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36 Assessing Functional Outcomes After Focal Therapy
Table 36.1 Classication of surgical complications
Grade Denition
Grade I Any deviation from the normal postoperative course without the need for pharmacological treatment
or surgical, endoscopic, and radiological interventions
Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgetics, diuretics,
electrolytes, and physiotherapy. This grade also includes wound infections opened at the bedside
Grade II Requiring pharmacological treatment with drugs other than such allowed for grade 1 complications
Blood transfusions and total parenteral nutrition are also included
Grade III Requiring surgical, endoscopic or radiological intervention
Grade IIIa Intervention not under general anesthesia
Grade IIIb Intervention under general anesthesia
Grade IV Life-threatening complication (including CNS complications)a requiring IC/ICU management
Grade IVa Single organ dysfunction (including dialysis)
Grade IVb Multiorgan dysfunction
Grade V Death of a patient
Sufx “d” If the patient suffers from a complication at the time of discharge (see examples in Table2), the
sufx “d” (for “disability”) is added to the respective grade of complication. This label indicates the
need for a follow-up to fully evaluate the complication
a
Brain hemorrhage, ischemic stroke, subarrachnoidal bleeding, but excluding transient ischemic attacks
CNS central nervous system, IC intermediate care, ICU intensive care unit
445
17–21: Mild erectile dysfunction
22–25: No signicant erectile dysfunction
EPIC
Individual questionnaires for specic domains
may be used to assess the functional outcome of
a specic area. EPIC-sexual domain can be used
to assess erectile function.
Safety Outcomes
Clavien-Dindo
The Clavien-Dindo classication is used to dene
and grade postoperative complications. It was
rst published in 1992 with a 4-level severity
grading [13]. The grading principle of this older
system was based on the therapy used to treat the
complication [14]. A revised classication was
sought to better grade and reect light- threatening
complications and long-term disability due to a
complication (Table36.1).
CTCAE
The Common Terminology Criteria for Adverse
Events is a descriptive terminology that can be
used to report adverse events. It has been developed by the National Cancer Institute of the
United States Department of Health and Human
Services. A grading scale measuring the severity
of each adverse effect is provided from 1 to 5.
Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated.
Grade 2: moderate; minimal, local, or noninvasive intervention indicated; limiting ageappropriate instrumental ADL.
6
Grade 3: Severe or medically signicant but
not immediately life-threatening; hospitalization
or prolongation of hospitalization indicated; disabling; limiting self-care ADL.
Grade 4: life-threatening consequences; urgent
intervention indicated.
Grade 5: death related to adverse effect.
Physical/Mental Outcomes
SF-12
SF-12 is a 12-item questionnaire used to assess
generic health outcomes and covers eight domains:
• Physical Functioning (PF)—limitations in
activity due to health problems.
• Role-Physical (RP)—limitations in usual role
activities due to physical health problems.
6
Activities of Daily Living
446
J. Jung et al.
• Bodily Pain (BP)—presence of pain and limitations due to pain.
• General Health (GH)—rating of general
health.
• Vitality (VT)—energy level and fatigue.
• Social Function (SF)—limitations in social
activities due to physical or emotional
problems.
• Role-Emotional (RE)—limitations in usual
role activities due to emotional problems.
• Mental Health (MH) - psychological distress
and well-being.
The SF-12 and SF-36 are part of the “SF fam-
ily” of patient-reported outcome measures, which
also include the SF-8 Health Survey and DYNHA
Generic Health Assessment [15]. These related
tools are cross-calibrated to maximize their comparability. The SF-36 is the most widely used
generic health outcome instrument in the world
but can be time-consuming for patients, and thus,
SF-12 was created that maintained the same eight
domains. The SF-12 provides norm-based scores
for Physical Component Summary (PCS) and
Mental Component Summary (MCS) only, with a
higher score indicating a better health state. The
SF-12 v2 provides a norm-based score in each of
the eight domains mentioned above.
