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38 Pathologic Assessment andImplications Following Focal Therapy ofProstate Cancer
465
sies [61]. mpMRI is gaining popularity as a surveillance technique in follow-up protocols, and
recommendations on its use in this setting have
been recently issued by the Société Internationale
d’Urologie and the International Consultation on
Urologic Diseases [62]. It is also controversial
whether histologic criteria for active surveillance
dened for systematic blinded biopsy are applicable to surveillance protocols in the era of
mpMRI and focal therapy [63].
Reporting Recommendations
forPostfocal Therapy Treatment
Biopsies
The following recommendations have been
recently updated by the Société Internationale
d’Urologie and the International Consultation on
Urologic Diseases [62]:
1. In biopsies from the treatment area, it is
important for the pathologist to report ndings that conrm that the treatment area has
been sampled. As stated above, these may
include necrosis, hemorrhage, acute and
chronic inammation, stromal edema, glandular atrophy, hemosiderin deposition, reactive broblasts, and stromal brosis should be
consistent with the treatment modality
employed.
2. In the treatment area, a diagnostic menu for
biopsy ndings may include:
(a) Benign prostatic tissue with posttreat-
ment changes, no residual carcinoma.
(b) High-grade prostatic intraepithelial neo-
plasia (HGPIN); this nding in the treated
area following focal therapy is of uncertain but likely little signicance, particularly if isolated.
(c) Atypical small glands, suspicious for car-
cinoma, a diagnosis usually rendered
after examination of multiple levels and/
or immunohistochemical studies.
(d) Prostatic adenocarcinoma. If no
treatment- induced changes are apparent
in the cancerous glands, a Gleason score
should be assigned to the nding of prostatic carcinoma in the treatment area. The
WHO/ISUP recommended prognostic
grade groups (1 through 5), which group
different combinations of Gleason grades
according to prognosis, should be
reported in parallel with the Gleason
grade [64].
3. In core and systematic biopsies outside of the
treatment areas, handling and reporting should
occur in conjunction with established
practices.
No large studies to date have dened the optimal follow-up biopsy schedule for prostatic adenocarcinoma treated with focal therapy, and
current recommendations are usually dened at
the level of expert panel consensus [65–67]. This
has resulted in variable approaches to follow-up,
ranging from dened post-treatment biopsy
schedules independent of clinical and biochemical (PSA) features for a given patient to biopsies
only limiting to when these features suggest the
presence of clinically signicant residual or
recurrent disease. Table38.4 contains a recommended schedule recently updated by the Société
Internationale d’Urologie and the International
Consultation on Urologic Diseases [62].
In summary, focal therapy is associated with
technique-dependent histopathologic changes
that the surgical pathologist will encounter more
frequently as these techniques gain popularity.
Pathologists not only need to familiarize themselves with the effects of these new treatment
modalities but should actively participate in the
development of criteria for determining therapeutic success or failure and their appropriate
reporting, as well as dening the optimal surveillance of both the treated and untreated areas of
the prostate.
466
Table 38.4 Recommendations for the use of biopsy after focal therapy. Société Internationale d’Urologie / International
Consultation on Urologic Diseases
Time after focal therapy Action
3–6months 4–6 cores bx of treated area
12–24months Target biopsy of treated area
12-core systematic biopsy
5years
Other biopsy triggers PSA kinetics, rising PSA, new mpMRI suspicious nding
Adapted from Tay etal. [62]
mpMRI +/− biopsy of abnormal areas
R. E. Jimenez et al.
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Salvage Treatment Following Focal Therapy
TheoM.de Reijke andDerekLomas
39
Introduction
As focal therapy for prostate cancer gains popularity, providers will more commonly face the
need to offer salvage treatments for those who
develop recurrences following it. While limiting
the amount of the prostate treated has led to
improved function outcomes with focal therapy
compared to whole gland radical therapies, cancer can recur in either the treated or remaining
prostate tissue. A recent large focal high-intensity
focused ultrasound (HIFU) series reported salvage whole gland treatment was needed in 7% of
patients, and 18% received a repeat focal treatment [1]. Based on Kaplan-Meier estimates from
the study, a quarter of men might expect to need
a salvage radical treatment at 7years. Therefore,
it is essential to have a discussion with the patient
regarding the potential need for retreatment after
focal therapy and what options will be available
to them.
