Focal irreversible electroporation for the treatment of localised prostate cancer: a systematic review

Introduction

Prostate cancer (PCa) is the second most commonly diagnosed solid tumour in men worldwide, with approximately 70% having organ-confined disease (1,2). Traditional whole-gland treatment for localised PCa, in the form of radical prostatectomy (RP) and radiotherapy (RT), may cause significant morbidity due to associated urinary, erectile, and bowel toxicity (3). Furthermore, recent evidence suggests that the majority of patients undergoing whole-gland treatment for intermediate-risk disease do not derive a significant metastasis-free or cancer-specific survival benefit (4).

Active surveillance (AS), with appropriate patient selection, is a safe management option that minimises the impact on patient quality of life (QoL) (5,6). However, it may not be feasible for all patients, such as those with features suggestive of a higher risk of progression (7,8) or in whom anxiety or compliance issues limit adherence to surveillance protocols (9,10).

Advances in imaging through multi-parametric magnetic resonance imaging (mpMRI) and prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT), and subsequent targeted biopsies, have allowed for more precise diagnosis and therefore treatment of PCa (11). Focal therapy is a hybrid approach which involves ablative treatment of the involved prostate gland and continued close monitoring of the untreated gland. This may include treatment of a purely unifocal cancer, or targeted ablation of the index lesion while sparing low-grade disease elsewhere (12). Various focal therapy energy sources provide improved functional outcomes compared to whole-gland treatment whilst demonstrating promising short- to medium-term oncological outcomes (12,13).

Irreversible electroporation (IRE) is an ablative technique first introduced in human tumour ablation therapy 15 years ago (14). It utilises repetitive high-voltage electrical pulses to create nanopores in the cell membrane, causing disruption of cellular haemostasis and subsequent apoptosis (15). Utilising a low-energy, non-thermal energy source minimises the deleterious thermal effects caused by other thermal energy sources, theoretically further decreasing the risk of collateral damage to surrounding tissue such as the urethra, external urethral sphincter, bladder neck, neurovascular bundle, and rectum (15,16).

The first human studies exploring the use of IRE in localised PCa successfully demonstrated the clinical feasibility and safety of ablating cancerous tissue whilst minimising damage to surrounding structures (17-19). Since then, focal IRE has shown promising initial oncological and functional outcomes, although robust evidence to support its efficacy and optimal utilisation is still maturing (20,21). IRE is already performed in accordance with clinical guidance for other cancer types, such as liver metastases, in some countries (22).

We therefore aim to provide a comprehensive summary of the existing literature exploring the oncological outcomes, functional outcomes, and safety profile of focal IRE for the treatment of localised PCa, in order to better understand its potential optimal use in this setting. We present this article in accordance with the PRISMA reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-678/rc) (23).

Methods

Protocol and registration

The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) in July 2025 (registration ID: CRD420251082831).

Search strategy

A comprehensive search across four electronic databases (MEDLINE, Embase, Web of Science, and Cochrane Database of Systematic Reviews) was conducted in July 2025.

Backwards citation searching (backwards pearl growing/mining/referencing) was performed on retrieved articles in order to identify any missed additional articles.

The Medical Subject Headings (MeSH) terms ‘prostatic neoplasms’, ‘prostate cancer’, ‘electroporation’, ‘irreversible electroporation’, and ‘irreversible electroporation device’ were combined with keywords ‘IRE’ and “NanoKnife’.

The search was limited to the English language and human species. There were no limitations placed on the year of publication. The complete final search strategy is provided (Appendix 1).

Eligibility criteria

The PICO (population, intervention, comparison, outcome) framework was used as follows:

• P: men with localised PCa;
• I: focal IRE;
• C: single-arm or comparative studies (retrospective or prospective);
• O: oncological outcomes [including prostate-specific antigen (PSA) kinetics, in-field recurrence rates, out-of-field recurrence rates, retreatment rates], functional outcomes (including urinary function and sexual function), and safety profile (including post-operative adverse events and complications).

Articles were included if:

• They reported on focal IRE for localised PCa, either in the primary or salvage treatment setting;
• They reported oncological and/or functional outcomes;
• Patients were aged over 18 years;
• The full text was available in English.

Articles were excluded if:

• They included only non-focal ablative techniques (e.g., whole-gland ablation);
• They reported only on men with locoregional or metastatic PCa;
• They were in the form of grey literature, conference abstracts, or letters to the editor;
• They were in the form of study protocols only.

Article selection

All identified citations following the search were collated and uploaded onto Covidence (Veritas Health Innovation, Melbourne, Australia) and duplicates removed. Title and abstract screening was then performed by two independent reviewers (J.C. and M.A.). Full texts were then reviewed in detail. Those not fitting eligibility criteria were excluded. Any disagreements were resolved by a third reviewer (J.G.).

