seemed to contain the dominant cancer. To put it another way, FT was initially performed by treating a region of the prostate that
encompassed both the predicted area of cancerous tissue and a varying amount of surrounding
normal prostate tissue. Unlike organ-preserving
therapies for other solid organ malignancies
(liver, kidney), which are guided visually by the
ability to image the tumor itself, prostate cancer
has been relatively invisible to imaging techniques. Therefore, FT of prostate cancer encompassed a region around which the cancer was
identied, which itself was based upon a blind
biopsy.
Multiparametric magnetic resonance imaging
(MP-MRI) of the prostate has begun to lift the
veil that has hid prostate tumors in situ [1].
Combined with in-bore or ultrasound fusion, targeted biopsy, and targeted ablation, the possibility of truly conformal prostate cancer therapy has
begun to seem a bit closer. However, limitations
remain as we discover the inability of the current
technology to accurately dene cancer volume
and margins [2]. FT continues to treat a margin
around the identied tumor that essentially
results in a zonal or regional ablation. Thus, it
continues to be important for us to accurately and
consistently describe our treatment intent in order
to best understand our outcomes.
In the early part of the twenty-rst century,
when Onik etal., and later Bahn etal., were the
rst to report treating patients with PCa by ablat-
© 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_24
275