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A. Light et al.
at median follow-up of 1.4 and 3.1 years postsalvage treatment, respectively [20]. Pad-free rate
was 85% and 74%, and erectile function preserved at 21% and 73% in the surgery and radiotherapy groups, respectively. It is less clear,
however, how oncological outcomes are impacted
by offering whole-gland versus focal therapies as
a second local treatment.
The number of men who require a second
local treatment is not insignicant, and men
should therefore be counselled upfront about the
possible need for a second treatment session and/
or whole-gland treatments. It should be noted,
however, that patients are typically advised
against offering third focal therapy sessions. If
cancer has locally recurred again, then either the
tumour is ablation-resistant or it is not possible to
effectively deliver the energy to the tumour. A
key advantage of focal therapy, nonetheless, is
that whole-gland treatments can still be offered in
a safe and effective manner.
Biochemical Recurrence
After radical treatments, a rising PSA can be
highly suspicious for disease recurrence. There
are well-established thresholds for this; a PSA
>0.2 or >0.4 ng/mL after radical prostatectomy
or a PSA >2.0 above nadir after radiotherapy
indicates this state [21]. However, biochemical
recurrence is a controversial concept within focal
therapy. Because tissue is spared to varying
degrees, PSA kinetics post-treatment are more
unpredictable, particularly in the rst 12 months.
After this point, PSA tends to stabilize and
become more interpretable and could be a sensitive marker for recurrence [22].
Only one study has attempted to dene biochemical recurrence criteria for focal therapy
[22]. Here, rises of >1.0 after nadir at 12 months
and >1.5 at 24 and 36 months were found to be
the best thresholds. Other studies have used
radiotherapy criteria, for example, the Phoenix,
ASTRO, and Stuttgart criteria [15]. No criteria
using the same energy modality and delivery system has been externally validated yet. Until such
point, PSA should be considered as a useful, sen-
sitive marker for recurrence but should be interpreted exibly within the context of individual
patients and as a stimulus that further investigations, such as MRI, PET CT, and biopsy, might
be required.
Functional Outcomes
Perioperative Complications
Focal therapy is generally a safe, day-case procedure. Antibiotics are typically continued postoperatively, and a catheter is left for 3–10 days due
to prostatic swelling. The rate of Clavien-Dindo
≥3 complications in HEAT analysis was 0.8%
[11].
Urine infections typically affect 2–10%, and
epididymo-orchitis <1% [11, 23–25].
Approximately one in ve men after focal therapy may develop temporary lower urinary tract
symptoms [26]. Acute urinary retention affects
around 1% [11]. Sometimes, this is due to debris
released from urethral sloughing. If this does not
respond to conservative management and
repeated failure to achieve spontaneous voiding,
transurethral resection of any obstructing necrotic
tissue may be required.
The most feared complication after focal therapy is the development of a recto-urethral stula,
which may require bowel diversion. In HEAT
analysis, two (0.1%) men developed this [11].
One was successfully managed with urethral and
suprapubic catheterization alone, whilst the other
required surgical intervention. In ICE data of 122
patients treated with cryotherapy, none experienced this complication [25]. Understandably,
stula rates were higher at 1.2% in historical
whole-gland HIFU and cryotherapy series [27,
28]. A focal approach and a better understanding
of energy choice have likely contributed to this
fall. This includes the development of concepts
like avoiding cryotherapy for posterior disease,
which risks the ice ball encroaching the prerectal
tissues, avoiding HIFU in larger prostates, and
performing HIFU from an anterior approach progressing posteriorly to limit heating of posterior
tissue.
35 Measuring Patient-Based Outcomes: Setting Realistic Expectations When Balancing Functional…
435
Urinary
The ProtecT trial has previously published 6-year
functional data on a per-protocol basis [29].
Urinary incontinence, requiring at least one pad/
day, affected 36% of radical prostatectomy
patients in the rst year and 20% at 6 years.
Radiotherapy, however, did not affect continence,
with only 1–3% of patients reporting pad use at 6
years.
Judgment of data from focal therapy studies
regarding functional outcomes should be carefully considered. Given its more individualized
nature, a given patient’s functional outcome will
be heavily inuenced by factors like treatment
pattern and the size and location of the treated
tumour with respect to proximity to structures
like the neurovascular bundles and the urinary
sphincter. With that said, urinary continence is
generally very well-preserved after focal therapy.