Data extraction

Data extraction was performed by two independent reviewers (J.C. and M.A.) and collated in an Excel spreadsheet (Microsoft Corporation, Redmond, WA, USA).

Variables included: study characteristics (study design, patient number, inclusion of salvage therapy, ablative pattern, follow-up duration), baseline demographics [age, PSA, prostate volume, International Society of Urological Pathology (ISUP) grade group (GG), clinical stage, risk group], technical details (IRE system, procedure duration, catheter duration, hospital stay duration, safety margin), oncological outcomes (PSA kinetics, imaging choice and timing, biopsy technique and timing, definition of disease recurrence, in-field and out-of-field recurrence rates, retreatment rate, retreatment modalities), functional outcomes (urinary function, sexual function), and complications. Data not included in individual articles were recorded with a “–”.

Results

Article selection

The electronic search resulted in a total of 968 articles as follows: MEDLINE (n=177), Embase (n=389), Web of Science (n=395), Cochrane Database of Systematic Reviews (n=0), and backwards citation searching (n=7). After 348 duplicates were removed, 620 titles and abstracts were screened, of which 73 full texts were reviewed. A total of 42 articles were excluded as they met exclusion criteria as detailed in Figure 1.

Figure 1 Study search strategy: PRISMA flow diagram. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

In total, 31 articles were included, with publication years ranging from 2014 to 2025.

Study characteristics and patient demographics

Study characteristics, patient demographics, and technical procedural details are summarised in Table 1. There was a total of 29 individual studies [two pairs of articles reported separately on the same two studies, and therefore will be referred to as two studies (41,42,48,49)]. Study designs included prospective (n=17), retrospective (n=9), combined prospective and retrospective (n=1), randomised controlled trial (RCT) (n=1), and non-randomised controlled trial (n=1). The RCT randomised patients into either focal or extended focal ablation groups (41,42), whilst the non-randomised controlled trial did not have a true control group but rather compared success in participants against historical oncological outcomes from previous studies (37).

Study participant number ranged from 10 to 429 patients, but the largest cohort of solely focal treatment was 411 (51) [one study included 429 patients but over a quarter had undergone whole-gland ablation (33)]. Median follow-up duration ranged from 6 to 60 months. In the study with longest reported follow-up, some patients were approaching 10 years of follow-up (46).

The majority of studies explored focal IRE as primary treatment. Three studies reported exclusively on salvage treatment for radio-recurrent disease (26,40,43), with another three studies reporting on a combination of both primary and salvage treatment (33,38,44).

All ISUP GG were represented across the studies, and tumour stage ranged from T1a to T3b if only including focal ablative patterns, or T4 if including a study that also reported on whole-gland ablation (although it was not specified what ablative pattern these patients underwent) (33).

Technical procedural details

The NanoKnife (Angiodynamics) system was used in 27 studies, Remedicine Co system in one (37), and one study did not specify which system was used (53).

Ablative patterns were primarily purely unifocal lesion-targeted, although some studies also described octant, quadrant, hemi-gland, bilateral, bifocal, extended and sub-whole-gland techniques. One study included whole-gland ablation in 28% of patients (33). Safety margins, if reported, ranged from 3 to 10 millimetres.

Bladder catheterisation, either urethral or suprapubic, was described in 26 studies. The average time to trial of void ranged from the same day to 15 days later, with a median of 2 days. Median length of hospital admission in all studies was either discharge on the same day or subsequent day. Median procedure duration ranged from 14 to 93 minutes, however there were variations in what aspect of the procedure was reported, as the former described only the ablation duration whereas the latter included the entire operating theatre time (24,37).

Baseline oncological characteristics

A summary of oncological outcomes is provided in Table 2. Patient risk group was specified in 14 studies, with the D’Amico, American Urological Association (AUA), National Comprehensive Cancer Network (NCCN), and European Association of Urology (EAU) risk stratification systems used. Most studies included low- and intermediate-risk groups only, with five studies also including patients from high-risk groups (20,33,35,46,53). The proportion of high-risk patients ranged from 3–9%, except for one outlier study in which they comprised 73% of all patients (33). Several studies that did not explicitly specify patient risk groups included ISUP GG 4–5 disease, thereby encompassing high-risk patients by definition (26,29,33,38,40,42).

Imaging and biopsy technique/timing

In the 27 studies that reported initial pre-treatment imaging modality, all utilised mpMRI. PSMA PET/CT was used in combination with mpMRI in nine studies, and in one study it was used as the sole imaging modality in a subset of patients (39). One study also employed contrast-enhanced ultrasound (CEUS) in combination with mpMRI (32). mpMRI was utilised in 25 out of 26 studies that included post-treatment imaging. Early follow-up imaging within one month of treatment was described in 14 studies, including one study performing repeat imaging 1-day post-treatment (32). Early follow-up imaging was primarily performed to confirm treatment effect/location or exclude rectourethral fistula, and comprised of contrast-enhanced magnetic resonance imaging (MRI), T2-weighted MRI, mpMRI or CEUS. Follow-up imaging was otherwise most often performed in the form of mpMRI at either the 3-, 6-, or 9-month mark. No studies utilised PSMA PET/CT routinely in follow-up.

