Personalized Treatment Strategy in “Low-Risk Prostate Cancer Active Surveillance Candidates” Using Irreversible Electroporation: Prospective Evaluation of Feasibility, Morbidity, Functional and Oncological Outcomes

Abstract

Purpose

To evaluate the morbidity, functional and oncological outcome of irreversible electroporation (IRE) as a focal therapy for prostate cancer (PCa) when used in “active surveillance (AS)” candidates refusing standard treatment options.

Materials and Methods

IRE was performed under general anaesthesia, and the transurethral catheter was removed one day after intervention in all patients. Pre- and post-interventional voiding parameters (measured by International Prostate Symptom Score Questionnaire [IPSS], uroflowmetry and post-void residue) were compared. Follow-up (FU) was observed over a minimum of six months, including oncological outcome (controlled by multiparametric magnetic resonance imaging, rebiopsy, prostate-specific antigen dynamic as well as the need and type of secondary treatment) and general functional outcome (International Index of Erectile Function Questionnaire, satisfaction of the procedure).

Results

Twenty-four patients refusing AS or standard treatment with a median FU of 18.7 months were included. IPSS showed nine patients with mild, 12 with moderate and two with severe obstructive voiding symptoms pre-intervention (focal IRE). Median IPSS pre-IRE was 9 points, 8.5 (p=0.341) at six months and 10 (p=0.392) after 12 months, respectively. Pre-IRE maximum urinary flow (Qmax) (median: 16.1±8.0 mL/sec) and Qmax after catheter removal (16.2±7.6 mL/sec) did not differ significantly (p=0.904). Thirteen PCa recurrences occurred (54.2%). Out-of-lesion-PCa was found in 12/13 patients (92.3%), while 4/13 patients showed in-lesion-PCa recurrence simultaneously (30.8%). In one patient, there was an in-lesion-PCa recurrence only (7.7%). Six out of 24 patients (25.0%) received a secondary treatment. All patients were satisfied with the IRE procedure.

Conclusions

Focal IRE underperforms regarding the overall oncological outcome and should not be offered as an equivalent therapy to established curative treatment strategies. Nevertheless, under a strict FU regimen, its lack of significant additional morbidity compared to an active surveillance strategy makes IRE a feasible alternative for low-risk PCa in highly selected patients as a personalised approach.

INTRODUCTION

Irreversible electroporation (IRE) has evolved into an ablative technique in the treatment of localised prostate cancer (PCa) in carefully selected men [1].

Due to the current screening strategies and methods for PCa, there is a marked migration towards favourable pathological stages in detected PCa [2]. Deciding which organ-sparing therapy from the currently available options should be chosen when diagnosing a localised PCa with a favourable histological pattern is a recurrent challenge every urologist faces, especially considering growing patient expectations.

Younger patients may profit more from an oncologically focused and aggressive strategy since they face a longer lifetime of coping with this disease. But they are the ones who may be affected intensely and longest by the occurring functional side effects (e.g., urinary incontinence [UI] and erectile dysfunction [ED]) [3]. Older patients, usually with more comorbidities and presumably shorter life expectancy, may not require the same invasive treatment as younger ones, with the potential benefits of less severe impairment by the side effects of a more radical therapeutic approach.

With the advent of IRE as a treatment for PCa, initial studies demonstrated safe and promising oncological and functional results. Limitations were mainly short follow-up (FU) durations [4]. Post-IRE prostatectomy specimens often showed no cancer tissue in the treated areas of the prostate [5]. Meanwhile, several studies with a longer FU were published on IRE as a primary treatment of PCa regarding the oncological outcome and the occurrence of functional side effects (ED, UI). There is still considerable variability in follow up duration and re-staging strategies after IRE procedures (e.g., biopsy vs. magnetic resonance imaging [MRI], biopsy approach) [6].

The reported residual tumour findings range from 0% [7] to a significant 43% [8]. On the other hand, IRE’s morbidity seems negligible compared to radical prostatectomy (RPE) or radiation therapy (RTX). Clavien-Dindo grade III adverse events range from 0% [4,8,9,10,11] to 8% [12]. Still, the majority of available studies have the limitation of a relatively small patient population.

