Irreversible electroporation for localized prostate cancer: risk-stratified oncologic outcomes and functional preservation.

1
Introduction
Prostate cancer (PCa) represents a critical public health burden, ranking as the second most frequently diagnosed malignant neoplasm globally among men.1,2 Traditional treatments, such as radical prostatectomy, often lead to complications affecting urinary and sexual functions.3,4 In the quest for alternative therapeutic strategies that offer efficacy comparable to radical prostatectomy while minimizing collateral damage to surrounding tissues, irreversible electroporation (IRE) has emerged as a promising modality.5 IRE employs precisely calibrated high-voltage electric fields (1,500–3,000 V/cm) to induce irreversible nanopore formation in tumor cell membranes through microsecond-duration pulsed currents (50–100 μs pulse width).6 This non-thermal ablation mechanism selectively disrupts phospholipid bilayer integrity via transmembrane potential destabilization, triggering caspase-mediated apoptosis through intracellular ion disequilibrium (calcium overload).7 IRE selectively ablates tumor cells via lower electric field strength, while sparing neurovascular structures through cholesterol-rich microdomains and myelin insulation (8 × 106 Ω m).5 This precision-driven approach aims to ablate tumor tissues while preserving functionally critical structures including periprostatic neurovascular bundles and urethral sphincter complexes, thereby maintaining urinary continence and sexual potency post-treatment. The application of IRE in PCa treatment is gaining traction due to its potential to address the shortcomings of radical prostatectomy.8 However, the long-term efficacy and safety of IRE in PCa patients remain subjects of ongoing research and debate. This follow-up study endeavors to provide a comprehensive assessment of IRE's therapeutic efficacy and safety profile in a cohort of PCa patients. By analyzing clinical data obtained from a retrospective review of patient records, we aim to elucidate the impact of IRE on PCa progression, urinary and sexual functions, and overall patient outcomes.

2
Material and methods
2.1
Case collection
A retrospective review was conducted on the clinical data of 49 PCa patients who received IRE therapy. Prior to commencing the study, ethical approval was obtained from the Institutional Ethics Review Committee of Wuhan Tongji Hospital (TJ-IRB202409097), ensuring compliance with strict ethical guidelines and regulations. Informed consent was secured from all patients included in the study. The data collected prospectively comprised age, prostate-specific antigen (PSA) level at admission, tumor stage, pathological type, Gleason score, and IRE surgery duration. In addition, baseline functional assessments, including the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function-5 (IIEF-5), were systematically recorded for all patients prior to the procedure. Exclusion criteria were carefully implemented to exclude cases with incomplete clinical and follow-up data, those who had undergone prior PCa treatments, and patients with metastasis at the time of surgery. Patients were categorized in accordance with the EAU risk classification criteria9 (Fig. 1).

2.2
Postoperative follow-up
A rigorous follow-up protocol was established to monitor the patients' progress post-IRE therapy. All patients underwent PSA and MRI follow-up examinations one month after the IRE procedure, with subsequent examinations conducted every 3 to 6 months. In addition, to comprehensively evaluate the patient's overall condition, quality of life was assessed using the World Health Organization Quality of Life-BREF (WHOQOL-BREF) questionnaire—a validated instrument that measures physical, psychological, social, and environmental domains of QOL. To evaluate functional outcomes, sexual function and urinary symptoms were assessed using the same instruments collected at baseline the (IIEF-5) scale and the (IPSS) questionnaire, respectively. Follow-up was primarily conducted via telephone, and the last follow-up date for these patients was January 2025. During the follow-up period, close monitoring of PSA trends and verification of imaging data were performed to assess PCa progression. Biochemical recurrence was diagnosed when PSA increased to the nadir plus 2 ng/mL.10 csPCa was defined as Gleason scores ≥3 + 4 on prostate biopsy (ISUP grade≥2).9 Post-IRE surveillance biopsies were not performed routinely but were triggered by biochemical recurrence and/or clinical suspicion on mpMRI (PI-RADS score ≥3). When indicated, a combined approach of targeted biopsy of the suspicious MRI lesion followed by a standard 12-core systematic biopsy was performed. During follow-up, mpMRI suggested recurrence (PI-RADS ≥3) without concurrent biochemical recurrence in 5 cases. Two of these underwent biopsy, confirming csPCa; the remaining three are under continued active surveillance. The time to recurrence-free survival was defined as the period from the date of IRE therapy to the last follow-up or recurrence.