Targeted biopsy, with or without template biopsy, was utilised in the majority of the 26 studies that reported on initial pre-treatment biopsy technique. Three studies utilised template biopsy alone in all patients (38,41,42). Post-treatment biopsy was performed in 23 studies, ranging from 6 to 18 months after IRE. Again, the majority of studies utilised targeted biopsy, often in combination with template biopsy. Five studies performed template biopsy alone in all patients, including all three which did so for pre-treatment biopsy (26,30,38,41,42). One study specifically targeted the ablation zone and margins (35).

PSA changes

Average baseline PSA was less than 10 ng/mL in all studies except two cohorts receiving salvage treatment (33,44). Post-treatment PSA changes were reported in 24 studies, most commonly at the 3-, 6-, 12-month mark, or as a nadir. The most significant reduction in PSA following primary treatment was an 84% decrease at 3 months (52), whereas in the salvage setting, one study reported a 98% reduction, representing a nadir of 0.12 ng/mL (43). There did not appear to be a clear relationship between PSA reduction and likelihood of negative biopsies. For example, two studies reported similar average PSA reductions of 78% and 84%, but in-field recurrence rates of 33% and 0% respectively (27,52). Conversely, the study that reported the smallest PSA reduction, 39%, had no in-field recurrence and out-of-field recurrence rates of 4% (44).

Disease recurrence

Definition of recurrent disease was varied, with ISUP GG ≥2 the most commonly used criteria, whilst several other studies defined any PCa as recurrence. Other studies specified certain combinations of maximum cancer core length (MCCL) or core involvement percentage cut-off values, with or without specific ISUP GG criteria. Some studies also included secondary definitions. The majority of studies reported in-field recurrence and out-of-field recurrence rates separately.

In the primary treatment setting, three studies reported no in-field recurrences at 6 to 9 months (defined as ISUP ≥2) (52), 7 months (ISUP GG 1 with core ≥5 mm or any ISUP GG 2–5) (25), and 12 months (ISUP GG >2) (44) respectively. All three studies were comprised of patients with ISUP GG 1–3 disease only. The highest in-field recurrence rate was 33% (ISUP GG ≥2 or MCCL ≥4 mm) (27). In-field recurrence rates ranged from 0–10% in the salvage setting. Out-of-field recurrence was reported in 22 studies. Rates ranged from 0–33% in the primary setting, and 0–14% for salvage therapy.

Three studies stratified recurrence by baseline ISUP GG (31,34,42). van den Bos et al. reported rates of recurrence (ISUP GG 1 with MCCL >5 mm/>50% core volume, or any ISUP GG 2–5) as 11% in ISUP GG 1 patients, 13% in ISUP GG 2, and 31% in ISUP GG 3 (31). This was compared to 9%, 17%, and 20% in the same respective groups reported by Blazevski et al. (recurrence defined as ISUP GG ≥2) (34). Both of these studies reported overall recurrence rates when stratified for ISUP GG, rather than dividing into in-field and out-of-field recurrence. Similarly, in their 2023 study comparing focal vs extended ablation, Zhang et al. reported a treatment failure rate (persistent cancer of similar or different grade in the ablated area) of 24% in ISUP GG 1, 32% in ISUP GG 2, and 0% in ISUP GG 3 within the focal ablation group, compared to 21% in ISUP GG 1, 29% in ISUP GG 2, and 0% in ISUP GG 3 in the extended ablation group (noting that only four patients in total were classified as ISUP GG 3) (42). In addition, Guenther et al. reported 72-month recurrence-free survival rates of 94% in ISUP GG 1, 85% in ISUP GG 2, and 60% in ISUP GG ≥3, although this included both primary and salvage treatment, as well as both focal and whole-gland ablative techniques (33).

Retreatment

Retreatment rates ranged from 0–37% in the primary setting and 0–24% in the salvage setting. Retreatment modalities included repeat focal IRE, focal high-intensity focused ultrasound (HIFU), RP including robotic-assisted radical prostatectomy (RARP), brachytherapy, external beam radiation therapy (EBRT), androgen deprivation therapy (ADT), transurethral resection of the prostate (TURP), and one instance of lymph node dissection after salvage IRE. Although some studies included AS in retreatment, AS was not considered retreatment for the purposes of this review and therefore manually removed from reported retreatment rates in any such cases.

Functional outcomes

Functional outcomes and complications are summarised in Table 3.