The safety of the IRE procedure, combined with the appeal of offering a following radical treatment, seems to justify its use in men rejecting active surveillance (AS) and the side effects of conventional treatment [13].

Despite the consensus regarding reduced invasiveness and good overall safety, there is none regarding the treatment parameters, nor the postoperative standard of care (e.g., catheterisation duration), and currently no comparison of IRE with AS regarding morbidity. Since it is postulated that IRE seems to have a negligible effect on functional performance, we want to prospectively evaluate the outcome of minimising patient impairment by removing the catheter the day after intervention, regardless of pre-existing obstructive voiding symptoms. Furthermore, we want to prospectively evaluate the functional outcomes of our patient population regarding micturition and erectile function alongside oncological results.

MATERIALS AND METHODS

1. Study design and patient selection

The study was performed as a single-institution, observational prospective clinical evaluation of IRE in the Department of Urology of the University Medical Center between May 2018 and June 2021. Prior approval of the University Medical Center institutional ethics review board was obtained (approval No. Goe 25/3/18), as well as written informed consent from each patient in accordance with the ethicsregulations validated protocol and the Declaration of Helsinki.

2. Patient selection

1) Inclusion criteria

(1) Histopathologic diagnosis of PCa

• - Maximum Gleason score (GS): 3+4=7a

• - Prostate-specific antigen (PSA) ≤20 ng/mL

• - Unifocal unilateral appearance (histology) and ≤15 mm in greatest diameter (multiparametric MRI, mpMRI)

• - Carcinoma lesions positively detected by mpMRI/transrectal ultrasonography (TRUS) fusion biopsy of the prostate (PIRADS Score >2) using a targeted and systematic biopsy protocol

• - mpMRI (PIRADS ver. 2.0): no involvement of the prostate capsule or extraprostatic extension

• - mpMRI minimum safety distance from positive lesion to rectal wall of 10 mm and urethral safety distance of 6 mm

(2) Karnofsky performance status scale: >80%

(3) No previous history of prostate malignancy or treatment

(4) Patient refusal of AS treatment and other standard treatment options

(5) Life expectancy >10 years (clinician’s expert opinion)

2) Exclusion criteria

Any other histological patterns of PCa, anesthesiological reasons (pace-maker/defibrillator implants, contraindications for i.v. anaesthesia or relaxant medication), clinical appearance (Karnofsky performance status scale, comorbidities) or patient’s preference for any other established curative treatment or AS led to exclusion from the study.

3. Outcome

The outcome of interest was the method’s functional performance regardless of patients’ pre-interventional voiding ability. The central aspect is the influence of the procedure on the immediate voiding performance, mainly in patients with pre-existing obstructive symptoms. As a secondary measure, we want to evaluate the impact on erectile and oncological outcomes.

4. Irreversible electroporation procedure and clinical course

All patients were clinically evaluated, and consent was obtained at least one day before surgery. During the preoperative assessment, patients answered the “International Index of Erectile Function” (IIEF) and “International Prostate Symptom Score” (IPSS) questionnaires. Besides the questionnaires, uroflowmetry and ultrasound studies (post-void residue, PVR) measured the patient’s voiding ability.

All IRE interventions were performed by a single surgeon under general anaesthesia, short-acting non-depolarising muscle relaxation and single-shot antibiotic prophylaxis between May 2018 and December 2020. Patients were placed into a lithotomy position, and a transurethral catheter was inserted. The unifocal target lesion, previously positively histologically identified by mpMRI/TRUS transperineal ultrasound-guided biopsy, was encircled by monopolar electrodes using biplanar transrectal ultrasound guidance and a table-mounted affixed transperineal template grid. The electrode locations and spatial configuration were recorded using the Nanoknife System (AngioDynamics). The de-isolation lengths ranged from 15 mm to 20 mm, and the needles were spaced 5 mm to 24 mm apart. The calculated treatment area (Nanoknife System software; AngioDynamics) was adjusted to overlap the MRI Lesion by at least 6 mm (treatment safety margin) and not extend over the prostatic capsule (posterior, lateral and apical margins). The pulse length was set at 90 microseconds, and adequate direct current (20–50 A) between each electrode pair was evaluated by ten test pulses applying the standard voltages (ca., 1,500 V/cm) and altered until the adequate current for each pair was reached. The treatment adhered to standards proposed by the international treatment protocol (Clinical Research Office of the Endourological Society). After the procedure, the electrodes were removed, and the urinary catheter was left in place.