In the aforementioned 2023 124-study systematic
review, the pad-free rate was reported by 60 studies, and ranged from 92 to 100% [30]. If a second
focal therapy session is needed, an analysis of
821 men from HEAT demonstrated only minor
reductions in pad-free rate, from 99% to 98% at
1–2 years follow-up, and 97% at 2–3 years follow- up, none of which were statistically signicant differences. Therefore, even if two focal
therapy sessions are required, excellent urinary
outcomes over radical prostatectomy and comparable to radiotherapy can be expected.
Sexual
In 6-year ProtecT data, erectile dysfunction
affected 95% post radical prostatectomy and 85%
at 6 years. After radiotherapy, 51% experienced
erectile dysfunction, and at six years, this was
52%, which was comparable to the active monitoring group.
The effect of focal therapy on erectile function
is less clear, with a wide heterogeneity in results
reported. For example, change in erectile function is reported in HIFU studies to affect 0–75%,
and in cryotherapy studies to affect 3–94% [30].
A combined analysis of three prospective HIFU
trials of 118 men demonstrated a return to baseline for median IIEF score by 1 year [31]. In the
analysis of HEAT data, 10% reported erectile
dysfunction at baseline, compared with 21% at
1–2 years follow-up and 18% at 2–3 years follow- up. In a prospective trial of MRI-guided
HIFU, of 40 patients with good baseline erectile
function, 22 (55%) reported some degree of erectile dysfunction at 24-month follow-up [32]. In
ICE data, erectile dysfunction affected 16% at a
median of 28 months follow-up. Given that the
neurovascular bundles are posteriorly located,
differences in treatment patterns may partially
explain the variation in reported rates.
Furthermore, heterogeneity in how erectile function is measured and how dysfunction is dened
could also contribute. Ejaculatory and orgasmic
dysfunction may also occur after focal therapy,
but rates of this are poorly reported in the
literature.
Bowel
Bowel toxicity is a particular issue following
radiotherapy; loose stools affect 24% at 1 year,
and 16% at 6 years, with fecal incontinence
affecting 8–10% at 6 years [29]. In contrast,
bowel function is typically unaltered after surgery. Rectal injury, however, is a rare but serious
complication of radical prostatectomy that may
require bowel diversion. In one American series,
the overall incidence was 0.5%; with robotic procedures, and this was lower at 0.2% [33].
Anecdotally, focal therapy is not believed to signicantly impact bowel function. Nonetheless,
there are no data describing bowel toxicity.
Importantly, although rectal-urethral stula is a
possible complication, this is very rare.
Decision Regret
A growing number of treatment options are available to men diagnosed with localized prostate
cancer, ranging from established guideline sup-
436
A. Light et al.
ported standard of care pathways and emerging
alternatives such as partial gland ablation.
Choosing between these methods can be a complex process and is best navigated with shared or
guided decision-making between physician and
patients. An important patient reported outcome
which has been increasingly examined is
decisional regret regarding therapeutic choice.
Decisional regret is often measured as distress
caused by considering alternative treatment
choices, with associated measures being measures of decision satisfaction after consideration
of alternative treatment choices.
Careful study of such patient-reported outcomes has been completed by a number of investigators over the years. Studies of decisional
regret for more established standard-of-care
options such as whole gland radiotherapy, surgery, and active surveillance have noted that specic treatment choices as well as ultimate
functional outcomes have, as expected, been
associated with decisional regret. Van Stam etal.
reviewed 1-year outcomes after localized prostate cancer management in 434 men [34]. They
noted that patient-reported outcomes of worsened urinary bowel and sexual quality of life
were associated with greater decisional regret.
They were unable to detect signicant differences in regret between treatment modalities of
surgery, radiation, and conservative surveillance
measures. At 12 months, the proportion of men
reporting regret about their initial treatment was
23% overall. In a longer-term analysis, Hoffman
et al. reviewed 15-year follow-up surveys in
SEER registry patients; they reviewed 934 men
treated between October 1994 and 1995 [35]. Of
these men, 72% underwent surgery, 17% underwent radiotherapy, and 11% chose conservative
measures (surveillance). Similar to more shortterm analyses, the authors noted that worsened
sexual function and bowel bother was associated
with increased regret. They noticed signicantly
higher regret in men treated with surgery and
radiotherapy in comparison to more conservative
surveillance measures (15% and 16.6% vs 8.2%,
p = 0.05). Given the potential for focal therapy to
result in improved quality of life outcomes versus
whole gland therapy, it stands to reason that deci-
sional regret may similarly be impacted favorably. Alrezi etal. reviewed 143 men who received
focal therapy with either HIFU or cryoablation
[36]. At a median follow-up time of 43 months,
they noted an overall regret of 19.7%. They noted
that greater than 80% of patients reported that
their decision to pursue focal therapy was the
right decision and that they would make the same
choice in hindsight. Treatment outcomes, including urinary and sexual quality of life, impacted
regret, as did recurrence/persistence of cancer on
follow-up.
