Interventional procedure overview of irreversible electroporation for treating prostate cancer

Article

Number of patients/follow up

Direction of conclusions

Reasons for non-inclusion in summary of key evidence section

Bates AS, Ayers J, Kostakopoulos N et al. (2021) A Systematic Review of Focal Ablative Therapy for Clinically Localised Prostate Cancer in Comparison with Standard Management Options: Limitations of the Available Evidence and Recommendations for Clinical Practice and Further Research. European Urology Oncology, 4(3): 405–423.

Systematic review
n=14 studies

The certainty of the evidence regarding the comparative effectiveness of FT as a primary treatment for localised PCa was low, with significant uncertainties. Until higher-certainty evidence emerges from robust prospective comparative studies measuring clinically meaningful outcomes at long-term time points, FT should ideally be performed within clinical trials or well-designed prospective cohort studies.

IRE outcomes not reported separately from other therapy outcomes.

Baydoun A, Traughber B, Morris N et al. (2017) Outcomes and toxicities in patients treated with definitive focal therapy for primary prostate cancer: systematic review. Future Oncology (London, England), 13(7): 649–663.

Systematic review
n=2288 (18 studies)

The outcomes of FT in PCa seem to be similar to those observed with whole gland therapy and with fewer side
effects. Further research, including prospective randomised trials, is warranted to elucidate the potential advantages of focal radiation techniques for treating PCa.

1/18 studies relate to IRE, which is already included in the appendix.

Beyer LP, Pregler B, Verloh N et al. (2017) Effect of irreversible electroporation of prostate cancer on microcirculation: Imaging findings in contrast-enhanced T1-weighted 3D MRI. Clinical Hemorheology and Microcirculation, 67(34): 399–405.

n=13
Follow up = 6 months

Ablated prostate was either homogeneously (8/13 [62%]) or heterogeneously (5/13 [38%]) hypo attenuating.
Peripheral contrast enhancement manifesting as a hyper attenuating margin was observed during the arterial (60 sec) (3/13
[23%]) and venous (240 sec) (10/13 [77%]) phase. The ablation defect showed a sharp (8/13 [62%]) or blurry (5/13 [38%])
margin.

Study focuses on imaging outcomes.

Collettini F, Enders J, Stephan C et al. (2019) Image-guided Irreversible Electroporation of Localised Prostate Cancer: Functional and Oncologic Outcomes. Radiology, 292(1): 250–257.

n=30
Follow up = median 20 months

The proportion of men with erection sufficient for penetration was 83.3% (25 of 30) at baseline and 79.3% (23 of 29; P . .99) at 12 months. Leak-free and pad-free continence rate was 90% (27 of 30) at baseline and 86.2% (25 of 29; P . .99) at 12 months. Urogenital function remained stable at 12 months according to changes in the modified International Consultation on Incontinence Questionnaire Male Lower Urinary Tract Symptoms, or ICIQ-MLUTS, and the International Index of Erectile Function, or IIEF-5, questionnaires (P = .58 and P = .07, respectively). PSA level decreased from a baseline median value of 8.65 ng/mL (interquartile range, 5–11.4 ng/mL) to 2.35 ng/mL (interquartile range, 1–3.4 ng/mL) at 12 months (P , .001). At 6 months, 28 of 30 participants underwent posttreatment biopsy. The rate of infield treatment failure was 17.9% (five of 28) as determined with multiparametric prostate MRI and targeted biopsies at 6 months.

Larger studies included.

Dong S, Wang H, Zhao Y et al. (2018) First Human Trial of High-Frequency Irreversible Electroporation Therapy for Prostate Cancer. Technology in Cancer Research & Treatment, 17: 1533033818789692.

n=40
Follow up = 6 months

A small amount of muscle relaxant was still needed, so there were no visible muscle contractions during the pulse delivery process. Four weeks after treatment, it was found that the ablation margins were distinct in magnetic resonance imaging scans, and the prostate capsule and urethra were retained. Eight patients underwent radical
prostatectomy for pathological analysis after treatment, and the results of hematoxylin and eosin staining revealed that theurethra and major vasculature in prostate have been preserved.

Larger studies with longer follow up included

Fallara G, Capogrosso P, Maggio P et al. (2020) Erectile function after focal therapy for localised prostate cancer: a systematic review. International Journal of Impotence Research, 33(4):418-427.