Improving Completion Rates
ofPatient-Reported Outcomes
It is critical to have high completion rates of
patient-reported outcomes to have the most accurate gures when counselling patients who are
considering focal therapy. A paper by King etal.
found that men are prepared to compromise
oncological outcomes for improved quality of
life [16]. They found severe urinary dysfunction
and bowel symptoms were the least tolerable side
effects of prostate cancer treatment, and severe
sexual dysfunction was relatively benign [16].
The authors concluded that patients are likely to
make decisions about treatment based on severe
side effects and not mild ones.
Nielsen etal. conducted a prospective, obser-
vational study involving Danish patients with
multiple myeloma who agreed to partake in completing patient-reported outcomes (PRO) as part
of the management of their disease [17]. They
found that electronic reminders signicantly
increased the completion of the questionnaires,
with 25.5% of not completed questionnaires
being completed after the electronic reminder
versus a 16.1% completion rate without the
reminder (p<0.001). The authors also described
predictors for non-completion and found frailty
(p = 0.001) and chose paper questionnaires
(p=0.05) as the strongest predictors. The results
of the study show that completion rates for PROs
may be increased when web surveys are provided, sparking the question-Should we go digital only for monitoring?
Web surveys offer advantages over traditional
survey methods as they allow a larger sample
size, decrease costs, geographic distance is no
longer an issue, and are time efcient [18]. A literature review by Sammut etal. provided input on
methods to increase response rates to electronic
surveys and questionnaires.
• Prenotication emails prior to the survey/
questionnaire can increase response rates up
to 5.7% compared to no prenotication [19].
• Short message service (SMS) is more effec-
tive than email prenotication and no prenoti-
cation [20].
• Surveys that take no more than 10minutes to
complete are likely to have higher response
rates.
• Semiautomatic logins and a blank subject line
in the email or a subject line of interest
improve response rates.
Monitoring Patients After Focal Therapy
It is important to have a standardized evaluation
of treatment to ensure consistent, high-quality
care and to advance the eld of focal therapy.
Standardization will allow for direct comparison
of patient outcome data between different modalities of treatment. As we await the results of randomized, controlled trials comparing focal
36 Assessing Functional Outcomes After Focal Therapy
447
therapy to whole gland treatment, we rely on consensuses using the Delphi method to guide our
practice. To assess functional outcomes following focal therapy, we recommend the following
assessment tools:
• Side effects ➔ Clavien- Dindo.
• Sexual ➔ IIEF or EPIC.
• Urinary ➔ IPSS +/− EPIC.
• Continence ➔ pad free rate, EPIC urinary
domain.
• Physical/Mental ➔ SF-12.
Minimum requirements for follow-up:
• Assessment of erectile function, continence,
and urinary symptoms.
• Frequency of assessment: 3–6 months until
stability/baseline reached.
References
1. Nicoletti R, Alberti A, Castellani D, etal. Functional
outcomes and safety of focal therapy for prostate
cancer: a systematic review on results and patientreported outcome measures (PROMs). Prostate
Cancer Prostatic Dis. 2023; https://doi.org/10.1038/
s41391- 023- 00698- 8.
2. Dellabella M, Branchi A, Di Rosa M, Pucci M,
Gasparri L, Claudini R, etal. Onco-logical and functional outcome after partial prostate HIFU ablation
with focal-one®: a prospective single-center study.
Prostate Cancer Prostatic Dis. 2021;24:1189–97.
3. Maestroni U, Dinale F, Minari R, Salsi P, Ziglioli
F. High-intensity focused ultra- sound for prostate
cancer: long-term followup and complications rate.
Adv Urol. 2012;2012:960835.
4. DiBlasio CJ, Derweesh IH, Malcolm JB, Maddox
MM, Aleman MA, Wake RW.Contemporary analysis
of erectile, voiding, and oncologic outcomes following primary targeted cryoablation of the prostate for
clinically localized prostate cancer. Int Braz J Urol.
2008;34:443–50.
5. Fernandez-Pascual E, Manfredi C, Martin C,
Martinez-Ballesteros C, Balmori C, Lledo-Garcia E,
etal. mpMRI-US fusion-guided targeted cryotherapy
in patients with primary localized prostate cancer: a
prospective analysis of oncological and functional
outcomes. Cancers. 2022;14:2988. https://doi.
org/10.3390/cancers14122988.