T. M. de Reijke (*)
Department of Urology, Amsterdam UMC,
University of Amsterdam,
Amsterdam, The Netherlands
e-mail: t.m.dereyke@amsterdamumc.nl
D. Lomas
Department of Urology, Mayo Clinic,
Rochester, MN, USA
e-mail: Lomas.derek@mayo.edu
Diagnosis ofRecurrence
It is unknown if PSA and MRI are predictive
parameters for recurrence. Criteria for biochemical recurrence used following radical prostatectomy (PSA >0.2 ng/mL) and external beam
radiotherapy (nadir +2ng/mL) are not applicable
for focal therapy. In a small study by Baskin etal.
PSA and MRI were not predictive for the identication of recurrent or persistent disease following focal cryotherapy [2].
When there is a suspicion of tumor recurrence,
e.g., rising PSA, following focal therapy, a proper
workup should be performed. Contrast-enhanced
MRI is mandatory, although there are no consensus guidelines for the determination of identifying suspicion of recurrence on MRI. The
PRECISE guideline is helpful for active surveillance protocols, but this protocol is not helpful in
the case of focal therapy [3]. Geboers etal. concluded that the diagnostic accuracy of mpMRI in
the follow-up after irreversible electroporation
(IRE) was low and that systematic biopsies
should be performed in the follow-up [4]. Giganti
et al. recently proposed a PI-FAB (Prostate
Imaging after Focal ABlation) score [5]. MRI
interpretation is often challenging following
focal therapy because of treatment-induced brosis. PI-FAB involves a 3-point scale for assessing
the three MRI sequences in sequential order:
1-DCE sequences, 2-DWI, and 3-T2-WI. Of
course, it is essential that the initial MRI is used
© 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_39
469
470
T. M. de Reijke and D. Lomas
for comparison. In case of a PI-FAB 3 score (high
signal intensity on the high-b-value sequence
AND focal enhancement AND low signal intensity on T2-WI and on the ADC map), the authors
recommend a biopsy.
Besides the availability of the prefocal therapy
MRI for proper interpretation of multiparametric
(mp)MRI in case of suspected recurrence, other
factors that are important to consider when assessing suspected recurrence include the energy
source used and the location and extent (targeted,
hemigland, or subtotal) of the prostate ablation.
Contrast-enhanced ultrasound (CEUS) has
been reported as an imaging modality during
HIFU to demonstrate adequate tumor ablation
[6]. Another recent ultrasound imaging modality
in use is the microultrasound. In a recent systematic review and metaanalysis, microultrasound
demonstrated comparable cancer detection rates
to MRI in this screening setting [7]. However, the
role of CEUS and microultrasound has not been
studied to assess recurrence after focal therapy.
PSMA PET scan has become the imaging of
choice for the assessment of suspected recurrence following radical treatment of prostate cancer [8]. Increasingly, PSMA PET scans are also
being used in the initial diagnosis and staging
evaluation. PSMA PET scan may also be a valuable tool for assessing recurrence after focal therapy, but more data are needed.
When recurrence is suspected, whether based
on PSA or imaging, targeted and systematic
biopsies should be obtained for histologic conrmation and to counsel the patient appropriately
on possible salvage treatment.
Salvage Treatment Modalities
Several salvage options are available for the treatment of recurrent disease after focal therapy. The
original diagnostic data and treatment plan can
help determine the next steps. The energy used
for the ablation can inuence the interpretation of
the Gleason grading. Therefore, a discussion
with the interpreting pathologist can be helpful in
determining if an accurate ISUP score can be
determined.