2.3
Statistical analysis
Data analysis was performed using IBM SPSS Statistics Version 26. For normally distributed continuous variables, descriptive statistics were presented as the mean ± standard deviation (SD). In the case of non-normally distributed continuous variables, the data were described using the median and interquartile range (IQR). Categorical variables were reported as frequencies (n) and percentages (%). Due to the limited sample size and the number of recurrence events, multivariable analyses to adjust for potential confounders were not performed to avoid model overfitting and unreliable results. The Kaplan-Meier estimator was applied to calculate the cumulative recurrence rate, and we utilized GraphPad Prism 9 to plot the corresponding cumulative recurrence curves for visualization.

3
Results
3.1
Baseline characteristics
This study encompassed a total of 49 patients, with a mean age of 64.7 ± 9.4 years. The median preoperative PSA level was 8.72 ng/mL, with an IQR extending from 6.16 to 14.62. Thirty-seven patients had a Gleason score of ≤6, while 12 patients exhibited a Gleason score of 7. Based on the EAU risk classification criteria, patients were categorized into low-risk (n = 21, 42.9%), intermediate-risk (n = 21, 42.9%), and high-risk (n = 7, 14.3%). The average duration of surgery for all patients was 77 minutes (Table 1).

3.2
Early oncological results
The median duration of follow-up was 11.5 months. It is important to note that the 30-month cumulative recurrence rate represents the outcome at that specific time point for patients with sufficient follow-up, while the median reflects the central tendency of the entire cohort's follow-up duration at the time of analysis. Fig. 2A illustrates the declining trend of PSA levels over time across the 49 patients, with a median PSA nadir of 1.69 ng/mL recorded throughout the follow-up duration. During the follow-up period, there were 8 cases of biochemical recurrence (Fig. 2B) and 7 cases of clinically significant recurrence. Of the 7 csPCa recurrences, 5 were located within the ablation zone (suggesting residual disease) and 2 were outfield failures (new lesions in a previously untreated sector). The cumulative csPCa recurrence rate for all PCa patients was 14.28% post-IRE (Fig. 2C). Risk stratification analysis (EAU criteria) revealed distinct recurrence patterns: low-risk patients exhibited a 30-month cumulative csPCa recurrence rate of 4.8% (1/21), while intermediate-risk patients showed a rate of 19.0% (4/21) at the same interval. In contrast, high-risk patients demonstrated a significantly higher recurrence rate of 28.6% (2/7) as early as 15 months post-IRE. Further analysis of PSA thresholds revealed differential sensitivities in detecting recurrence across risk strata. For instance, while a PSA threshold of >10 ng/mL demonstrated limited sensitivity (28.6%, 2/7) within this cohort, lower thresholds (>4 ng/ml) exhibited improved sensitivity (57.1%, 4/7). Notably, no tumor metastasis was observed during the follow-up period. Additionally, the mean duration of catheterization post-treatment was 6.1 ± 2.8 days (Table 2).

3.3
Postoperative safety assessment
A comprehensive assessment of postoperative complications revealed multiple domains of clinical sequelae. Urinary morbidity included re-catheterization in 3 patients (6.1%), persistent urinary difficulties in 2 patients (4.1%) at 6 months, and 1 case (2.0%) of urethral stricture requiring dilation. Functional outcomes revealed that 3 patients (6.1%) experienced urinary incontinence, defined as reliance on ≥2 nightly urinary pads for a minimum of 6 months. Additionally, 2 patients (4.1%) reported intermittent urethral pain (approximately 1–2 times per day) at the 6-month follow-up. Sexual dysfunction was observed in 2 patients (4.1%), including one case of moderate erectile dysfunction (IIEF-5 score: 13) at the 1-year postoperative mark and another case of transient ejaculatory discomfort. Additionally, psychological distress emerged in 5 patients: 4 cases (8.2%) of mild anxiety (QOL-BREF scores <60) within 3 months post-IRE, managed through brief counseling, and 1 patient (2.0%) exhibiting moderate sleep disturbances (QOL-BREF score: 73) at 1 year, potentially attributable to cancer-related distress (Table 3).