6. Al-Hakeem Y, Raz O, Gacs Z, Maclean F, Varol
C.Magnetic resonance image-guided focal laser abla-
tion in clinically localized prostate cancer: safety and
efcacy. ANZ J Surg. 2019;89:1610–4.
7. Walser E, Nance A, Ynalvez L, Yong S, Aoughsten
JS, Eyzaguirre EJ, et al. Focal laser ablation of
prostate cancer: results in 120 patients with lowto intermediate- risk disease. J Vasc Int Radio.
2019;30:401–9.e2.
8. Chelly S, Maulaz P, Bigot P, Azzouzi AR, Lebdai
S. Erectile function after WST11 vascular-targeted
photodynamic therapy for low-risk prostate cancer
treatment. Asian J Androl. 2020;22:454–8.
9. Barry MJ, Fowler FJ, O'Leary MP, etal. The American
urological association symptom index for benign
prostatic hyperplasia. The measurement Committee
of the American Urological Association. J Urol.
1992;148(5):1549–57.
10. Wei JT, Dunn RL, Litwin MS, Sandler HM, Sanda
MG. Development and validation of the expanded
prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology.
2000;56(6):899–905.
11. Rosen RC, Riley A, Wagner G, Osterloh IH,
Kirkpatrick J, Mishra A.The international index of
erectile function (IIEF): a multidimensional scale
for assessment of erectile dysfunction. Urology.
1997;49(6):822–30.
12. Rosen RC, Cappelleri JC, Smith MD, Lipsky
J, Peña BM. Development and evaluation of an
abridged, 5-item version of the international index
of erectile function (IIEF-5) as a diagnostic tool for
erectile dysfunction. Int J Impot Res. 1999;11(6):
319–26.
13. Clavien P, Sanabria J, Strasberg S. Proposed
classication of complication of surgery with
examples of utility in cholecystectomy. Surgery.
1992;111:518–26.
14. Dindo D, Demartines N, Clavien PA.Classication of
surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205–13.
15. Turner-Bowker D, Hogue SJ. Short form 12
health survey (SF-12). In: Michalos AC, editor.
Encyclopedia of quality of life and Well-being
research. Dordrecht: Springer; 2014. https://doi.
org/10.1007/978- 94- 007- 0753- 5_269.
16. King MT, Viney R, Smith DP, Hossain I, Street D,
Savage E, Fowler S, Berry MP, Stockler M, Cozzi
P, Stricker P, Ward J, Armstrong BK. Survival
gains needed to offset persistent adverse treatment
effects in localised prostate cancer. Br J Cancer.
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bjc.2011.552.
17. Nielsen LK, King M, Möller S, Jarden M, Andersen
CL, Frederiksen H, Gregersen H, Klostergaard A,
Steffensen MS, Pedersen PT, Hinge M, Frederiksen
M, Jensen BA, Helleberg C, Mylin AK, Abildgaard
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18. Sammut R, Griscti O, Norman IJ. Strategies to
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Biochemical Assessment ofCancer
Outcomes Following Focal Therapy
AlirezaGhorei andAmirH.Lebastchi
37
Introduction
Advancements in diagnostic technologies, such
as multiparametric magnetic resonance imaging
(mpMRI), and targeted biopsies, have improved
the localization of prostate tumors and detection
of the largest focus of cancer (i.e., index lesion)
[1]. These evolutions have impacted the treatment paradigm for prostate cancer (PCa),
enabling focal therapy (FT) in select patients
with localized disease. The goal is to reduce
treatment-associated side effects, including urinary incontinence, sexual dysfunction, and
quality- of-life factors, without compromising
oncological control [2]. Studies have shown that
FT for localized PCa is well accepted by patients
and is associated with a low regret rate [3].