Systematic review
n=26 studies

Overall, reported sexual function outcomes after these treatment modalities were generally good, with many studies reporting a complete recovery of EF at 1-year follow up. However, the quality of current evidence is affected both by the lack of well-conducted comparative studies and by a significant heterogeneity in terms of study design, study population, erectile and sexual function assessment modalities.

All included IRE studies in Table 2 or appendix.

Giganti F, Stabile A, Giona S et al. (2019) Prostate cancer treated with irreversible electroporation: MRI-based volumetric analysis and oncological outcome. Magnetic Resonance Imaging, 58: 143–147.

n=30
Follow up = median 16 months

Six men were undertreated and showed mpMRI recurrence after 6 months. At 1-year, three additional men had recurrence. Overall, four of these 9 men (44%) were retreated. The other five men did not receive any further treatment. Median time to re-treatment was 15 months. Median pre-treatment lesion volume was 0.65 cc, 0.66 cc and 0.43 cc on the different mpMRI sequences (T2-weighted, diffusion-weighted, and dynamic contrast enhanced imaging). Median necrotic volume was 10.77 cc. Median overall residual fibrosis volumes were 0.84 cc and 0.95 cc at 6-month and 1-year mpMRI. Pre-treatment, necrotic and residual fibrosis volumes were significantly different (p < 0.001). Pre-treatment tumour volumes on diffusion-weighted imaging and necrotic volumes were correlated (r = 0.18; p = 0.02).

Larger studies included.

Hopstaken JS, Bomers JGR, Sedelaar MJP et al. (2022) An Updated Systematic Review on Focal Therapy in Localised Prostate Cancer: What Has Changed over the Past 5 Years? European Urology, 81(1): 5–33.

Systematic review
n=5827 (72 studies)

Twenty-seven studies reported on high-intensity focused
ultrasound (HIFU), nine studies on irreversible electroporation, 11 on cryoablation, eight on focal laser ablation and focal brachytherapy, seven on photodynamic therapy (PDT), two on radiofrequency ablation, and one on prostatic artery embolization. The majority of studies were prospective
development stage 2a studies (n = 35). PDT and HIFU, both in stage 3, showed promising results. Overall, HIFU studies reported a median of 95% pad-free patients and a median of 85% patients with no clinically significant cancer (CSC) in the treated area. For PDT, no changes in continence were reported and a median of 90% of patients were without CSC. Both treatments were well tolerated.

All eligible IRE studies in Table 2 or appendix.

Jung EM, Engel M, Wiggermann P et al. (2021) Contrast enhanced ultrasound (CEUS) with parametric imaging after irreversible electroporation (IRE) of the prostate to assess the success of prostate cancer treatment. Clinical Hemorheology and Microcirculation, 77(3): 303–310.

n=50
Follow up = 6 months

While 13 patients showed local recurrence, 37 patients were successfully treated, meaning no local recurrence
within six months after ablation. 18 patients showed signs of prostatitis after IRE. Tumorous changes were visually characterized by dynamic early nodular hypervascularization with fast and high wash-in. Correspondingly, nodular red and yellow shades were seen in parametric imaging. All patients with remaining tumor were correctly identified with CEUS and parametric imaging. After IRE there is a relevant decrease in tumor microcirculation in all patients, as seen in more purple shades of the prostate. The sensitivity for detecting residual tumor with CEUS compared to MRI was 76%, the specificity was 81%.The corresponding positive predictive value (PPV) was 73% and the negative predictive value (NPV) was 83%.

Study focuses on imaging outcomes.

Kayano PP, Klotz L (2021) Current evidence for focal therapy and partial gland ablation for organ-confined prostate cancer: systematic review of literature published in the last 2 years. Current Opinion in Urology, 31(1): 49–57.

Systematic review
n= 30 studies

Focal therapy and partial gland ablation for organ-confined prostate cancer is an option for patients with intermediate-risk disease because of its low complication profile and preservation of QOL. Trials comparing the outcome of different focal therapy technologies have not been carried out, and the existing evidence does not point to one approach being clearly superior to others. Long-term oncologic outcome is lacking.

All included IRE studies in Table 2 or appendix.

Morozov A, Taratkin M, Barret E et al. (2020) A systematic review of irreversible electroporation in localised prostate cancer treatment. Andrologia, 52(10): e13789.