The postoperative management of the entire patient cohort was standardised concerning pain medication, diet, and physical therapy. In the absence of postoperative complications (e.g., fever or macrohematuria), the transurethral catheter was removed the day after surgery.

Afterwards, uroflowmetry and PVR ultrasound documented micturition performance after catheter removal. Patients were discharged the day after intervention.

5. Oncologic and functional follow-up

Six months after IRE, new mpMRI imaging of the prostate was obtained, and a subsequent mpMRI/TRUS fusion biopsy of the prostate was performed, according to the recommendations of the Delphi consensus on focal therapy FU [14]. At this time, micturition performance was re-recorded using uroflowmetry and PVR ultrasound, and new IPSS and IIEF questionnaire values were obtained.

In case of histological progression, definitive treatment was offered. In cases where no evidence of PCa or, at most, AS-eligible PCa was detected, patients were offered a similar FU after 12 and 18 months, including mpMRI and rebiopsy.

Complications were recorded using the standardised Clavien-Dindo classification.

6. Statistical analysis

Variables are described using the median and the overall range, or the mean±standard deviation for continuous variables. Categorial variables are described using frequencies and percentages. The data analysis of each patient was carried out up to the last known FU appointment data point. Statistical comparisons of categorical variables between groups were performed using the chi-square test. Continuous variables were compared using the Wilcoxon rank-sum test. All analyses were performed using IBM SPSS version 20.0 (IBM Corp.). Statistical tests with p<0.05 were considered significant. All p-values are two-sided.

RESULTS

1. Study cohort

Twenty-four patients underwent an IRE procedure and were included in this study, and their data were considered for statistical evaluation.

Essential patient characteristics and histological findings before treatment are summarised in Table 1.

Table 1. Clinical and histological characteristics of all patients at Baseline.

Variable	Value
Age (y)	65.2±4.9
Pre-IRE PSA (ng/mL)	7.9±3.5
Prostate volume (mL)	58.9±24.2
No. of cores taken	18 (14–19)
No. of positive cores	1 (1–2)
Biopsy density–no. of cores/prostate volume	0.33±0.15
GS 3+3, risk classification (D’Amico) low	14 (58.3)
GS 3+4, risk classification (D’Amico) intermediate	10 (41.7)

Values are presented as mean±standard deviation, median (interquartile range), or number (%).

IRE: irreversible electroporation, PSA: prostate-specific antigen, GS: Gleason score.

Table 2 shows the perioperative outcomes. Three needle electrodes per IRE procedure were used with a median 15 mm treatment depth (de-isolation). There were at least 110 (100–130) impulses applied at a minimum of 20 A until the target impedance reduction of 15% was reached and the treatment was deemed electrically effective.

Table 2. Perioperative outcome after irreversible electroporation.

Variable	Value
No. of probes used (median/range)	3 (3–4)
Hospitalisation in 1 day	24 (100)
Catheterisation time in days (median/range)	1 (1–2)
No. of patients successfully voiding after catheter removal (day 1)	22 (91.7)

Values are presented as median (range) or number (%).

2. Toxicity

Urinary retention occurred as an immediate postoperative short-term complication after IRE (n=2, 8.3%).

3. Follow-up/functional outcomes

Twenty-one male patients (87.5%) were considered per protocol for the FU statistical analysis, while 3 patients (12.5%) were partially available for functional FU data but denied the protocol inherent repeat biopsy (Table 3). Median FU was 18.7 months (6.40–42.47 months).

Table 3. Functional outcomes after irreversible electroporation.