Current guidelines consider FT in select
patients with intermediate-risk PCa [4]. Unlike
whole-gland treatment options (radical prostatectomy and radiation), FT is associated with the
preservation of viable, noncancerous prostate tissue. Hence, it is important to note that the remaining volume of viable prostate epithelium produces
PSA, which may impair the accurate interpreta-
A. Ghorei · A. H. Lebastchi (*)
Department of Urology, Keck School of Medicine,
University of Southern California,
Los Angeles, CA, USA
e-mail: Alireza.Ghorei@med.usc.edu; amir.
lebastchi@med.usc.edu
tion of serum PSA levels. This inuences the role
of post-FT PSA, the traditional biomarker used
for the assessment of treatment success or failure.
Therefore, there is an ongoing debate regarding
the optimal threshold for PSA following FT and
the ideal denition of treatment success and biochemical recurrence (BCR).
In this chapter, we review the latest evidence
on available biomarkers for the follow-up of FT
for PCa. In addition, we discuss the various denitions of treatment failure or success associated
with this biomarker.
PSA
PSA has been traditionally used for the followup of patients undergoing whole gland treatments for PCa. It is produced by normal
prostatic cells and is expected to be undetectable after radical prostatectomy. Despite the
fact that PSA does not usually reduce to undetectable levels after nonextirpative therapies,
measurement of this biomarker is broadly used
to monitor the treatment response after radiation therapy, and well- established criteria exist
to dene BCR in this setting [5–7]. Nevertheless,
the role of PSA in patients undergoing FT is yet
to be determined.
During partial gland ablation, the index lesion
is treated, and the remainder of the prostate
gland tissue is preserved. This can lead to PSA
© 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_37
449
450
Fig. 37.1 Depictions
and etiologies of in-eld
and out-of-eld
recurrences following
FT
A. Ghorei and A. H. Lebastchi
In-field recurrence
insufficient energy•
•
delivery or targeting error
Out-of-field recurrence
•
progression of known grade
group 1 cancer
•
identification of previously
unrecognized tumor
•
development of de-novo disease
secretion from the remaining prostate tissue in
situ. Also, false-positive PSA values can be
detected due to other nonmalignant entities, such
as infection, inammation, or urinary obstruction. On the other hand, malignant events,
including in- and out-of-eld persistence or
recurrences, may also affect PSA values [8, 9]
(Fig.37.1). All these events can affect the postFT serum PSA.
PSA Nadir
Studies have shown that serum PSA levels
decrease even after partial gland ablation, and
the PSA nadir can predict cancer persistence
and BCR in a statistically signicant manner
[10]. Various thresholds for PSA nadir have
been suggested. In two studies of patients who
underwent focal high-intensity focused ultrasound (HIFU), the best oncological outcomes
were seen when a PSA nadir of ≤0.2 was
reached [11, 12]. Also, Huber et al. recommended a PSA nadir of 1.0ng/mL at 12months
and 1.5 ng/mL at 24 to 36 months following
focal HIFU to be used to triage men requiring
further workup, including MRI and biopsy [8].
These PSA thresholds were associated with a
100% sensitivity and 96–100% negative predictive value to detect failure. An external validation of this model was recently reported,
demonstrating its high accuracy in predicting
the necessity for additional treatment and failure after focal HIFU for localized PCa [13].
Percentage ofPSA Reduction
The percentage of PSA reduction seems to be a
useful tool for post-FT assessment. In a multicenter study of 703 men receiving HIFU, the
median percentage of PSA reduction following
treatment was 73%. Moreover, this variable was
an independent predictor of any additional treatment (hazard ratio [HR]: 0.96) and radical treatment (HR: 0.97) after FT.In this study, for a PSA
reduction of >90% vs. <10%, the probability of
any additional treatments within 5years was 20%
vs. 70%, respectively. The authors recommended
that men who have a percentage PSA reduction
of <25% could be considered for more intensive
posttreatment surveillance [14]. Although experts
have proposed a PSA reduction of 50–80% as
indicative of successful FT, PSA alone seems to
be insufcient to determine oncologic success
[15].
