Interventional procedure overview of irreversible electroporation for treating prostate cancer
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Summary of key evidence on irreversible electroporation for treating prostate cancer
Study 1 Guo (2021)
Study type | Systematic review and meta-analysis |
|---|---|
Country | Australia, UK, Netherlands, Switzerland, USA, Germany, Russia, Romania, Slovenia, Italy, Turkey, China, France, Canada, Brazil, Israel, Sweden, Singapore, Belgium, Japan |
Recruitment period | 2001 to 2019 |
Study population and number | n=7,383 patients with prostate cancer across 56 studies (22 studies including 2870 patients on cryoablation, 19 studies including 3012 patients on high intensity focused ultrasound (HIFU), 8 studies including 768 patients on IRE and 7 studies including 733 patients on VTP). |
Age and sex | IRE median age across all studies: 63 to 68 years |
Patient selection criteria | Inclusion criteria: Randomised controlled trials (RCTs), prospective case series, and retrospective case series; use of CA, HIFU, IRE or VTP in a total or subtotal manner (focal, quadrant, hemi-ablation, etc.); (3) patients with biopsy-proved prostate cancer; outcomes including positive biopsy after procedure, biochemical recurrence-free survival, cancer-specific survival, overall survival, failure-free survival, metastasis-free survival; English language studies. Exclusion criteria: Duplicate studies, case reports, studies with fewer than 5 patients, conference abstracts, studies performed in salvage treatment setting. |
Technique | Patients underwent either CA, HIFU, IRE, or VTP for treatment of prostate cancer. |
Follow up | CA: median follow up 12 to 101.5 months HIFU: median follow up 6 to 127.5 months IRE: median follow up 6 to 72 months VTP: median follow up 6 to 48 months |
Conflict of interest/source of funding | No conflicts of interest reported. Study funded by Scientific Research Starting Foundation for PhD/MD (Grant BJ-2019-135) and Scientific Research Foundation for Central Health Care (Grant 2020YB10). |
Analysis
Study design issues: The systematic review was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two independent reviewers did a literature search of PubMed, EMBASE, and the Cochrane Library to identify studies; disagreements were resolved through discussion.
Clinical efficacy was assessed through biochemical recurrence-free survival, cancer-specific survival, overall survival, failure-free survival, and metastasis-free survival. A random effects model was used to do a proportional meta-analysis, and statistically significant heterogeneity was assumed when I2>50% and p value<0.1.
Funnel plots were constructed for each meta-analysis to detect publication bias, and Egger's test was used to assess publication bias statistically. A p value was regarded as statistically significant when less than 0.05. All analyses were done using STATA (version 14). The meta-analyses done in this study did not specify a time period for each outcome and included studies with differing lengths of follow up.
Other issues: Overlap with other Table 2 studies; Guenther (2019), Blazevski (2020), van den Bos (2018), Scheltema (2018b) and Blazevski (2021).
Most patients included in this study had procedures other than IRE.