	Variable	Value	p-value
FU in mo		18.69 (6.40–42.47)
No. of patients with at least		21 (87.5)
	6 mo of FU and at least one
	FU mpMRI/TRUS fusion biopsy
IIEF
	Preoperative	19 (2–25)
	6-mo FU	17.5 (1–25)	0.766
	Last FU	19 (1–25)	0.653
IPSS
	Preoperative	9 (0–22)
	6-mo FU	8.5 (4–14)	0.341
	12-mo FU	10 (3–24)	0.392
	Last FU	8 (3–15)	0.179
Uroflowmetry (Qmax [mL/sec])
	Preoperative	16.1±8.0
	Postoperative	16.2±7.6	0.904
	6-mo FU	17.1±10.9	0.397
	Last FU	18.3±9.0	0.161
PVR (mL)
	Preoperative	48.2±81.3	-
	Postoperative	37.4±73.0	0.451

Values are presented as median (range), number (%), or mean±standard deviation.

FU: follow-up, mpMRI/TRUS: multiparametric magnetic resonance imaging/transrectal ultrasonography, IIEF: International Index of Erectile Function, IPSS: International Prostate Symptom Score, Qmax: maximum flow during micturition, PVR: post-void residue.

Potency did not differ between preoperative and postoperative (6 months) status (IIEF: median score 19 vs. 17.5, p=0.766), as well as at last FU (p=0.653). No patients suffered incontinence immediately after catheter removal or during the FU time, nor did any grade of rectal dysfunction occur.

Fourteen patients (58.3%) suffered preoperatively from obstructive voiding symptoms (IPSS≥8). The IPSS scores did not significantly differ after intervention (pre-IRE 9 [0-22], at 6-month FU 8.5 [4-14], p=0.341; at 12-month FU 10 [3-24], p=0.392; and at last FU 8 [3-15], p=0.179, respectively).

4. Early disease control

Oncological FU showed histologically detected PCa in 13/24 patients post-IRE (54.2%), diagnosed by transperineal mpMRI/TRUS fusion biopsy. Recurrence or persistence of cancer was detected in nine patients within the first year after IRE (69.2%) and in four patients 18 to 30 months after IRE (30.8%).

Out-of-lesion-PCa was found in 12 patients (92.3% of all patients with PCa recurrence), and four patients had in-lesion-PCa simultaneously (30.8% of all patients with PCa recurrence). One patient showed a solitary in-lesion-PCa recurrence (7.7% of all patients with PCa recurrence). At the first rebiopsy (6-month FU), four patients (30.8% of all PCa persistence) had detectable tumours, with one patient with in-lesion-PCa and 3 patients with out-of-lesion PCa.

Seven patients showed clinically insignificant disease (equivalent to Gleason pattern 3) and opted for further AS (29.2%). Six patients (25.0%) received secondary definitive PCa treatment by RPE (five patients, 20.8%) and RTX (one patient, 4.2%). Bilateral nerve-sparing (NS) could be performed in four RPE and unilateral NS in one IRE, all without positive margins.

One (4.2%) lower urinary tract infection occurred post RPE one week after catheter removal (Clavien-Dindo II adverse event) and was treated by oral antibiotics.

PSA levels during the FU period are shown in Table 4. There was no significant difference between the initial levels at PCa detection (7.9±3.5 ng/mL) and PSA measurements at preoperative (8.2±3.4 ng/mL, p=0.130), 6-month FU (6.1±2.9 ng/mL, p=0.162), 12-month FU (6.6±4.1 ng/mL, p=0.276) and at last FU timepoints (7.2±3.8 ng/mL, p=0.204), respectively, when accounting for missing/censored data. When accounting for the lowest measured PSA value after IRE treatment, there was a significantly lower PSA compared to initial diagnosis (nadir PSA 6.0±3.4 ng/mL, p=0.003). There were no significant differences identified when analysing the PSA nadir values (6.04±3.7 vs. 5.9±2.7 ng/mL, p=0.966) or the PSA differential from diagnosis to nadir (1.5±3.4 ng/mL, p=0.200) between patients with or without tumour persistence/recurrence, respectively.

Table 4. Oncological outcomes after IRE.