4
Discussion
IRE continues to emerge as a compelling therapeutic option for PCa, distinguished by its capacity to achieve precise tumor ablation while minimizing collateral damage to adjacent normal tissues and critical anatomical structures. The mechanism underlying IRE involves the application of high-voltage electrical pulses to induce irreversible membrane poration, leading to apoptotic or necrotic cell death.11 Unlike thermal ablation techniques, IRE operates under non-thermal principles, thereby preserving extracellular matrix integrity, blood vessels, and neurovascular bundles.12 This property is particularly advantageous in the context of PCa, where preserving urinary continence and erectile function is paramount to maintaining patients' quality of life.
Our follow-up study reveals a marked enhancement in tumor control outcomes when compared with our previous research findings.13 Specifically, the cumulative recurrence rate after IRE therapy was observed to be 14.28%. This represents a notable improvement over the 30-month cumulative recurrence rate of 27.3% reported in our prior study, which predominantly focused on elderly patients (aged ≥65 years) with PCa. A key distinction between the two studies lies in the sample size and demographic composition. The present study boasts an expanded sample size (n = 49), encompassing a broader age range (mean age: 64.7 ± 9.4 years). In contrast, the prior study was confined to elderly patients only (mean age: 69.0 ± 3.5 years). This broader age spectrum in the current cohort not only enhances the statistical power of our analysis but also improves the generalizability of our findings. Notably, a larger proportion of younger patients was included in the current study. It is plausible that these younger patients, who may exhibit less aggressive tumor biological behavior or fewer comorbidities, contributed to the improved treatment response observed. The cumulative recurrence rate of 14.28% is particularly encouraging, suggesting that IRE may hold promise as an effective modality for controlling PCa progression. Risk-stratified analysis revealed recurrence rates of 4.8%, 19.0%, and 28.6% among low-, intermediate-, and high-risk patients, respectively. These outcomes compare favorably with those reported in the updated HIFU studies,14 which showed pathological disease-free survival rates of 91.6%, 84.8%, and 86.6% across risk groups at 48 months. Notably, IRE demonstrates comparable oncologic control to HIFU, particularly in the low- and intermediate-risk categories. However, it is imperative to acknowledge that the recurrence rate remains a significant concern that warrants further investigation in future research. To enhance tumor control, several strategies could be explored. These include optimizing treatment parameters to maximize therapeutic efficacy, combining IRE with other immunotherapeutic modalities (immune checkpoint inhibitors,15 oncolytic virus,16 and DNA damage repair inhibitors17) to achieve synergistic effects, and refining patient selection criteria to identify those most likely to benefit from IRE therapy.
PSA remains a cornerstone biomarker in prostate cancer management, yet its role in post-IRE surveillance warrants critical evaluation.18,19 In this cohort, PSA monitoring demonstrated a true positive rate of 57.1% (4/7 cases) for detecting clinically significant recurrence. While PSA elevation serves as an early indicator of biochemical recurrence (defined as nadir + 2 ng/mL), its limitations in predicting clinically significant recurrence by merely (PSA >4 ng/ml) are evident. PSA's utility is further complicated by its susceptibility to confounding factors such as prostatic inflammation, benign hyperplasia, or urethral trauma post-catheterization.20 However, its cost-effectiveness, widespread availability, and non-invasive nature solidify its role in longitudinal monitoring, particularly in resource-limited settings. Future strategies to improve surveillance may incorporate PSA kinetics (e.g., doubling time) or density, along with the use of novel molecular biomarkers such as the Prostate Health Index (PHI)21,22 and the 4Kscore,23,24 to enhance early detection of clinically significant recurrences. Updated protocols should also optimize PSA monitoring by individualizing threshold levels according to risk category. For instance, patients with intermediate-to high-risk disease may benefit from lower PSA thresholds and shorter intervals between assessments, whereas those at low risk could be managed with more conservative criteria.
The safety profile of IRE in this follow-up cohort remains favorable, with a low incidence of procedure-related morbidity. Urinary complications, including re-catheterization (6.1%) and persistent voiding dysfunction (4.1%), were observed in a limited subset of patients, potentially attributable to transient tissue edema, anatomical variability, or disease progression. Notably, IRE demonstrates superior preservation of sexual function compared to radical prostatectomy. The incidence of erectile dysfunction at one year was 5%–10% after IRE,25,26 significantly lower than the 50–70% observed following radical surgery.27 This advantage is attributable to IRE's mechanism of non-thermal ablation and its capacity for selective neurovascular sparing. Furthermore, when compared to cryoablation—which reports a 73% potency preservation rate at 12 months28—IRE shows notably better outcomes, with only 4.1% of patients experiencing sexual dysfunction. This marked difference underscores IRE's enhanced ability to maintain sexual function without compromising oncological efficacy.
To further enhance therapeutic precision, future protocols should prioritize computational modeling for electroporation parameter optimization (e.g., voltage gradients, pulse duration). Integration of advanced preoperative imaging modalities (e.g., PET/CT or PET/MRI) for lesion mapping, coupled with intraoperative AI-assisted ultrasound to ensure accurate electrode-needle puncture and mitigate iatrogenic neural damage.29 Moreover, future research should consider incorporating preoperative baseline assessments, such as the IPSS and the IIEF-5, to quantitatively evaluate the preoperative and postoperative functional outcomes for individual patients.
While IRE demonstrates advantages in preserving anatomical structures, our findings highlight previously underreported psychosocial sequelae: 8.2% of patients developed mild anxiety, and 2.0% reported moderate insomnia during follow-up. These observations align with studies linking focal therapies to “treatment ambiguity syndrome” – persistent anxiety about residual malignancy despite negative biomarkers.30 The delayed onset of sleep disturbances (1-year post-IRE) may reflect cumulative psychological burden from prolonged surveillance protocols. Proactive integration of mental health screening into follow-up pathways, as recommended by the NCCN Clinical Practice Guidelines in Oncology,31 could mitigate these effects.