Key efficacy findings
Number of patients included: 7,383 (CA: n=2870 across 22 studies, HIFU: n=3012 across 19 studies, IRE: n=768 across 8 studies, VTP: n=733 across 7 studies)
Proportion of positive biopsy following procedure
CA (median follow up 12 to 101.5 months): 20% (95% CI 12 to 28%; 12 studies, n=1476; I2 = 88.8%, p=0.000)
HIFU (median follow up 6 to 127.5 months): 20% (95% CI 12 to 28%; 17 studies, n=2010; I2 = 90.8%, p=0.000)
IRE (median follow up 7 to 20 months): 24% (95% CI 18 to 31%; 5 studies, n=193; I2 = 0%, p=0.734)
VTP (median follow up 6 to 48 months): 36% (95% CI 29 to 44%; 7 studies, n=733; I2 = 77%, p=0.000)
Cancer-specific survival
CA (median follow up 44.4 to 101.5 months): 96% (95% CI 92 to 101%; 4 studies, n=274; I2 = 83.7%, p=0.000)
HIFU (median follow up 39 to 127.5 months): 98% (95% CI 97 to 100%; 4 studies, n=1867; I2 = 70.3%, p=0.018)
IRE (median follow up 6 to 7 months): 98% (95% CI 94 to 102%; 2 studies, n=48; I2 = 0%, p=0.966)
Overall survival
CA (median follow up 44.4 to 101.5 months): 93% (95% CI 86 to 99%; 4 studies, n=274; I2 = 89.9%, p=0.000)
HIFU (median follow up 39 to 127.5 months): 85% (95% CI 78 to 92%; 4 studies, n=1867; I2 = 89.7%, p=0.000)
IRE (median follow up 6 to 36 months): 99% (95% CI 98 to 101%; 3 studies, n=171; I2 = 0%, p=0.736)
Failure-free survival
CA (median follow up 58.5 to 63 months): 65% (95% CI 15 to 115%; 2 studies, n=95; I2 = 97.5%, p=0.000)
IRE (median follow up 6 to 72 months): 90% (95% CI 83 to 98%; 3 studies, n=575; I2 = 87.8%, p=0.000)
VTP (median follow up 6 to 48 months): 90% (95% CI 83 to 115%; 3 studies, n=374; I2 = 80.6%, p=0.006)
Metastasis-free survival
HIFU (median follow up 39 to 76.8 months): 95% (95% CI 93 to 98%; 3 studies, n=1855; I2 = 80.1%, p=0.007)
IRE (median follow up 6 to 36 months): 99% (95% CI 98 to 101%; 2 studies, n=146; I2 = 0%, p=0.665)
Key safety findings
No safety outcomes reported.
Study 2 Guenther (2019)
Study type | Case series |
|---|---|
Country | Germany |
Recruitment period | 2011 to 2016 |
Study population and number | n=429 patients with prostate cancer (471 IRE treatments) |
Age and sex | Mean age 64±8 years |
Patient selection criteria | Inclusion criteria: Patients with prostate cancer (all stages) who would potentially benefit from IRE-treatment of their PCa and who refused all types of standard therapy Exclusion criteria: Patients not well enough for total intravenous anaesthesia; patients with defibrillators. |
Technique | IRE electrodes (AngioDynamics Inc., USA) were manually inserted through the perineum under ultrasound guidance without a brachytherapy grid. The IRE-field was planned in a way that it exceeded the macroscopic tumour extent by at least 8mm towards the centre of the prostate. Towards the capsule the electrodes were, whenever possible, placed within a couple millimetres inside the prostatic capsule. All treatments were carried out with the NanoKnife (AngioDynamics Inc., USA). |
Follow up | 4 months to 6 years |
Conflict of interest/source of funding | None |
Analysis
Follow up issues: Follow up MRI and PSA scores had a median time till last follow up data-point of 12 months. High rate of loss to follow up; of 429 patients that had IRE, 20% (44/429) of patients were lost to follow up after 6 months and 60% were lost to follow up after 12 months.
Routine follow up comprised PSA-tests and MRI scans. PSA-testing was recommended every 3 months in the first 2 years, then every 6 months and MRI was recommended after 1 day, at 3, 6, 12 months after IRE, then annually.
Study design issues: Retrospective case series. Biochemical recurrences were defined by a rise in PSA above the baseline value at 3 months after IRE with confirmation by multi-parametric MRI, and in some cases by additional biopsy or prostate specific membrane antigen PET or X-ray CT scans. All data was discussed by a board of urologists or oncologists and radiologists who had at least 10 years of experience in the field. Kaplan–Meier curves and analysis of oncological outcome was done with Prism GraphPad 5.
Urinary continence was primarily assessed by interviewing the patients concerning any involuntary loss of urine related to the IRE-treatment and the different forms of incontinence (such as stress, urge, overflow-incontinence).
ED was evaluated by 2 methods; standard IIEF-5 score before and after IRE (ranging from 5 to 25 where 25 represents no ED and 5 represents the most severe ED) and additional evaluation algorithm in which patients were asked whether they 1) had experienced any negative change in erectile function related to IRE and 2) were unable to have satisfactory intercourse and no spontaneous nocturnal erection. Patients in whom both statements were true were classified as having an IRE-related significant ED.