Variable		Value	p-value
PSA (ng/mL)
	Preoperative	7.9±3.5
	6-mo FU	6.1±2.9	0.162
	12-mo FU	6.6±4.1	0.276
	Last FU	7.2±3.8	0.204
	PSA nadir after IRE	6.0±3.4	0.003
	Delta PSA from nadir value	1.5±3.4	0.200
No. of biopsy core samples
	During	19 (14–19)
	In the target lesion	5 (4–6)
Positive biopsy
	During FU	13 (54.2)
	Only inside target lesions	1 (4.2) 7.7% of rec. PCa
	Only outside of target lesions	8 (33.3) 61.5% of rec. Pca
	In and outside of the target lesions	4 (16.7) 30.8% of rec. Pca
Secondary definitive PCa treatment		6 (25.0)
Metastasis or death		0 (0)
Treatment decision satisfaction		24 (100)

Values are presented as mean±standard deviation, median (interquartile range), or number (%).

IRE: irreversible electroporation, PSA: prostate-specific antigen, FU: follow-up, rec. PCa: prostate cancer recurrence/persistence.

Patients reported being satisfied with the IRE treatment decision, including the ones who had to receive a following secondary treatment. Patients would almost unanimously refer other patients to the same treatment regimen when eligible, except for one patient satisfied with the treatment but considering the FU schedule burdensome. No patient suffered from metastases or switched to a systemic treatment during the FU duration of the study.

DISCUSSION

Low- (T1-T2; GS, ≤6; and PSA, <10 ng/mL) and very-low-risk PCa (clinical stage, T1c; GS, ≤6; PSA, <10 ng/mL; PSA density <0.15 ng/mL/cm³; and <8-mm total cancer length in ≤4 positive biopsy cores) have minimal mortality or risk of metastatic disease [15,16]. Intermediate-risk carcinomas, especially favourable intermediate-risk PCa (Gleason 6 and PSA 10–20 ng/mL, and Gleason 7 [3+4], PSA less than 10 ng/mL), appear to have a similar course, although the increased risk of metastases makes the necessity of therapy more likely [16,17].

The superior preservation of continence and erectile function of IRE over RPE has already been proven in prospective head-to-head trials [5]. The most significant advantage of IRE may be the lack of thermal damage to the surrounding tissue, since cell death occurs well before reaching harmful thermal thresholds [18]. This explains its continued existence in patient preferences alongside other definitive therapy options, even though the oncological benefits have been disappointing over the years compared to established methods such as RPE or RTX.

Studies about the oncological and functional outcomes of IRE treatment in a small number of patients are already abundant. Even though some focus on genitourinary toxicity and its influence on urinary function, no current study focuses on the impact and course of IRE on obstructive voiding disorders or vice versa. That is the niche this study fits in, as in many potential AS candidates, the impact of lower urinary tract symptoms on quality of life (QoL) can be assumed to be higher than the impact of the asymptomatic low-risk PCa. We aimed to evaluate the feasibility of IRE instead of AS, even in patients with pre-existing conditions like borderline lower urinary tract symptoms. According to the IPSS evaluation, 9 patients (37.5%) were mildly, and 14 (58.3%) were moderately or severely symptomatic before the IRE treatment. An IPSS >8 and the presence of symptoms is usually a clinical threshold for medical or surgical treatment in patients with lower urinary tract symptoms [19].

The postoperative impact of IRE treatment on voiding performance is quite unclear, as post-interventional catheterisation time is very heterogeneous in previous publications. Scheltema et al [20] left the catheter in place between 2–5 days when encountering preoperatively existing obstructive voiding symptoms, whereas Collettini et al [21] used an indwelling catheter between 2–10 days, depending on the treated lesion size. Valerio et al [10] performed urinary drainage by transurethral or suprapubic catheters between 0–10 days without mentioning the reasoning for particularly choosing one over the other nor for the catheterisation duration.

Most studies [10,20,21] also focused more on genitourinary function loss regarding UI and postulated that IRE does not affect urinary continence.

Regardless of prostate volume, PVR, preoperative uroflowmetry, or IPSS values, we removed the transurethral catheter one day after IRE. Urinary retention occurred in 2 men (8.3%). This rate is comparable to minor invasive interventions like prostate biopsy or cystoscopy, and it can be argued that it might just as well result from urethral/prostate manipulation (via catheterisation) or even the impact of general anaesthesia as a trigger for urinary retention [22]. Whether catheterisation is necessary at all is thus a question that remains to be answered in a subsequent investigation. In our experience, there was no increased morbidity in IRE compared to the standard AS strategy (especially considering the recurrent biopsy necessity).