Urinary function

Pad-free rate was the most commonly used measure of urinary function, whilst various other patient-reported outcome measures (PROMs) such as the International Prostate Symptom Score (IPSS), Expanded Prostate Cancer Index Composite (EPIC) urinary domain, Prostate Quality of Life Survey, and AUA Symptom Score were also utilised.

Primary setting

In the primary treatment setting, baseline pad-free rates ranged from 67–100%, and post-IRE pad-free rates ranged from 71–100%. Of the 15 studies that reported changes in pad-free rate, there was an overall decrease in the percentage of pad-free patients in four studies, no change in 10 studies, and an increase in one study. Decrease in pad-free rates ranged from 1–2%, and the increase seen was 1%. Out of the 10 studies with no overall change in pad-free rate, five studies reported an initial transient decrease in pad-free rate (ranging from 2–6%) which returned to neutral at last follow-up (25,29,31,32,35).

Twelve studies reported on change in PROMs. There was no overall change in PROMs in six studies (29,31,35,45,50,51), and an improvement in six studies (24,27,37,39,49,52). The improvement in these six studies were as follows: prostate QoL score improvement in 11% of patients (24), median IPSS decrease from 9.0 to 4.5 (37), mean IPSS decrease from 10.1 to 7.5 (39), AUA Symptom Score decrease of 7.0 (52), and unspecified improvements in EPIC urinary domain scores (27,49). An initial, transient deterioration was demonstrated in four studies, with eventual improvement to at least baseline level of function (24,35,49,51).

Salvage setting

In the salvage treatment setting, baseline pad-free rates ranged from 61–100%, and post-IRE pad-free rates ranged from 44–100%. There was an overall decrease in the percentage of pad-free patients in three studies and no change in three studies. The decrease in pad-free rates were 4%, 17% and 33%. In the third study, there was no change in pad-free rate in the corresponding primary treatment cohort (38).

Both studies that included changes in urinary PROMs reported an overall deterioration, with reductions in EPIC urinary domain scores from 96 to 92 (26) and 88 to 81 (40) respectively.

Sexual function

Sexual function was most commonly measured using either erections sufficient for intercourse or the International Index of Erectile Function (IIEF) and EPIC sexual domain PROMs. One study used the Sexual Health Inventory for Men (SHIM) (52), another utilised the Prostate Quality of Life Survey, whilst three studies did not specify what measure of erectile function was employed (33,44,53).

Primary setting

In the primary treatment setting, baseline erections sufficient for intercourse rates ranged from 31–83%, and post-IRE rates ranged from 45–79%. Of the 13 studies that reported on changes in potency, there was an overall decrease in the percentage of potent patients in 10 studies, no change in one study, and an increase in two studies. Decrease in potency rates ranged from 3–22%. Both studies that reported an overall increase in potency rates (6% after 12 months and 12% after 6 months) noted initial transient decreases (15% at 6 months and 6% at 6 weeks respectively) (24,25).

Deterioration in overall PROMs were demonstrated in eight studies, whilst five studies reported no significant change. Similar to urinary function, an initial transient deterioration with eventual return to baseline was also noted (49).

Salvage setting

In the salvage treatment setting, baseline erections sufficient for intercourse rates ranged from 33–38%, and post-IRE rates ranged from 11–23%. All four studies that reported on changes in potency noted an overall decrease, with reductions of 15%, 16%, 20% and 22%. Similarly, a deterioration in overall PROMs was seen in all four studies that reported changes in PROMs.

Safety

Post-IRE complications were reported in 24 studies. The Clavien-Dindo classification was utilised in 13 studies, Common Terminology Criteria for Adverse Events (CTCAE) in eight, and three studies did not specify what classification was used.

Clavien-Dindo grade I events ranged from 5–59%, grade II events ranged from 6–27%, and grade III events ranged from 1–19% amongst six studies. There were no grade IV or V events reported.

CTCAE grade 1 events ranged from 7–49% of patients, grade 2 events from 10–29%, grade 3 events from 3–11%, and grade 4 events were reported in two studies (41,51). One death was reported, but this was deemed unrelated to IRE, occurring 11 months post-treatment due to pneumonia (49).

The most common complications included haematuria, haematospermia, dysuria, urinary tract infection (UTI), acute urinary retention (AUR), and epididymitis. One case of rectourethral fistula was reported in two studies (48,49,52) and one case of rectal fistula in another (43). Both cases of rectourethral fistula occurred after primary ablation to the peripheral zone, and were delayed presentations attributed to robotic inguinal hernia repair surgery and potential complicated urethral catherisation; both resolved after several weeks of suprapubic catheter placement. The case of rectal fistula occurred after salvage IRE following previous low-dose-rate brachytherapy, with the ablation field involving the right seminal vesicle.