PSA Density
PSA density (PSAD), calculated as PSA level
divided by prostate volume, has been investigated
in the preoperative setting and proven to be an
informative indicator when making biopsy decisions [16]. In addition, a Task Force on Prostate
Cancer and the Focal Lesion Paradigm proposed a
PSAD <0.15 among the inclusion criteria when
selecting patients for FT [17]. In a recent study of
1057 men enrolled in active surveillance between
1996 and 2017, higher PSAD at diagnostic tran-
37 Biochemical Assessment ofCancer Outcomes Following Focal Therapy
451
srectal ultrasound was associated with a lower
likelihood of being a good candidate for FT at
conrmatory biopsy (odds ratio [OR]: 1.79 for
being a non-FT candidate) [18]. Although PSAD
can potentially demonstrate a marked reduction of
the treated portion of the gland following FT, data
supporting its routine use in the post-FT setting
are sparse. In a study of 73 men who underwent
HIFU for localized PCa, PSAD at 12months after
HIFU was independently associated with tumor
persistence, even among those with (false) negative mpMRI ndings [19]. With the increased use
of MRI for follow-up after FT and the advent of
fully automated segmentation techniques [20,
21], PSAD can potentially serve as a complemen-
tary tool to standard follow-up measurements.
PSA Velocity andDoubling Time
The PSA velocity (PSAV) and doubling time
(PSADT) demonstrate the PSA kinetics and are
mainly used as a guide to identifying patients
with higher risk PCa [22]. PSAV and short
PSADT have been used as important triggers for
active intervention in patients who are on surveillance, as prognostic factors after radiation, and as
a guide timing of initiation of systemic therapy in
the metastatic PCa setting [23–25]. PSAV and
PSADT have high sensitivity but low specicity
in the diagnosis and prognosis of PCa [22]. Due
to the lack of evidence, the use of these markers
in the post-FT setting is yet to be determined.
Other Molecular Biomarkers
dictor of high-stage, high-grade, and high- volume
disease [28]. Other markers, such as tissue
genome prostatic scores or cell cycle progression
scores, also showed some efcacy in predicting
high-grade disease, which may help in detecting
post-FT disease recurrences or progression [29].
Nevertheless, despite the potential efcacy of
these non-PSA biomarkers, their role in patients
undergoing FT remains unclear, and they should
only be used for research purposes.
Denition ofBCR After FT
In general, FT success is dened as the absence
of disease in the treated zone (i.e., no in-eld
recurrence), while treatment success is the
absence of disease recurrence/progression
regardless of the location [15]. Therefore, imaging and biopsy ndings are more commonly used
to assess failure following FT, and BCR is mainly
used as a trigger for performing imaging or
biopsy. In a recent review study, BCR was the
main denition of FT failure in only 3 out of the
22 (14%) studies assessing oncological outcomes, while biopsy-proven PCa and/or need of
an additional treatment were the most frequent
denitions adopted [15].
Three main criteria for BCR have been used in
FT studies (Table 37.1). While the Phoenix [6]
and American Society for Therapeutic Radiology
and Oncology (ASTRO) [5] criteria were originally developed for the surveillance after radiation therapy and extrapolated for the use in
patients after focal therapy, the Stuttgart criteria
was dened specically for patients treated with
Biomarkers other than PSA have been investigated, particularly in the diagnosis, risk stratication, and active surveillance of patients with PCa.
Prostate cancer antigen 3 (PCA3), a urine-based
molecular test, has been introduced as a promising biomarker in predicting clinically signicant
and multifocal disease [26, 27]. Serum [−2] proPSA, along with total and free PSA, was used to
calculate the prostate health index (PHI). The
PHI score has been shown to be an accurate pre-
Table 37.1 Current denitions for biochemical recurrence following focal therapy for prostate cancer
Criteria (ref) Denition
Phoenix [6] PSA nadir +2ng/mL
ASTRO [5] Three consecutive PSA rises after a
nadir with the date of failure as the
point halfway between the nadir date
and the rst rise or any rise great
enough to provoke initiation of
therapy
Stuttgart [30] PSA nadir +1.2ng/mL
452
A. Ghorei and A. H. Lebastchi
HIFU [30]. Nevertheless, the majority of FT
studies have adopted and utilized the Phoenix criteria [31]. In a study, comparing various BCR
denitions following cryoablation of the prostate,
Pitman etal. reported Phoenix criteria as the best
predictor of local recurrence following treatment
[32]. However, other studies showed that both
Phoenix and Stuttgart criteria as useful denitions to determine BCR.In a retrospective study
of patients who underwent primary focal cryosurgery, among those who underwent biopsy
after BCR, residual/recurrent cancer was detected
in 54% and 51% using Phoenix and Stuttgart
denitions, respectively. In addition, 57% of
patients with BCR by the Phoenix denition and
67% of those with BCR by the Stuttgart denition were found to have a clinically signicant
disease (Gleason grade≥2) [33]..