In this study, there were also no significant reductions in erectile function measured with 7 patients (29.2%) even reporting a subjective increase in erectile function during the first 6 months post-intervention. These findings also concur with previously reported clinical trials [20,21].

Patient selection seems to be the most demanding issue when considering focal therapy for PCa. Some authors suggest that patients suffering from intermediate-risk PCa are most suitable to be offered focal therapy [23] since very-low and low-risk PCa could be treated by AS as progression is unlikely. In contrast, high-risk PCa needs a radical treatment (RPE or RTX) as being very likely to progress. When confronted with a patient’s preference for an active stance against the disease, we believe IRE can be considered in patients rejecting AS or other active treatment strategies, especially since no additional functional impairment incurs, as presented herein.

Still the oncological FU shows persistent PCa in 54.2% of our population. Six patients received a definitive secondary treatment (25.0%), while another seven patients showed clinically insignificant disease and opted for AS (29.2%). This persistence rate is high but concurrent with previously published results, especially considering only in-field recurrence rates [6,8]. These numbers suggest that PCa might not be safely eradicated by IRE, especially as a focal treatment and needs good patient counselling and a strict FU regimen (similar to AS). In our opinion, IRE fills a gap between AS and curative treatment and should be critically discussed and not routinely offered in everyday clinical life. It can however offer a chance to extend the time to curative treatment when needed without suffering the morbidity of a standard curative treatment in patients rejecting AS. Our study cohort emphasises this benefit through the feasibility of secondary treatment without any complications from the initial IRE treatment. Even without undergoing a curative/radical treatment with negative impact on urinary continence and erectile function, there is still a proven reduction of QoL in patients under AS because of psychological stress (tumour anxiety waiting for cancer progression and the morbidity of repeat biopsies) [24].

One of the most extensive investigations regarding AS, the Göteborg trial by Godtman et al [16] published in 2016, with 474 patients and a median FU of 8 years, showed that AS can only be considered a safe strategy in men with very-low-risk PCa. Very-low-risk carcinoma was defined as T1c, not N1 or M1, GS ≤6, PSA density <0.15 ng/mL, fewer than three cores with cancer and ≤50% cancer in any core. They postulated that the chance of curative treatment could be missed easily in men with low and intermediate-risk PCa. Furthermore, they even questioned if patients in the lowest risk constellation and a long-life expectancy are suitable candidates for AS [16].

With 54.2% persistent carcinoma in the FU biopsies, despite carefully selected men, the oncological outcome of IRE cannot be satisfactory.

Interestingly, at the time of the first rebiopsy (6-mo. FU), there were only four patients (30.8% of all PCa persistence) with detectable tumours, 1 patient (1 of 4) in the previous IRE target area only and the other only outside the previously treated area (3 of 4 patients). This finding has a twofold significance. It again validates and reinforces the Delphi consensus on a FU biopsy after focal treatment at 6 months for detecting early treatment failure [13]. Furthermore, it suggests that even with the advent of mpMRI and mpMRI/TRUS fusion biopsy of the prostate, a significant percentage of tumours are unreliably detected in primary and secondary intent.

Because of this circumstance of possibly missed carcinoma via biopsy, IRE treatment protocols, like subtotal, hemi- or whole gland ablation, still have to show their effectiveness to be accepted in broad clinical practice [25]. Scheltema et al [25] introduced a study in 2016 dealing with this issue by randomising 200 patients with a unilateral localised PCa (clinical stage T1c–T2b) in two groups. Group A received a focal ablation of the carcinoma-afflicted area, and Group B underwent hemi-ablation of the carcinoma-bearing prostate side. The results are still pending.

Many recurrences or persistence thus strengthen the necessity of a strict FU. FU duration is another question to be considered, especially if the rate of positive in-lesion biopsies increases during an extended FU period, further reducing oncologic IRE efficacy. Despite the small number of patients, in-lesion-carcinoma occurred relatively late in two of the four patients, after 26 and 30 months, respectively. Another issue is whether focal therapy of only carcinoma-burdened areas is sufficient treatment for PCa, but this was not the focus of the current investigation.