Next, the following issues are important: 1-the
recurrent tumor in the treated area, 2-the tumor
outside the treated area or contralateral or bilateral, 3-number of positive biopsies, 4-ISUP score
at which location, 5-time interval until demonstrated recurrence, and 6-lifetime expectancy of
the patient. Based on these factors, a risk assessment should be completed for the recurrence, and
the clinician should determine whether this recurrence will inuence the patient’s risk of dying
from the disease. In most cases, studies to exclude
metastatic disease are not necessary, as most
patients likely had intermediate-risk prostate cancer at the time of initial treatment. However,
additional staging studies should be completed
before salvage treatment if pathology shows
adverse features.
In some cases, active surveillance may be
most appropriate. For example, if the recurrence
is ISUP score 1 or 2 without cribriform growth
pattern or there has been a long time interval
from treatment to recurrence. This is supported
by the work by Pound etal., which demonstrated
favorable outcomes when there were longer time
intervals for PSA recurrence following radical
prostatectomy [9]. While active surveillance may
be suitable for many, patients must be advised of
the need for eventual treatment. In a retrospective
study of patients with focal therapy recurrence
managed with active surveillance, the authors
reported a high rate of need for secondary treatment [10]. In those with ISUP ≥2 and good life
expectancy, salvage treatment should be considered. Salvage treatment strategies after focal
therapy recurrence include repeat focal therapy,
radiation therapy, and radical prostatectomy.
Concerning all three salvage treatment
approaches, only case reports and small series
have been described.
Repeat Ablation
The least invasive way to treat a recurrence is
with another ablative treatment. This may be
administered either in a focal or whole-gland
fashion, depending on the characteristics of the
recurrence. Many large focal therapy series
39 Salvage Treatment Following Focal Therapy
471
include data regarding repeat ablation rate, but
overall evidence regarding oncologic and functional outcomes of repeat ablation remains limited. At present, the optimal repeat focal therapy
strategy and the optimal patient and tumor characteristics have not been described [11, 12].
Reddy etal. recently published their 15-year
experience with focal HIFU in a prospective
cohort of 1379 men [1]. In this study, 18.3% of
patients had undergone at least one repeat focal
treatment. At a median follow-up of 32months,
16.3% (n = 225) had undergone one, 1.9%
(n=26) had undergone two, and one patient had
undergone a total of four focal therapy treatments. Oncologic and functional outcomes for
these repeat procedures were not specically
reported.
Qaoud etal. performed a retrospective review
of patients who underwent repeat focal ablation
with HIFU for recurrences after a focal HIFU
[12]. At a median follow-up of 27months, half of
patients achieved oncologic control. From a
functional standpoint, patients had no signicant
changes in their International Prostate Symptom
Score (IPSS) and International Index of Erectile
Function (IIEF) scores following repeated
ablation.
In a single-center prospective cohort treated
with focal irreversible electroporation, the repeat
IRE treatment rate was 10.5% (24/229) [13].
Over half of the patients (54%) treated with
repeat IRE progress to requiring radical therapy
during follow-up.
Repeat ablation for recurrence has also been
described in those undergoing focal cryotherapy.
Tan etal. reported on 82 patients who underwent
focal cryotherapy, of whom nine experienced a
biopsy-proven recurrence of grade group 2 or
higher disease [14]. Five patients underwent a
second focal cryoablation. Of those, four had a
biochemical response with PSA nadir to under
1 ng/mL, while one required eventual radiation
therapy.
Salvage Radical Treatment
While repeat focal treatment may be an option
for some patients, others may have disease fea-
tures that require more aggressive salvage treatment. Since focal therapy is still investigational
and chosen for its ability to preserve continence
and sexual function, it is essential to demonstrate
that salvage treatment by radical prostatectomy
or external beam radiotherapy does not compromise functional outcomes. Several groups have
reported on these issues. However, these are all
selected series, and proper interpretation should
be done with great care.