Discussion

This systematic review included 29 studies published between 2014 and 2025 that assessed the oncological outcomes, functional outcomes, and safety profile of focal IRE for localised treatment of PCa in both the primary and salvage setting. Despite a high proportion of prospective reviews (17 out of 29), there were only two controlled trials (37,41,42), with the randomised trial comparing focal IRE against extended focal IRE, and not a separate treatment modality.

Only one study directly compared focal IRE against another treatment modality, by pair-matching participants against nerve-sparing RARP (30). Scheltema et al. demonstrated that IRE was superior to RARP in preserving both pad-free continence and erections sufficient for intercourse during 12 months of follow-up, with an absolute risk reduction (ARR) of 14% and 22% respectively. None of the RARP patients experienced biochemical recurrence (BCR) (PSA ≥0.2 ng/mL), but 30% of men post-IRE had residual significant PCa with a retreatment rate of 14% (excluding AS).

In the primary treatment setting, both in-field and out-of-field recurrence rates ranged from 0–33%. Valerio et al. reported the highest in-field recurrence rate of 33% despite no out-of-field recurrence, in a cohort comprised of only low- (37%) and intermediate-risk (63%) patients (27). This high in-field recurrence rate was potentially attributed to the lack of treatment margin, as electrodes were placed at the margin of the lesions, and the authors acknowledged that a margin of 9 mm may need to be considered in larger lesions. Similarly, other studies noted a decrease in in-field recurrence rates as margins increased (31,34). van den Bos et al. found that those with smaller safety margins were statistically significantly more likely to have in-field residual disease, and that the chance of having in-field recurrence significantly decreased after increasing their margin from 5 to 10 mm (31). Likewise, Blazevski et al. performed a separate analysis that excluded the initial 32 patients when using a 5 mm margin (the margin was increased to 10 mm for subsequent patients) and demonstrated an in-field recurrence rate of 9.8% in the entire cohort but only 2.7% after excluding this group (34). Notably, out-of-field recurrence rates were similar at 12.7% and 12.1% respectively, suggesting that out-of-field recurrences are independent to the margin used. Expert consensus from 2015 concluded that a 5 mm margin should be utilised; however, it should be noted that all panel members had most focal experience with energy sources other than IRE (54). This raises the possibility that optimal margins may vary amongst different focal therapy modalities, and may need to be tailored to IRE, with some suggesting 9 mm as the optimal distance (27,45,55). Alterations in margins likely represent one aspect of the learning curve when implementing a new treatment technique. van den Bos et al. found that system errors were more likely to lead to in-field recurrence (31), and both Blazevski et al. and Shin et al. demonstrated decreased rates after excluding initial patients, which they attributed to increased technical skills and decreased operator error (34,47). Thirteen studies did not specify if margins were included—is important for future studies to report this in order to better determine the optimal threshold.

Out-of-field recurrence rates were often quite disparate from in-field recurrence rates within individual cohorts, with as high as 31% greater out-of-field recurrence compared to in-field (44). This could potentially be explained by several reasons. Firstly, PCa is understood to be a multifocal disease process, with often multiple spatially and genetically separate foci (56). Consequently, despite effective treatment of the index lesion, other foci may not be treated and may continue to progress (57). Post-IRE systematic template biopsies can help detect this out-of-field disease, and accordingly the majority of studies utilised per-protocol template biopsies in addition to targeted biopsies, in some cases using template alone (26,30,38,41,42). This reflects the expert consensus that in addition to targeted biopsies, systematic biopsies should be performed in untreated areas (58). Secondly, clinically significant PCa (csPCa) (ISUP GG ≥2) may not be detected on pre-IRE imaging and therefore not included in the ablation zone (59). Post-IRE out-of-field csPCa in such instances is therefore residual rather than recurrent disease, and may better be classified as ’selection failure’ rather than treatment failure (38,58).

Such ’selection failure’ is possible despite the sensitive nature of mpMRI, with csPCa being missed in up to 10% of ‘negative’ scans [Prostate Imaging Reporting and Data System (PI-RADS) score <3] (60). To minimise this risk, the Delphi Consensus Project suggests pre-treatment systematic biopsies in addition to lesion-targeted biopsies (61). This practice was reflected in focal IRE, as the majority of studies in this review utilised pre-IRE systematic biopsies. PSMA PET/CT may play a role in appropriate patient selection by detecting lesions negative on mpMRI. Furthermore, it may be used to confirm concordance with mpMRI lesion location in order to guide target delineation and subsequent ablation location (62). Although several studies performed pre-IRE PSMA PET/CT in addition to mpMRI in all patients for staging purposes as per standard protocol, Shin et al. was the only study specifically exploring its role in lesion detection and patient selection (47). They demonstrated one case of mpMRI negative disease visible on PSMA PET/CT who underwent target biopsy and successful ablation with no recurrence on follow-up biopsy. Thus, it can be hypothesised that PSMA PET/CT may have the ability to exclude patients with multifocal disease otherwise not visible on mpMRI, thereby reducing the chance of ’selection failure’ and subsequent out-of-field residual csPCa.