A selected number of patients might need more than just AS for varying personal reasons (e.g., psychological stress caused by tumour anxiety). At the same time, the same group might not profit from a more invasive treatment, thus risking their QoL, unnecessary following treatments, and a not insignificant personal and system-based economic impact. Even when faced with pre-existing (obstructive) voiding symptoms, the feasibility and lack of negative impact of IRE make it easier to counsel AS candidates towards focal therapy if there is a clear therapy preference.

On the other hand, it is the authors’ opinion that feasibility does and should not be equated to the liberal offering of (focal) IRE to AS candidates. One considerable and insidious risk, also present in this study cohort but not limited to the IRE method, is the inherent lack of symptoms in lower-risk and early detection of PCa. This hidden risk of later systemic irreversible disease might be psychologically more readily underestimated by patients who have already undertaken an “active” role in the management of their PCa disease and could lead to disregarding FU exams, as this cohort shows (3 patients, 12.5%). Combined with the PCa recurrence or persistence risk after IRE (54.2% in this study) and the overall risk of missing the optimal curative time under AS in low and intermediate-risk PCa, as shown by the Göteborg trial [16], the authors feel it is vital to emphasise a strict FU regimen including histological specimens beyond the AS guidelines and strongly include this in patient counselling and selection.

Whether AS or focal therapy by IRE is the best strategy to offer patients with low-risk PCa constellation should remain an individual and personal decision between the patient and the urologist, carefully considering patient age, comorbidities, life expectancy, cancer characteristics, as well as personal preferences and risk assessment ability.

As an important observation, it is the opinion of the authors that the accrued data clearly shows that the PSA values and changes were sorely inadequate in predicting not only the persistence or recurrence of disease but also the time point at which such detection might be achieved, and should not be used as a decision-making tool at least in the herein presented scenario (deferred AS by IRE as focal therapy).

Although a prospective study and the first evaluating this topic, several limitations are worth mentioning. Predictive variables for urinary retention could not reliably be evaluated. Because of the small number of treated patients, it was not advisable to divide the population into subgroups according to target lesion size, prostate volume, or grade of voiding symptoms.

Also, histopathological analysis and grading of the recurrent (inside target lesion) and/or persistent (outside target lesion) PCa was performed analogue to the untreated tumour appearance. Most guidelines do not recommend ISUP or GS grading of previously treated PCa [19]. However, there was a pragmatic clinical necessity in comparing in and outside-lesion-carcinoma and evaluating AS eligibility outside the initial scope (i.e., after treatment). This is undoubtedly a valid debatable issue, but considering the previously proven local scope of IRE and lack of thermal modifications [5], the authors highly believe this choice is justifiable because of the explorative character of this clinical observational study and previous explicit patient counselling on this issue.

It is to be hoped that a larger patient cohort, preferably enrolled in a multi-centre trial, can help resolve the remaining unsolved questions resulting from this investigation, with the benefit of avoiding underpowered statistical testing and achieving better reliability.

CONCLUSIONS

Regarding its morbidity, IRE seems to be a highly feasible alternative in treating low-risk and selected favourable intermediate-risk PCa patients since the current results show no additional morbidity compared to AS. Pre-existing obstructive voiding symptoms seem not to limit the indication for IRE as a focal treatment for PCa, and the perioperative urethral catheterisation can be safely limited to 24 hours after intervention, with similar overall unaffected erectile function after intervention.

Because of underwhelming oncological outcomes, IRE should not be offered as an equally effective therapy to established curative treatment strategies in PCa. Still, it can be considered helpful in carefully selected patients as an alternative to AS.

The high number of recurrences emphasises the necessity of a strict FU, including histological sampling, and does not favour PSA-triggered rebiopsy strategies only, instead reinforcing the mandatory early (6-months FU) mpMRI/TRUS fusion biopsy after focal treatment.

Nevertheless, in case of disease recurrence or persistence and secondary treatment necessity, the perioperative risk and complications in RPE or RTX are not increased.

Data Sharing Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.