Study population issues: 123 out of 471 treatments (26.1%) were uni-lobar or focal (<50% volume ablation), 153 out of 471 (32.5%) were bi-lobar but did not involve the whole gland (50% to 90% volume ablation), and 134 out of 471 (28.5%) involved the whole gland (>90%). In 63 out of 471 (13.3%) patients treatment extent either could not be determined or patients were having treatment for recurrent disease.
According to the D'Amico Risk Classification, 312 out of 429 (66%) patients were high risk, 88 out of 429 (19%) were intermediate risk, and 25 out of 429 (5%) were low risk. In 4 patients D'Amico risk classification was impossible because of lack of biopsy. According to Gleason score cancer grading (with 6 as low grade, 7 as intermediate grade, 8 to 10 as high-grade cancer) 82 out of 429 patients had a Gleason score of 6, 225 out of 429 with a Gleason score of 7, and 113 out of 429 patients had a Gleason score of >7 (with no Gleason score available for 9 patients because of refusal of biopsy). Mean PSA at baseline across all patients was 10±250 nanograms/ml.
Other issues: Study also included in Guo 2021 systematic review.
Key efficacy findings
Number of patients analysed: 429 (471 treatments)
Recurrence (Kaplan–Meier analysis)
Clinical severity at baseline | Number of recurrences at 72 months (n=471 treatments) | Estimated % recurrence free survival at 72 months | Estimated % recurrence rate at 5 years (95% CI) |
|---|---|---|---|
Gleason 6 (low grade) | 3 | 94 | 5.6 (1.8 to 16.93) |
Gleason 7 (intermediate grade) | 18 | 85 | 14.6 (8.8 to 23.7) |
Gleason >7 (high grade) | 26 | 60 | 39.5 (23.5 to 61.4) |
Recurrence in or adjacent to IRE field (Kaplan–Meier analysis):
Clinical severity at baseline | Number of recurrences at 72 months (n=471 treatments) | Estimated % recurrence free survival |
|---|---|---|
Gleason 6 (low grade) | 1 | 98 (64 months) |
Gleason 7 (intermediate grade) | 10 | 93 (72 months) |
Gleason >7 (high grade) | 16 | 75 (72 months) |
Key safety findings
Rate of adverse events
Adverse events | % of treatments (n=471) |
All mild events | 19.7 (93/471) |
Mild haematuria | 3.8 (18/471) |
Transient urinary retention | 9.1 (43/471) |
Dysuria | 6.8 (32/471) |
All moderate events | 3.8* (18/471) |
Prostatitis | 0.2 (1/471) |
Proctitis (uncertain genesis) | 0.2 (1/471) |
0.6 (3/471) | |
0.2 (1/471) | |
Urinary tract infection | 2.5 (12/471) |
All severe or medically significant events | 1.5* (7/471) |
Permanent urinary retention | 0.8 (4/471) |
0.2 (1/471) | |
Bladder perforation by catheter | 0.2 (1/471) |
Severe prostatitis | 0.2 (1/471) |
*: Correction of rounding errors in paper
Sexual dysfunction
Clinical outcome (n=124) | |
|---|---|
Mean point reduction of IIEF-5 score by neurovascular bundle (NVB) involvement 12 months post IRE | None: -1.6 Left or right: -6.4 Both: -10.5 |
Mean point reduction in IIEF5 score by prostate ablation volume | <50%: -5.3 (-17.7%) 50-90%: -7.7 >90%: -11.1 (-37%) |
Mean points reduction of IIEF5 score before and after 18 months post IRE | <18 months: -8.7 >18 months: -3.9 P value for significance = (0.045) |
Subjective assessment of ED 12 months post IRE | Reduction of erectile function: 45% (56/124) Transient severe ED (resolved within 12 months):11.4% (14/124) Persistent severe ED (>12 months): 3% (4/124) |
Urinary incontinence
IPSS score analysis revealed that in 7.7% (12/155) of the evaluated patients scores increased temporarily from below 8 to above 19 (severe symptoms) after IRE.
In patients fully continent before IRE, no urinary incontinence was seen 12 months after IRE or later during the observation period. In terms of urinary symptoms, 72.8% of evaluated patients reported no change or an improvement in quality of life and 27.2% reported a decrease.