Conversely, post-IRE imaging modality and timing was varied. Fourteen studies performed early follow-up imaging within one month of IRE to confirm treatment effect and location, or exclude rectourethral fistula. Early post-IRE mpMRI and CEUS interpretation is relatively well described in the literature already and therefore will not be explored further for the purposes of this review (63,64). Despite studies demonstrating the utility of mpMRI in assessing medium-term treatment effect (28), other studies have found it to have a low diagnostic accuracy in detecting residual csPCa (65). A contributing factor to this lack of consistency and accuracy is the absence of a standardised scoring system analogous to pre-treatment PI-RADS. A novel scoring system, Prostate Imaging after Focal Ablation (PI-FAB), has been proposed (66). However, its diagnostic accuracy in all forms of focal therapy, not just IRE, is yet to be determined. None of the included studies in the review utilised this system. This uncertainty in optimal mpMRI interpretation is reflected in expert opinion, as there was no consensus on mpMRI findings suggestive of failure from a 2020 international consensus of focal therapy (58). The same experts agreed that first post-treatment imaging should be performed within 6 months, with subsequent mpMRI occurring 12 months later. Timing of mpMRI in the included studies largely reflected this, with most performing initial mpMRI at 3, 6 or 9 months (excluding early imaging). Latest initial imaging was performed 12 months post-IRE, and some studies also performed mpMRI multiple times within the first year, such as at 3, 6 and 12 months (33). Currently, there is a paucity of literature describing the optimal imaging timing for focal therapy, and IRE in particular. Post-IRE PSMA PET/CT was not utilised routinely in any of the studies. Scheltema et al performed PSMA PET/CT in three cases of biochemical failure (PSA nadir + 2 ng/mL) and demonstrated local recurrence, bony metastases, and pelvic lymph node disease (26). A 2023 study by Jafarvand et al. explored the use of PSMA PET/CT in patients with biochemical failure post-HIFU and cryotherapy, and demonstrated a sensitivity, specificity, positive predictive value and negative predictive value of 94%, 25%, 91% and 33%, respectively (67). However, there are no studies exploring this role of PSMA PET/CT post-IRE. Similarly, there are no studies assessing the accuracy of PSMA PET/CT in per-protocol detection of local recurrence post-IRE. Duan et al. demonstrated that PSMA PET/CT could identify clinically significant residual disease and ipsilateral recurrences post-HIFU (68). Further studies are required to explore if this reproducible post-IRE.

Optimal re-biopsy timing is also unclear. Expert opinion for focal therapy in general suggests image-guided biopsy within one year of treatment and systematic biopsy between 6 and 12 months (58). All studies performed per-protocol biopsy between 6 and 12 months, with the majority at either the 6- or 12-month mark. Again, there does not appear to be an obvious optimal timing for re-biopsy; there was no clear correlation between later biopsy and increased recurrence rates. It is known, however, that radiation-based modalities such as focal brachytherapy experience delayed, continued treatment effects, and therefore more delayed biopsy is suggested (58,69). This may be the case with other non-radiation-based modalities (which conversely may have earlier effects); therefore, it is important to consider focal IRE as potentially having its own unique optimal post-treatment biopsy schedule that needs to be explored further.

In the primary setting, retreatment rates ranged from 3–37% (excluding AS), with multiple factors potentially contributing to this variability. Foremost, patients with high-risk disease were included in several studies (20,29,33,35,38,46,51), despite current consensus that focal therapy should not be offered to these men (except potentially in clinical trials) (61,70). Likewise, proportion of risk-groups were naturally highly varied amongst studies. Zhang et al. deliberately did not include any specific exclusion criteria in order to reflect real-world practice, including both ISUP GG 4 (3%) and ISUP GG 5 (4%), as well as CT3a/CT3b disease (51). They reported a csPCa recurrence rate of 24%, although only an overall retreatment rate of 7%. Conversely, Miñana López et al. reported an overall recurrence rate of csPCa of 30%, but a retreatment rate of 37% (45). The level of granularity required to identify which patients did or did not receive retreatment (and the rationale behind this) is often not possible in high-powered studies. However, the discrepancy between recurrence and retreatment rates is indeed a reflection of real-world practice, in which different institutions utilise different protocols, which also cannot always be strictly adhered to due to factors including individual patient requirements and preferences.