Balancing theDiscussion
Focal therapy should be presented to the patient
as a less intensive alternative treatment to radical
treatments, with advantages, disadvantages, and
some remaining uncertainties. Shared decisionmaking can be poor in surgery, and holistic
efforts should be made to describe focal therapy
in comparison to other strategies [37].
Although data support good oncological control for up to 5–10 years, these are observational
data based on HIFU alone. Other modalities cannot be assumed to perform comparatively at present. Furthermore, it should be stressed that even
with active surveillance, mortality rates within
this follow-up period would probably be
comparable.
Recruitment to randomized-controlled trials
has been very difcult and, even if recruitment
were successful, meaningful oncological endpoints would need trial follow-up over 10 years,
akin to the ProtecT trial. Indeed, one of the major
reasons underlying poor recruitment is a lack of
clinician equipoise [38]. The present uncertainty
regarding longer-term outcomes, as compared to
radical treatments and active surveillance, should
be conveyed as a potential disadvantage for
choosing focal therapy.
Regardless, there are certainly advantages
that should be presented. First, focal therapy is a
safe, daycase procedure, and does not necessitate an overnight stay unlike radical prostatectomy. Second, functional outcomes are also
improved, with a high chance of retaining uri-
35 Measuring Patient-Based Outcomes: Setting Realistic Expectations When Balancing Functional…
437
nary continence, acceptable erectile function
outcomes, and a very low risk of bowel toxicity.
Although local recurrence may affect around
1in 5 men, a second focal therapy session is usually feasible and should not compromise functional outcome. Alternatively, if patients then
wish to pursue radical treatments, these remain a
feasible option.
Conclusion
Focal therapy is an appealing novel treatment
option for localized prostate cancer. However, it
should discussed objectively in the context of its
advantages, disadvantages, and uncertainties, and
explicit comparison should be given to radical
treatments and active surveillance. This chapter
has outlined the key comparative outcomes to be
aware of and conveyed during such discussions.
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Assessing Functional Outcomes After Focal Therapy
JasonJung, MatthijsJ.Scheltema,
andPhillipD.Stricker
36
Focal therapy aims to minimize quality-of-life
issues compared with whole gland treatment in
the management of localized prostate cancer.
There are many variations in the measurement
and reporting of functional outcomes, as there is
no standardized protocol. In this chapter, we discuss the current functional outcomes and recommendations following focal therapy.
Quality ofLife Outcomes Following
Focal Therapy
The major domains of quality of life can be broken down into the following categories:
J. Jung (*) · M. J. Scheltema
Garvan Institute of Medical Research & The
Kinghorn Cancer Centre, Sydney, NSW, Australia
St. Vincent’s Prostate Cancer Research Centre,
Darlinghurst, Sydney, NSW, Australia
P. D. Stricker
St. Vincent’s Prostate Cancer Research Centre,
Darlinghurst, Sydney, NSW, Australia
St. Vincent’s Private Clinic, Departments of Urology,
Darlinghurst, Sydney, NSW, Australia
© 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_36
• Adverse events/side effects
– Often measured/classied using the Clavien-
Dindo or CTCAE1 grading system
• Urinary
– Quality of Life symptom scores (e.g., IPSS,
AUA-72)
– Continence
– Other (e.g., hematuria, irritative urinary
symptoms, etc.)
• Sexual
– Erectile function and sexual function
• Bowel
– Bothersome bowel symptoms
– Other major side effects such as stulae
• Physical
– Examples include activities of daily living,
return to work
• Mental
– Examples include mental distress and
anxiety
Quality of life outcomes following focal therapy tend to focus on functional outcomes related
to treatment, thus the most reported and discussed
are on urinary and sexual domains. A recent systematic review by Nicoletti etal. looked at functional outcomes and safety of focal therapy for
prostate cancer [1]. They looked at all modalities
of focal therapy and reported on the results and
patient-reported outcome measures.
1
Common Terminology Criteria for Adverse Events
2
American Urological Association Symptom Score
441
442
J. Jung et al.
High-Intensity Focused Ultrasound (HIFU)
• Twenty-six studies reported functional outcomes after focal HIFU, with 21 studies being
prospective and ve retrospective case series.
• The most used assessment tools were IPSS
and EPIC for urinary function and IIEF for
erectile function.