Study 3 Blazevski (2020)
Study type | Case series |
|---|---|
Country | Australia |
Recruitment period | 2013 to 2018 |
Study population and number | n=123 patients with localised apical prostate cancer |
Age and sex | Median age 68 years (IQR 62 to 73 years) |
Patient selection criteria | Inclusion criteria: Low (high-volume > 4 mm) to intermediate risk PCa according to D'Amico criteria; Gleason score ≤ 7 (ISUP ≤ 3); unilateral or midline anterior/posterior index tumour, allowing single targeted ablative therapy; PSA ≤ 15 ng/ml; life expectancy ≥ 10 years; no previous treatment for PCa; no previous androgen suppression treatment for PCa; minimum 12-month follow up; multiple lesions which can be encompassed in one treatment Exclusion criteria: Bilateral significant disease; metastatic disease; multiple lesions that cannot be treated within one treatment field |
Technique | All patients underwent standardised focal irreversible electroporation (IRE) procedure performed by a single urologist using Nanoknife device (Angiodynamics, Inc., Queensbury, New York). All patients underwent a general anaesthetic with full muscle paralysis and also received IV antibiotics at induction. Safety margins of 5 or 10 mm from the targeted area were used to adjust for MRI volume underestimation. The number of electrodes placed was dependent on the size and location of the lesion. |
Follow up | Median follow up 36 months (IQR 24-52 months) |
Conflict of interest/source of funding | One author reports receiving consultant fees from Angiodynamics and proctor fees for training surgeons in IRE. Funded by Australian Commonwealth Department of Health and Ageing and the St.Vincent's Prostate Cancer Centre |
Analysis
Follow up issues: All patients were followed up for a minimum of 12 months. Serial PSA levels were measured every 3 months for at least 2 years. Follow up multiparametric MRI was performed at 6 months and follow up (TTMB with additional targeted biopsies of the ablation zone and margins was performed at 12 months. Functional and QoL data were prospectively collected from patients who provided consent using the EPIC and the SF-12 questionnaires completed at baseline, at 6 weeks postoperatively, and 3, 6, 12, and 24 months postoperatively.
Study design issues: Single-centre retrospective analysis of predefined and prospectively collected data.
Significant PCa on follow-up biopsy was defined as Gleason score 3+ 4. A significant positive biopsy found within the targeted area was deemed in-field treatment failure and any found outside the target zone was designated as out-of-field failure. Initial analysis was done for the entire cohort, and then for patients after the treatment margin was increased and technical skills improved.
Failure-free survival was defined as progression to whole-gland or systemic treatment or metastasis or death and reported 3 years after initial treatment and was stratified for both the ISUP subgroup and the National Comprehensive Cancer Network risk category. Metastasis-free survival and overall survival were calculated at 1, 3, and 5 years after IRE.
Adverse events were recorded using the Clavien-Dindo classification (grouped 1 to 5, with 5 being the most severe).
Study population issues: According to the D'Amico Risk Classification, 11 out of 123 (%) patients were low risk, and 112 out of 123 (%) were intermediate risk. A total of 12 (9.8%) had (ISUP) grade 1, 88 (71.5%) had ISUP 2, and 23 (18.7%) had ISUP 3 (measured grades 1 to 5 with ISUP 5 being the most severe). Mean PSA at baseline across all patients was 5.7 nanograms/ml (IQR 3.8 to 8 nanograms/ml).
Other issues: The authors did analysis with all 123 patients and with exclusion of the first 32 patients to account for increased treatment margin to 10 mm and improved technique. Study also included in Guo (2021) systematic review and possible overlap with Blazevski (2021) which focuses solely on patients with apical prostate cancer.