Despite this variability, retreatment rates should nonetheless be benchmarked against agreed standards. A 2015 consensus meeting agreed that acceptable early rates of retreatment with focal therapy was <20% and salvage post-IRE whole-gland therapy were <10% (54). If following these standards, then focal IRE appears to have acceptable oncological outcomes, as the majority of studies were within these thresholds. Focal IRE should also be compared against other focal modalities. A 2024 systematic review by Nicoletti et al. explored oncological outcomes from 124 studies utilising 10 focal modalities, primarily HIFU (40 studies), cryotherapy (24 studies), IRE (13 studies), brachytherapy (11 studies) and laser ablation (10 studies) (71). They reported overall salvage retreatment rates ranging from 1–54%, with HIFU alone ranging from 2.3–54%. Again, the variations rates were partially attributed to differences in imaging, biopsy, and treatment protocols between studies.

Although there are no studies directly comparing focal IRE to another focal modality, Sidana et al. indirectly provided comparisons to patients receiving focal HIFU and cryotherapy within the same study (52). Patients generally followed the same selection process and follow-up protocol, but were not formally matched, nor was analysis performed to assess for statistically significant differences in baseline characteristic or outcomes. Nonetheless, pathological failure (ISUP GG ≥2 on re-biopsy) was comparable between IRE (14.3%), HIFU (13.3%), and cryotherapy (20.0%), although retreatment was not assessed. Controlled trials are required to directly compare oncological outcomes between focal IRE and other focal modalities; to our knowledge there are no trials currently registered. Rates of short- to medium-term recurrence following primary focal treatment contrast with the longer-term BCR rates after RP, which are described as 30–35% at 15–20 years in intermediate-risk cohorts (72,73). Naturally, radical whole-gland treatment confers greater oncological control than focal IRE, at the expense of functional outcomes; an optimal, acceptable balance between these trade-offs has yet to be established. Furthermore, both oncological and functional outcomes following salvage IRE remain less well defined than those after salvage treatment post-RP.

Multiple forms of salvage treatment post-IRE were utilised, including a large proportion who underwent RP, or RARP specifically, ranging from 13–100% of all retreatment modalities within studies. Scheltema et al. explored the oncological and functional outcomes at their institution (46,72) and others (73), and reported acceptable although sub-optimal oncological outcomes of salvage RARP after IRE. Functional outcomes were encouraging, with 94% pad-free rates and 53% preserved erections sufficient for intercourse. These outcomes compared favourably to salvage RARP following other focal modalities such as HIFU (74).

Focal IRE in the salvage setting was explored in six studies, either exclusively or in addition to primary treatment, although one study did not separate their findings from the salvage (70 patients) and primary cohorts (33). From the five studies where meaningful salvage data was available, there were a cumulative 142 patients undergoing salvage IRE, all with radio-recurrent disease (26,38,40,43,44). Oncological outcomes were promising, with overall recurrence rates of 0%, 11%, 20%, and 21% in the studies that performed post-salvage biopsy (26,38,40,43). However, it is worth noting that in the first study, only two out of six patients had undergone biopsy, and ISUP GG 2 disease was found in TURP chips in another (38). It is not only this relatively small sample size (largest study 74 patients), but also low uptake of post-salvage biopsy that may limit oncological results, with only just over half of all overall patients undergoing biopsy. Retreatment rates were comparable with those for primary treatment, with rates of 0%, 17%, 20% and 24%. However, these suffered from the same limitations as mentioned above. Furthermore, there was a large variation in patient selection based on PSA level, with median values ranging from 2.2–11.9 ng/mL. This reflects the lack of overall consensus in patient selection in salvage ablative therapy in general (75).

Overall, focal IRE appears to be relatively safe with a low proportion of serious adverse events. Overall complication rates are comparable to other focal modalities. A 2021 systematic review exploring focal HIFU studies with over 50 patients reported complications in 13–41% of patients (76). The nature of complications appears similar to other modalities, although rectourethral fistula may be less prominent compared to other focal modalities, with only two cases reported amongst IRE compared to rates as high as 3.3% with HIFU (77). A noticeable difference in safety profile between the salvage and primary setting was the relatively high rate of urethral sloughing following salvage IRE. Blazevski et al. reported urethral sloughing requiring transurethral resection in 19% of patients, postulating that the lower resistance of irradiated tissue may lead to unintended heating of the urethra despite the non-thermal nature of IRE (40).

Impact on urinary function is particularly promising in the primary setting. Only four out of 15 studies reported a decrease in pad-free rates, with reductions of only 1–2%. Furthermore, overall deterioration in urinary PROMs was not reported in any studies, with an improvement noted in six studies. In comparison, three out of six studies reported an overall decrease in pad-free rates in the salvage treatment setting, with reductions of 4%, 17% and 33%. A deterioration in urinary PROMs was noted in both studies reporting on change in urinary PROMs. This supports the theory that prior radiation increases disposition to damage of structures such as the urethra and urinary sphincter (26,33,40). Salvage patients were also more likely to have lower baseline urinary function (16). A similar decline in urinary function has been previously noted in other focal salvage trials (78). Another recurring pattern was that decline in urinary function was often transient during early follow-up, but improved over time. Nine studies reported initial deterioration in either pad-free rate or PROMs, with eventual return to the level of or above baseline function. This phenomenon has been noted in other focal modalities such as HIFU (76). Effect on urinary function appears to be comparable to other focal treatments, with the majority of studies exploring other modalities also reporting no deterioration in continence rates or PROMs (77). When directly compared to RARP, IRE was superior in preserving continence, with an ARR of 44% at 1.5 months and 14% at 12 months (30).