Salvage Radical Prostatectomy
Marconi etal. evaluated 82 patients with demonstrated local recurrence and found a progressionfree survival rate of 74%, 48%, and 36% at 12-,
24-, and 36 months following salvage radical
prostatectomy, respectively [15]. The continence
rate at 1year was 83%. They identied an in-eld
recurrence after focal therapy as a prognostic factor for more aggressive behavior.
Herrera-Caceres etal. reported on 34 patients
undergoing a salvage radical prostatectomy following different focal therapy approaches (HIFU,
laser, brachytherapy, and cryotherapy) and found
four patients with a bladder neck contracture
[16]. At a mean follow-up of 4.3 years, a biochemical recurrence was found in 20.6%, and
functional results were good, with 31 patients
being continent. Also, in this series, a high number of patients had pT3a (47.1%) and pT3b disease (11.8%), and 38% showed positive surgical
margins.
The RAFT (Robotic Surgery After Focal
Therapy) study was a prospective single-group
assignment interventional study of 23 patients
that evaluated the toxicity of surgery after focal
therapy based on the Expanded Prostate Cancer
Index Composite (EPIC)-26 questionnaire and
early oncologic control outcomes [17]. Thirtynine percent of the patients had ISUP grade group
3 or higher disease at initial diagnosis. Following
salvage radical prostatectomy most men maintained good urinary function at 12months, with
83% pad-free and 96% requiring 0 to 1 pads.
Conversely, median sexual function scores
declined at 12months (22.2 vs 58.3, P<0.001).
Biochemical recurrence-free survival at
472
T. M. de Reijke and D. Lomas
12 months after surgery was 82.6%, and four
patients went on to receive salvage radiotherapy.
In this series, 26% had pT3a disease, 30% had
pT3b disease, and 35% had positive surgical
margins.
Two recent studies have reported on salvage
radical prostatectomy after IRE. In a single
institution, a single surgeon series of 15 patients,
Blazevski et al. reported good functional and
oncologic outcomes [18]. Specically, all patients
were pad-free at 6 months, and 9 of the 15
patients had erections sufcient for intercourse
without the need for medication. Positive margins were present in one patient, and at a median
follow-up of 22 months, no patient had a biochemical recurrence. Van Riel et al. reported on
39 patients in an international, multicenter, retrospective analysis undergoing salvage radical
prostatectomy following IRE [19]. Salvage radical prostatectomy was not compromised by previous IRE focal therapy, and with the short
follow-up, oncological and functional outcomes
were comparable with primary radical prostatectomy data. Interesting to see was that 38.5% of
patients showed a pT3a and 7.7% a pT3b tumor
and a positive surgical margin rate of 25.6%. One
patient had metastatic disease.
Bhat etal. performed a matched pair analysis
on patients undergoing primary or salvage radical
prostatectomy (n = 53) following focal therapy
[20]. There was a signicant difference in positive surgical margin rate and positive lymph node
status in favor of the primary radical prostatectomy. The complication rate was comparable. A
recent systematic review and meta-analysis
reporting on 12 publications, including 482
patients undergoing salvage radical prostatectomy, found a complication rate of 15% (4.6%
Clavien-Dindo >=3) [21]. Again, a high positive
surgical margin rate was found (27%) and biochemical recurrence was seen in 23% of patients
at 2 years, functional outcomes at 12 months
were modest (67% pad-free and maintained
potency rate of 37%).
In the randomized trial evaluating the role of
vascular-targeted photodynamic therapy with
padeliporn, 45 patients underwent a salvage
radical prostatectomy [22]. One Clavien-Dindo
3B complication was found, pT3 was found in
31%, and 31% had positive surgical margins.