• In general, urinary and sexual function were
impaired early after treatment with HIFU but
returned to baseline within 6 months.
• Pad-free rate was between 93.3 and 100%
among 14 studies.
• The risk of requiring two or more pads daily
was 1.1 to 7% [2, 3].
• The risk of incontinence tends to be low following HIFU; however, there is an increased
risk of urinary retention immediately postoperatively, ranging from 0.7 to 35.7%.
• Recto-urethral stula rate was reported from
0.1 to 3.3%.
• Urethral strictures were reported from 0.9 to
23.8%.
Cryotherapy
• Twenty-two studies reported functional outcomes, with six prospective studies and 16
retrospective case series.
• The most used assessment tools were EPIC,
IPSS, and AUA-7 for urinary function and
IIEF, SHIM,3 and EPIC for erectile function.
• Pad-free rate was 92–100%.
• Post-procedural worsening in erectile function
ranged from 3.3 to 41.9%.
• The overall rate of ED was 33.8% at 1-year and
43.6% at 2-year follow-up, with only 25.7% of
pretreatment potent patients able to have appropriate erections for sexual intercourse [4].
• Urethral stricture rate 3.2% at 1-year and
1.6% at 2-year follow-up [4].
• Fernandez-Pascual et al. reported urinary
tract infections (7.2%) and acute urinary
retention (1.4%) were the most common complications [5].
3
Sexual Health Inventory for Men
Irreversible Electroporation (IRE)
• Fourteen studies reported functional outcomes
with eight prospective studies and six retrospective studies (sample sizes ranging from 10
to 429 patients).
• Urinary function was assessed using IPSS,
EPIC, AUA-7, ICIQ-MLUTS,4 and QoL
Survey Urinary function. Erectile function
was assessed using EPIC and IPSS.
• Pad-free rate was 96.5–100%.
• Six studies reported no signicant change in
urinary function.
• Erectile function worsened by 3–13%.
• Seven studies reported postoperative complications using the Clavien-Dindo classication
and found 0.9–4% Grade 3 complications and
no Grade 4 complications.
Focal Brachytherapy
• Eleven studies were included, and most of
them were early-stage studies (sample sizes
ranging from 5 to 318 patients).
• Urinary function was assessed with IPSS and
ICIQ-UI SF,5 and erectile function was
assessed with IIEF, CTCAE, and SHIM.
• Most patients had no signicant changes in
continence after treatment.
• Pad-free rate was reported to be 100%.
• Seven studies reported no signicant changes
in erectile function, while four studies presented a decline in potency.
• Complication rates were reported by ve studies: three studies reported no adverse events
and one study reported CTCAE grade-3
adverse events.
Focal Laser Ablation (FLA)
• Eleven prospective studies were included (a
total of 308 patients).
4
International Consultation on Incontinence Questionnaire
Male Lower Urinary Tract Symptoms Module
5
International Consultation on Incontinence
Questionnaire-Urinary Incontinence Short Form
36 Assessing Functional Outcomes After Focal Therapy
443
• Urinary function was assessed using IPSS and
AUA-7, and erectile function was assessed
using SHIM or IIEF-5.
• No statistically signicant difference in urinary continence or erectile function pre- and
posttreatment with FLA.
• One study did report a slight worsening of erectile function with a signicant drop from baseline up to 12-months postprocedurally [6].
• The most common complication was hematuria (up to 28%) and hematospermia (up to
26.5%). Other complications include worsening of LUTS, urinary retention (up to 10.2%),
and infections of the urogenital tract (UTI,
epididymitis, and prostatitis) with an incidence of up to 6.6% [7].
• Two cases of recto-urethral stula were
reported, which resolved after 4–6 weeks of
catheterization [7].
Photodynamic Therapy (PDT)
• Eight prospective studies were included (more
than 400 patients).
• Urinary function was assessed using IPSS and
AUA symptom scores. Erectile function was
assessed using IIEF, SHIM, and a self-reported
questionnaire.
• Pad-free rates ranged from 93 to 100%.
• Erectile function worsened by 11–32.9%.
Long-term erectile function showed a decrease
in IIEF-5 scores by three from baseline in the
rst 6 months; however, there was no difference after the 3 years [8].
Microwave Ablation
• Three prospective studies were included (total
of 51 patients).
• All used IPSS for continence and IIEF-5 for
erectile function.
• No signicant difference in any outcome.
• Complications include hematuria, urinary
urgency, dysuria, and perineal discomfort.
Partial Prostatectomy
• Three studies were included, two retrospective and one prospective (total of 36 patients).