Systematic review
n= 433 (10 studies)

In-field recurrence rate was 0%–39% and out-field 6.4%–24%. In all studies, PSA level decreased: twice lower than baseline after 4 weeks and by 76% after 2 years. Most of the authors noted sexual and urinary toxicity during the first half year after surgery. However, functional outcomes recovered to baseline
after 6 months with mild decrease in sexual function. Complication rates after irreversible electroporation were 0%–1% of Clavien–Dindo III and 5%–20% of Clavien–
Dindo I–II. Irreversible electroporation has promise oncological outcomes, rate of post-operative complications and minimal-to-no effects on erectile and urinary function. However, medium and long-term data on cancer-specific and recurrence-free survival are still lacking.

All studies already included in Table 2 or appendix.

Murray KS, Ehdaie B, Musser J et al. (2016) Pilot Study to Assess Safety and Clinical Outcomes of Irreversible Electroporation for Partial Gland Ablation in Men with Prostate Cancer. The Journal of Urology, 196(3): 883–890.

n=25
Follow up = median 10.9 months

Grade 3 complications occurred in 2 patients including epididymitis (1) and urinary tract infection (1). Fourteen patients experienced grade ≤ 2 complications, mainly transient urinary symptoms, hematuria, and urinary tract infections. Of 25 patients, 4 (16%) had cancer in the zone of ablation on routine follow up biopsy at 6 months. Of those with normal urinary function at baseline, 88% and 94% reported normal urinary function at 6 and 12 months after prostate gland ablation, respectively. By 12 months, only 1 patient with normal erectile function at baseline reported new difficulty with potency and only 2 patients (8%) required a pad for urinary incontinence. Prostate gland ablation with irreversible electroporation is feasible and safe in selected men with localised prostate cancer. Intermediate-term urinary and erectile function outcomes appear reasonable. Irreversible electroporation is effective in ablation of tumor-bearing prostate tissue, as a majority of men had no evidence of residual cancer on biopsy 6 months after prostate gland ablation.

Larger studies included.

Niessen C, Jung EM, Beyer L et al. (2015) Percutaneous irreversible electroporation (IRE) of prostate cancer: Contrast-enhanced ultrasound (CEUS) findings. Clinical Hemorheology and Microcirculation, 61(2): 135–141.

n=13
Follow up = 6 months

EUS images showed significantly reduced microcirculation of the lesions (mean 0.9 ± 0.6 cm (0.5–1.5 cm) after IRE. Microcirculation was reduced from 2.15 ± 0.56 prior to ablation to 0.65 ± 0.63 (p < 0.001) immediately after the ablation and to 0.27 ± 0.44 one day after IRE (p < 0.001).

Study focuses on imaging outcomes.

Scheltema MJ, Postema AW, de Bruin DM et al. (2017) Irreversible electroporation for the treatment of localised prostate cancer: a summary of imaging findings and treatment feedback. Diagnostic and Interventional Radiology (Ankara, Turkey), 23(5): 365–370.

n=32
Follow up = 1-12 months

The mean AZV on T2-weighted imaging 4 weeks following IRE was 12.9 cm3 (standard deviation [SD]=7.0), 5.3 times larger than the planned AZV. Linear regression showed a positive correlation (r=0.76, P = 0.002). For CEUS the mean AZV was 20.7 cm3 (SD=8.7), 8.5 times larger than the planned AZV with a strong positive correlation (r=0.93, P = 0.001). Prostate volume is reduced over time (mean= -27.5%, SD=11.9%) due to ablation zone fibrosis and deformation, illustrated by 3D reconstruction.

Study focuses on imaging outcomes.

Scheltema MJ, van den Bos W, Siriwardana AR et al. (2017) Feasibility and safety of focal irreversible electroporation as salvage treatment for localised radio-recurrent prostate cancer. BJU International, 120: 51–58.