Biochemical recurrence at 6–12 months was
found in 12%. Functional outcomes were modest: 64% continent, only 11% fully potent, and
23% erections with complementary therapy.
In conclusion, for salvage radical prostatectomy following focal therapy, only a small series
have been published which have shown that surgery is feasible with a low complication rate;
however, functional outcomes are marginal.
Prognostic factors for recurrence are not clear,
although possibly in-eld recurrence is a poor
prognosticator. Almost all published series demonstrated a high surgical positive margin and
upstaging to pT3a,b. This is worrisome, especially if the patient is counseled that a secondary
treatment with curative intent is still possible in a
salvage strategy approach. This means that
improvements must be made to identify the right
patient for focal therapy.
Salvage Radiotherapy
Most of the series published on salvage radiation
treatment after focal therapy report on external
beam radiotherapy, and no data exist on salvage
brachytherapy following focal therapy. Mesci
et al. reported on 14 men treated with salvage
radiotherapy (70–74Gy) +/− ADT [23]. No serious complications were seen, but 50% of patients
developed a biochemical recurrence. Nathan
et al. compared the results of salvage radical
prostatectomy and salvage radiotherapy following different methods of focal therapy that were
retrospectively and prospectively collected [24].
In both groups, 100 patients were evaluated for
functional and oncological outcomes. In the salvage surgical group, there were more high-risk
patients. Pad-free rates were comparable, but
erectile dysfunction was more likely in the surgical group. Gastrointestinal complications were
seen more frequently in the salvage radiation
group (grade 3 or 4, 4 and 5%, respectively).
Biochemical recurrence-free survival was comparable for both groups in the intermediate-risk
group. Still, in the high-risk group, biochemical-
39 Salvage Treatment Following Focal Therapy
473
free survival was better at 3 years follow-up for
salvage radiotherapy (66.0 vs 86.3%,
respectively).
Von Hardenberg etal. compared outcome data
of salvage radiotherapy, surgery, and active surveillance in a German cohort of 90 men [10].
Following relapse after focal therapy, 50 men initially were under an active surveillance protocol,
and 13 subsequently underwent follow-up salvage treatment. In total, 44 men received salvage
surgery and 13 salvage radiotherapy. In the surgical group, adverse pathology was seen in
52.3%—progression-free survival at 3 years
80.4% following surgery, and 100% following
radiotherapy.
Cafuta et al. evaluated in 13 patients the
Quality of Life and functional outcomes following salvage radiotherapy after HIFU (extent of
treatment not reported) [25]. The group of
patients were older (median age 80years). After
a median follow-up of 76months, no gastrointestinal or genitourinary toxicity ≥3 was reported.
Health-related Quality of Life was not changed at
3 and 12months follow-up.
In conclusion, salvage radiotherapy following
focal therapy is feasible with modest side effects
and good oncological outcomes. However, the
data are scarce, and selection bias is substantial.
Discussion andConclusion
Focal therapy remains an investigational option
for the treatment of prostate cancer. Patient selection, treatment schedules, and energy sources differ among the treating physicians. Expert groups
advise follow-up schedules, but they are still not
universally the same. Also, interpretation during
follow-up of PSA uctuations or velocity and
MRI is more complicated. This can be responsible for different stages of the disease in case of
recurrence in-eld or out-eld. The proper interpretation of pathology might be difcult following the different energy sources used.
These are some of the issues that will result in
various strategies for salvage treatments. As seen
from the reports, there are no solid data that can
help counsel the patient about the best strategy
for salvage treatment nowadays. Of course, if
imaging clearly shows a progression of the lesion,
treatment with curative intent is to be advised for
the patient, depending on his life expectancy.
However, if standard follow-up biopsies reveal a
low-grade in-eld or out-eld recurrence or both,
there are no good guidelines to help the physician
counsel the patient in the best way.
Hopefully, registries will help the focal therapy community to solve this dilemma, but for the
time being, it is still a matter of shared
decision-making.
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