Follow-Up Protocols After FT
Robust data are not available regarding the optimal biomarker assessments following FT. An
expert consensus published in 2019 recommended recording post-treatment PSA levels,
including density, nadir, and other kinetics, for
future research purposes [34]. In addition, the
panel stated that there are insufcient data to
incorporate PSA derivatives, such as PSAD, and
biomarkers beyond PSA into a post-FT protocol.
Given the lack of evidence regarding follow-
up protocols and molecular biomarker assess-
ments in patients undergoing FT, consensus
efforts were undertaken using a Delphi process
(Table 37.2). Two studies agreed on a similar
follow-up protocol [35, 36]. Based on these
agreements, serum PSA should be checked
every 3 months for the rst year and every
6months thereafter for at least 5years. However,
Lebastchi etal. acknowledged that PSA alone is
insufcient to determine oncological success
[36]. In addition, Muller et al. stated that
although PSADT seems to be the most important parameter that could indicate treatment failure, no consensus could be reached about a
denition of BCR [35]. Marra et al. recently
published results of a Delphi consensus with the
aim of understanding the potential utility of
molecular biomarkers in FT for localized PCa
[37]. They showed that evidence for molecular
biomarkers in FT is absent/low (80% agreement), and these markers should not be used in
routine clinical decision-making (71% agreement). Nevertheless, the panel agreed that PSA
and PSAD have a role in the context of FT (77%
and 73% agreements, respectively) and should
be included in studies assessing the role of
molecular biomarkers in FT (81% and 85%
agreements, respectively). The panel also proposed their recommendations for non-PSA biomarkers. Thus, 72% of the participants disagreed
that PCA3 has a potential role in the context of
FT. In addition, more than 70% of the panel
were uncertain regarding the role of SelectMDx,
4K score, ConrmMDx, Promark, and ExoDx
Table 37.2 Summary of Delphi consensus statements for biochemical follow-up after FT
No. of responders
(Delphi rounds),
Study, yr (ref)
Muller etal.
2015 [35]
Lebastchi etal.
2020 [36]
Marra etal.
2022 [37]
agreement threshold Biochemical follow-up recommendation (consensus level)
46 (3), >75% PSA should be included in the follow-up following FT. the rst PSA
should be taken 3-month posttreatment. After the rst measurement, PSA
should be taken every 3months during the rst year; after the rst year,
PSA should be taken every 6months
48 (3), >80% The panel recommends obtaining the rst posttreatment PSA
measurement within 3months after treatment (89%) and subsequently
every 3months during the rst year (91%). After that, PSA should be
measured every 6months (80%)
42 (3), >70% PSA and PSAD have role in the context of FT (77% and 73%,
respectively) and should be included in studies assessing the role of
molecular biomarkers in FT (81% and 85%, respectively)
37 Biochemical Assessment ofCancer Outcomes Following Focal Therapy
453
in FT. Finally, no consensus was reached for
PHI, Prolaris, OncotypeDx, Decipher, and My
Prostate Score 2.0.
Perspectives andFuture Directions
Despite growing evidence supporting the role of
FT in the management of patients with localized
PCa, data regarding the biochemical assessment in
the post-FT setting are limited. Further data are
needed to optimize postoperative evaluation and to
determine the most appropriate denition for
BCR. Novel blood-, tissue, and urine-based biomarkers, such as circulating tumor cells, exosomes, circulating tumor DNA (ctDNA), and
RNA (ctRNA), can potentially help to predict the
response to FT and determine success/failure following ablation [38]. Future studies are required to
shed light on this important topic and to optimize
precision medicine in the management of PCa.
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