Evidence for Irreversible Electroporation (IRE) Using NanoKnife for Recurrent Prostate Cancer
IRE is not recommended as a first-line salvage treatment for recurrent prostate cancer after radiotherapy, as it has inferior oncological outcomes compared to salvage stereotactic body radiotherapy (SBRT), high-dose rate (HDR) brachytherapy, or radical salvage prostatectomy. 1
Current Guideline Position on Salvage Focal Therapy
The evidence base for focal ablative therapies, including IRE, remains limited for recurrent prostate cancer:
The 2021 European Urology Oncology systematic review found no strong evidence that focal therapy compares favorably with standard treatments for localized prostate cancer, and consequently does not recommend focal therapy for routine standard practice. 2 This applies to both primary treatment and salvage settings.
The 2025 American Radium Society guidelines for intraprostatic radiorecurrent disease prioritize salvage reirradiation (SBRT or HDR brachytherapy) over ablative modalities due to better-established efficacy data. 2
IRE is specifically mentioned in guidelines as an emerging modality still under investigation, with advantages including lack of heat sink effect and ability to treat near critical structures, but requiring general anesthesia with deep muscular blockade. 2
Oncological Outcomes for Salvage IRE
The limited available data on salvage IRE after radiotherapy shows modest results:
A 2025 systematic review of salvage IRE identified only 5 eligible studies, with local oncological control ranging from 67-78%, in-field recurrence rates of 3-10%, and out-field recurrence rates of 8-14%. 3 These recurrence rates are substantially higher than those reported for salvage radiation approaches.
Only one study reported long-term outcomes, showing 91% metastasis-free survival and 60% 5-year progression-free survival. 3 This compares unfavorably to the 50-60% 5-year biochemical recurrence-free survival reported for HIFU salvage therapy in meta-analyses of over 11,000 patients. 1
The largest retrospective series of 471 IRE treatments (including 63 for recurrent disease after prior radical prostatectomy or radiotherapy) showed 5-year recurrence rates of 5.6% for Gleason 6,14.6% for Gleason 7, and 39.5% for Gleason 8-10 disease. 4 However, this mixed cohort included primarily treatment-naive patients, limiting applicability to the salvage setting.
Functional Outcomes and Safety Profile
IRE demonstrates favorable functional preservation but with important caveats:
Post-salvage IRE continence rates range from 73-100%, which is superior to the approximately 12% incontinence rate reported with salvage HIFU. 3, 1
Erectile function preservation is variable, with two studies showing 50% preservation of erections sufficient for intercourse, while others reported decline in erectile function. 3 This compares favorably to the 61% erectile dysfunction rate with salvage HIFU. 1
Complications are predominantly Clavien-Dindo grade I-II (mild to moderate), with severe complications occurring in only 1.4% of cases in the largest series. 4 However, rectal fistula formation has been reported. 3
The 2019 prospective study of 30 treatment-naive patients showed only one grade III adverse event (urethral stricture), with stable urogenital function at 12 months. 5 These results cannot be directly extrapolated to the salvage setting where prior radiation increases complication risk.
Critical Pre-Treatment Requirements
Before considering any salvage therapy including IRE, the following workup is mandatory: 2, 1
Histological confirmation of recurrence via systematic and targeted prostate biopsy is required, as up to 59% of patients may have occult lesions if only targeted biopsies are performed. 1 PSMA PET has an 8% false-positive rate due to post-treatment changes. 6, 1
Both PSMA PET and multiparametric MRI should be performed for staging to exclude metastatic disease. 2, 1
Patient life expectancy should exceed 5-10 years, and recurrence should be Grade Group ≥2. 1
The competitive risk of death or distant metastases should be low, and toxicity from previous radiotherapy should be minimal or resolved. 1
Algorithmic Approach to Salvage Treatment Selection
For biopsy-proven local-only intraprostatic recurrence after radiotherapy:
First-line options: Offer salvage SBRT, HDR brachytherapy, or LDR brachytherapy, which have favorable toxicity profiles and more established efficacy data. 2, 1, 7
Second-line option: Consider radical salvage prostatectomy for selected patients with favorable anatomy and no significant radiation-related tissue changes. 1
Investigational option: IRE may be considered only within well-designed clinical trials or prospective registries, particularly for patients who decline standard salvage options or have contraindications to radiation/surgery. 2, 1
Key Limitations and Pitfalls to Avoid
Critical practice points to prevent inappropriate patient selection:
Never perform IRE based solely on positive imaging findings without histological confirmation, as PSMA PET has an 8% false-positive rate from post-treatment changes. 6, 1
Do not combine biopsy and focal ablation in the same session; histological confirmation must always precede treatment. 6, 1
Do not use the Phoenix criterion (nadir + 2 ng/mL) to define failure after IRE, as this was validated for radiation therapy, not ablation. 6, 1
Whole-gland treatment (prostatectomy or radiation) should remain the standard for confirmed focal recurrences; focal IRE should only be offered in research settings. 1
Evidence Quality Assessment
The evidence supporting salvage IRE is substantially weaker than for other salvage modalities:
No randomized controlled trials compare salvage IRE to other salvage treatments. 3
The systematic review identified only 5 eligible studies, all retrospective or single-arm prospective designs with small sample sizes. 3
Follow-up duration is limited, with most studies reporting short-to-intermediate term outcomes only. 3
The 2021 EAU systematic review excluded studies with fewer than 50 patients per arm, which would exclude all current salvage IRE studies. 2
Clinical Bottom Line
IRE for recurrent prostate cancer after radiotherapy should be considered investigational and offered only within clinical trials or prospective registries. 2, 1 The 67-78% local control rates and 60% 5-year progression-free survival are inferior to established salvage radiation approaches. 3 While functional outcomes appear favorable with 73-100% continence preservation, the oncological efficacy data remain insufficient to recommend IRE as standard salvage therapy. 3 Patients should be counseled that salvage SBRT, HDR brachytherapy, or radical salvage prostatectomy represent better-established options with superior oncological outcomes. 2, 1