• IPSS was used to assess urinary function,
while SHIM and IIEF-5 were used to measure
erectile function.
• Unchanged continence postoperatively; however, 3/17 patients had urinary urgency for
2–3months.
• Erectile function remained stable in 10/12
(83%) of patients.
• Complications include UTI, transient anastomotic leak, which resolved with an indwelling
urethral catheter, postoperative ileus, and
acute urinary retention.
Bipolar Radiofrequency Ablation (bRFA)
• Two prospective studies (total of 20 patients).
• Continence and erectile function were measured using EPIC and IIEF-5, respectively.
• Preserved urinary function.
• Moderate to severe erectile dysfunction was
the most common adverse event occurring in
four patients (40%).
• Signicant decrease in EPIC-26 sexual subdomain score from 75 to 47 (p = 0.075) and
IIEF-5 score from 22 to 10 (p=0.031).
Prostatic Artery Embolization (PAE)
• One single prospective pilot study (10
patients).
• No statistically signicant change in IPSS and
IIEF scores when comparing 6 months posttreatment to baseline.
444
J. Jung et al.
Instruments Used toAssess
Functional Outcomes
Urinary Function
IPSS
The International Prostate Symptom Score (IPSS)
is a screening tool consisting of eight questions
and is used to screen, diagnose, and track the
symptoms of lower urinary tract symptoms and
benign prostatic hyperplasia. It was created in
1992 by the American Urological Association and
was previously called the American Urological
Association symptom score (AUA-7), consisting of seven questions such as feeling of incomplete bladder emptying, urinary frequency,
intermittency of urine stream, urinary urgency,
weak stream, straining to void, and nocturia [9].
The World Health Organization International
Consultation on benign prostatic hyperplasia took
the AUA-7 and added an additional question on
the patient’s perceived quality of life and called it
the IPSS.Each question related to urinary symptoms is given a numerical range from 0 to 5, with a
total score of 35. The scores are grouped into mild
[1–7], moderate [8–19], and severe (20–35) cat-
egories. The quality- of-life question is measured
independently and given a range from 0 to 6, 0
being delighted with current urinary symptoms to
6 being very unhappy with symptoms. The IPSS
can be used multiple times and is typically used to
compare the progression of symptoms and assess
the effectiveness of treatment.
EPIC
The Expanded Prostate Cancer Index Composite
(EPIC) is a comprehensive instrument used to
measure health-related quality of life in patients
for the management of prostate cancer. Its development was expanded from the University of
California-Los Angeles Prostate Cancer Index
(UCLA-PCI) to capture additional concerns relevant to different modalities for the treatment of
prostate cancer, including brachytherapy, external
bead radiation, radical prostatectomy, and androgen deprivation. EPIC supplemented the UCLAPCI with specic questions regarding irritative and
obstructive voiding symptoms, hematuria, addi-
tional bowel symptoms, and hormonal symptoms
[10]. The original EPIC questionnaire consisted of
50 items but was successfully reduced to a shorter
26-item form (EPIC-26). The 26 individual questions have 4–5 responses options which denote
function ranging from poor to excellent. Each
response is standardized to a value between 0 and
100, and a domain score is calculated as an average of the scores on the questions in that domain.
The higher the domain score, the better the functional outcome. There are ve domains in the
EPIC-26 such as urinary incontinence, urinary irritative/obstructive, bowel, sexual, and hormonal.
ICIQ-SF
The International Consultation on Incontinence
Questionnaire-short form is a four-item questionnaire used to assess the frequency, severity, and
impact on the quality of life of urinary incontinence in both clinical practice and research. It
was developed by the WHO-sponsored
International Consultation on Incontinence with
the aim of providing a series of high-quality,
robust questionnaires to assess pelvic problems
that are fully validated. There are various modules for lower urinary tract dysfunction, vaginal
symptoms, and lower bowel dysfunction, which
have been translated into many languages.
Erectile Function
IIEF
The International Index of Erectile Function is a
15-item questionnaire used to measure erectile
function with the aim of being culturally, linguistically, and psychometrically valid [11]. It was developed to provide sensitive and specic outcome
assessments to be used by clinicians and researchers
[11]. An abridged version of the IIEF containing
ve items (IIEF-5) was developed and is also known
as the Sexual Health Inventory for Men (SHIM)
[12]. The ve items are scored from a range of 1–5,
and a cumulative total is calculated.
5–7: Severe erectile dysfunction
8–11: Moderate erectile dysfunction
12–16: Mild-to-moderate erectile dysfunction