5
Conclusion
This follow-up cohort study reaffirms the therapeutic potential of IRE in managing localized prostate cancer. The 30-month cumulative clinically significant recurrence rate of 14.28%, alongside preserved urinary and sexual function in the vast majority of patients, underscores IRE's role as a viable tissue-sparing alternative to radical interventions. While the observed safety profile and functional outcomes are encouraging, the elevated recurrence risk among intermediate-high risk patients highlights the necessity for refined patient selection criteria and multimodal therapeutic approaches. Future studies should prioritize extended follow-up, integration of adjuvant therapies, and validation of predictive biomarkers to optimize treatment protocols. Collectively, these advancements will enhance the precision and applicability of IRE in the evolving landscape of prostate cancer management.

Author contribution
Zhi-Yu Xia: Conceptualization; Data curation; Formal analysis; Writing – original draft.
Jia-Cheng Xiang: Data curation; Investigation; Methodology; Writing – original draft.
Yu-Xuan Yang: Software; Validation; Visualization.
Fan Xiao: Resources; Project administration.
Jun Yang: Supervision; Writing – review & editing.
Shao-Gang Wang: Funding acquisition; Supervision; Writing – review & editing.
Qi-Dong Xia: Conceptualization; Supervision; Writing – review & editing.

Data availability statement
All data generated or analyzed during this study are fully included within the manuscript. No external repositories or additional sources are required to access the data.

Ethics approval
This study has been approved by the Institutional Ethics Review Committee of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology (TJ-IRB202409097), and all enrolled patients have completed the informed consent process.

Funding
None.

Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.