n=18
Follow up = median 21 months

No high-grade adverse events (CTCAE >2) or recto-urethral fistulae occurred. No statistically significant declines were observed in QoL outcomes (n = 11) on the EPIC bowel domain (P = 0.29), AUA symptom score (P = 0.77), or the SF-12 physical (P =0.17) or SF-12 mental component summary (P = 0.77)
questionnaires. At 6 months, patients who had undergone
salvage therapy experienced a decline in EPIC sexual domain
score (median of 38–24; P = 0.028) and urinary domain
(median of 96–92; P = 0.074). Pad-free continence and
erections sufficient for intercourse were preserved in 8/11
patients and 2/6 patients at 6 months, respectively. The
mpMRI was clear in 11/13 patients, with two single out-field
lesions (true-positive and false-positive, respectively). The
median (interquartile range) nadir PSA was 0.39 (0.04–
0.43) lg/L. Three and four patients experienced biochemical
failure using the Phoenix and Stuttgart definitions of
biochemical failure, respectively. Eight out of 10 of the
patients were clear of any PCa on follow up biopsy, whereas
two patients had significant PCa on follow up biopsy
(International Society of Urological Pathology grade 5).

Larger studies included.

Valerio M, Stricker PD, Ahmed HU et al. (2014) Initial assessment of safety and clinical feasibility of irreversible electroporation in the focal treatment of prostate cancer. Prostate Cancer and Prostatic Diseases, 17(4): 343–347.

n=34
Follow up = median 6 months

After a median follow up of 6 months (range 1-24), 12 grade 1 and 10 grade 2 complications occurred. No patient had grade >/= 3 complication. From a functional point of view, 100% (24/24) patients were continent and potency was preserved in 95% (19/20) men potent before treatment. The volume of ablation was a median 12ml (IQR= 5.6 - 14.5ml) with the median PSA after 6 months of 3.4ng/ml (IQR= 1.9 - 4.8ng/ml). MpMRI showed suspicious residual disease in six patients, of whom four (17%) underwent another form of local treatment.

More recent studies included.

Valerio M, Dickinson L, Ali A et al. (2017) Nanoknife Electroporation Ablation Trial: A Prospective Development Study Investigating Focal Irreversible Electroporation for Localised Prostate Cancer. The Journal of Urology, 197(3pt1): 647–654.

n=19
Follow up = 12 months

Of the patients 16 were available for estimating the first outcome as 1 was lost to follow up and 2 had received another form of treatment by study end. All 16 men had pad-free/leak-free continence at 12 months. The proportion of men with erection sufficient for penetration decreased from 12 of 16 (75%) to 11 of 16 (69%). No serious adverse events were recorded. There was a statistically significant improvement in urinary symptoms according to changes in UCLA-EPIC (UCLA Expanded Prostate Cancer Index Composite) and I-PSS (International Prostate Symptom Score) (p = 0.039 and 0.001, respectively). Erectile function remained stable according to the change in IIEF-15 (15-Item International Index of Erectile Function) (p = 0.572). Median prostate specific antigen significantly decreased to 1.71 ng/ml (p = 0.001). One man refused followup biopsy. No residual disease was found in 11 patients (61.1%). One man (5.6%) harbored clinically insignificant disease and the remaining 6 (33.3%) harbored clinically significant disease.

Larger studies included.

van den Bos W, de Bruin DM, van Randen A et al. (2016) MRI and contrast-enhanced ultrasound imaging for evaluation of focal irreversible electroporation treatment: results from a phase I-II study in patients undergoing IRE followed by radical prostatectomy. European Radiology, 26(7): 2252–2260.

n=16
Follow up = 4 weeks

Evaluation of the imaging demonstrated that with T2-
weighted MRI, dynamic contrast enhanced (DCE) MRI, and
CEUS, effects of IRE are visible. T2MRI and CEUS closely
match the volumes on histopathology (Pearson correlation r=
0.88 resp. 0.80). However, IRE is not visible with TRUS.

Study focuses on imaging outcomes.

Walker NA, Norris JM, Shah TT et al. (2018) A comparison of time taken to return to baseline erectile function following focal and whole gland ablative therapies for localised prostate cancer: A systematic review. Urologic Oncology: Seminars and Original Investigations, 36(2): 67–76.

Systematic review
n=17 studies

WG cryotherapy was associated with a significant decline in EF at 6 months with minimal improvement at 36 months. Baseline IIEF-15 of patients undergoing focal HIFU fell 30 points at 1 month but returned to baseline by 6 months. The remaining focal therapies demonstrated minimal or no effect on EF, but the men in these studies had small foci of disease. The review is limited by lack of randomised studies and heterogenous outcome measures.

All included IRE studies in Table 2 or appendix.