Sexual function likewise demonstrated promising results, albeit with slightly higher rates of deterioration when compared to urinary function. In the primary setting, 10 out of 13 studies reported decreased rates of erections sufficient for intercourse, with a reduction of up to 22%. There was a deterioration in PROMs in 11 out of 16 studies. Similar to urinary outcomes, sexual function appeared to be more commonly affected after salvage IRE than primary; deteriorations in potency rates and PROMs were noted in all studies that reported on these outcomes. However, the difference in the extent of deterioration between the primary and salvage settings appeared less marked than as seen in urinary function; the largest reported reduction in potency rate was 22% in both the primary and salvage groups. As was the case with urinary function, there was often an initial decrease in erectile function that improved over time; however, unlike urinary function, this returned to baseline less often. One study demonstrated no significant difference in sexual function based on tumour location (anterior vs. posterior, apex vs. base, unilateral vs. bilateral) (29). Impact on erectile function appears favourable compared to other focal modalities. Patients returning to baseline erectile function or sufficient for penetration ranged from 14% to 92.6% for HIFU (77), whilst worsening erectile function was as high as 41.9% in cryotherapy (79). In the pair-matched comparison to RARP, the ARR in erections sufficient for intercourse was 32% at 1.5 months, and 22% at 12 months (30). This aligns with established literature demonstrating a more pronounced decline in erectile function after RP, with recovery often delayed for up to 2 years and often not returning to baseline despite penile rehabilitation (80,81).

There were several limitations to this review. Foremost, data were often quite heterogenous. There was significant variation in several aspects, including but not limited to: patient selection, pre-treatment investigations, definitions of recurrence, post-treatment imaging and biopsy protocols, and measures of functional outcomes. Not only does this lead to difficulty in performing a meta-analysis, it also causes difficulty in direct comparisons between studies and precludes an appropriate risk of bias assessment. In particular, definitions of recurrent disease varied substantially across studies, limiting the comparability of reported oncological outcomes and hindering the ability to draw consistent conclusions about treatment efficacy. This appears to be an overarching theme amongst all modalities of focal therapy, with multiple systematic reviews noting a similar issue (71,76,77). Furthermore, data were sometimes either not presented, or lacked the granularity to extract meaningful results. For instance, only three studies presented enough data to stratify recurrence rates by baseline ISUP GG. Such stratification is essential for accurately assessing oncological outcomes across individual disease grades and guiding appropriate, safe patient selection, and should be included in future studies. Secondly, there is a relative paucity of longer-term data. Five studies had a median follow-up of less than 12 months, with another seven studies having median follow-up of 12–24 months. Although promising, data are required to mature before long-term outcomes, particularly oncological, can be confidently drawn. This is the natural evolution as evidence for a newly introduced technique accumulates; a 2020 systematic review exploring focal IRE contained only one-third of the amount of articles included in this review (82). Lastly, there is a lack of comparative studies and controlled trials. Only one study directly compared IRE to other treatment (RARP), and one RCT compared focal IRE to extended focal IRE. Comparative trials must be developed to rigorously benchmark IRE against traditional whole-gland treatment and other focal modalities. Given the promising and often similar results of many focal modalities, coupled with the heterogeneity of available data, comparative studies will help determine how focal IRE performs amongst these other modalities, and potentially identify certain disease or patient factors where it may be more suitable compared to others.

Despite these limitations, this systematic review has several strengths. It contains the most exhaustive number of published studies exploring focal IRE not only for primary treatment but also in the salvage setting. Moreover, it includes a comprehensive summary of study characteristics, oncological outcomes, functional outcomes, and safety profile, in a format that allows easier comparison between often varied and heterogenous data.

Conclusions

Focal IRE is a promising treatment modality for localised PCa. Oncological outcomes, although still maturing, appear promising. Functional outcomes compare favourably against whole-gland treatment, particularly in the primary treatment setting. Although data are limited, focal IRE also appears to have a role in salvage treatment. Longer-term data are required to more definitively assess focal IRE’s efficacy in oncological control, whilst comparative studies are needed to further evaluate its role amongst the growing array of treatment options for localised PCa.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-678/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-678/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-678/coif). H.K. reports that the Nanoknife machine was provided by Angiodynamics to the institution free of charge—with no direct conflicts of interest on this systematic review manuscript. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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