Key efficacy findings
PSA and MRI outcomes
Outcome | All patients (n=123 for PSA, n=112 for MRI outcomes) | Excluding initial cohort (n=91 for PSA, n=80 for MRI outcomes) |
Median PSA at 12-month follow up | 2.5 nanograms/ml (IQR 1.43 to 5.675) | – |
Median PSA nadir (IQR) | 3.48 nanograms/ml (1.43 to 5.67) (n=123) | 3.37 (1.04 to 5.7) (n=91) |
MRI at 6 months – clear % | 80 (90/112) | 87.5 |
MRI at 6 months – in field lesion % | 2.6 (3/112) | 1.25 (1/80) |
MRI at 6 months – Adjacent-to-field lesion % | 5.4 (6/112) | 3.75 (1/80) |
MRI at 6 months – out-of-field lesion | 9.8 (11/112) | 7.5 (6/80) |
MRI at 6 months – both in and out-of-field lesion | 5.4 (6/112) | 0 |
Biopsy outcomes
Outcome | % of all patients (n=102) | % of patients excluding initial cohort (n=74) |
Significant in-field disease at 12 months | 9.8 (10/102) | 2.7 (2/74) |
Significant out-of-field disease at 12 months | 12.7 (13/102) | 12.1 (9/74) |
Whole gland free of clinically significant cancer at 12 months (%) | 77.5 (79/102) | 85.1 (63/74) |
Survival outcomes
Failure-free survival (estimated): 96.75%
Metastasis-free survival: 98.5% (68/69) at 3-year follow up
Overall survival: 100% (69/69) at 3-year follow up
Key safety findings
Rate of adverse events
Clavien-Dindo classification | Complications listed* | % incidence (n=123) |
Perineal pain, haematuria, dysuria, urgency frequency, | 22 (27/123) | |
2 | Urinary tract infection, incontinence, acute urinary retention | 9 (11/123) |
*Rates for each individual complication are not reported
Study 4 Scheltema (2018)
Study type | Non-randomised comparative study |
|---|---|
Country | Australia |
Recruitment period | 2013 to 2016 |
Study population and number | n=100 patients with prostate cancer (50 IRE versus 50 robot-assisted radical prostatectomy (RARP)) |
Age and sex | IRE: median age 67 years (IQR 62 to 73 years) RARP: median age 67 years (IQR 64 to 71 years) |
Patient selection criteria | Patients receiving single ablative IRE or nerve-sparing robot-assisted radical prostatectomy (RARP); clinical stage T1c-T2b; low to intermediate-risk PCa (ISUP 1 to 3); written informed consent for QoL evaluation, minimum of 6 months follow up. |
Technique | IRE was done by a single surgeon and was executed following the methods as described by Ting et al. (2016). A transurethral indwelling catheter was placed to drain the bladder before treatment. RARP was done by a single-surgeon (PS) employing the techniques described by Patel et al. and executed using the Da-Vinci Xi surgical system with 6 access ports (Intuitive Surgical Sunnyvale®, CA, USA). |
Follow up | 12 months |
One author reports receiving consulting fees from AngioDynamics. Funded by the Australian Commonwealth Department of Health and Ageing and the St Vincent's Prostate Cancer Centre. |
Analysis
Follow-up issues: 88% (44/50) IRE patients had follow-up biopsies, 10% (5/50) refused and 1 patient was still awaiting biopsy at the time of analysis. Patient reported QoL data was also collected at baseline, 1.5, 3, 6, and 12 months after procedure. At 1.5, 3, 6, and 12 months, the response rate for questionnaires was 93%, 97%, 94% and 71% of the 100 patients, respectively.
Study design issues: Retrospective analysis of prospectively collected data (single centre). IRE patients were matched 1:1 to RARP patients using propensity score matching.
Rates of urinary continence (defined as pad-free continence) and ESI were compared between IRE and RARP up to 12 months. Oncological failure rates for IRE were defined by positive follow-up biopsies at 12 months with significant PCa (high-volume ISUP 1 or any 2 or 3). For RARP, this was defined as biochemical failure (PSA≥0.2 micrograms/litre) or the need for adjuvant radiotherapy within 12 months. Early surgical complications were classified as specified by the Clavien–Dindo classification (ranging from 1 to 5, with 5 being the most severe).
Study population issues: No statistically significant differences between the matched IRE and RARP populations. In the IRE group, 8 out of 50 patients (16%) had ISUP grade 1 biopsy, 33 out of 50 (66%) had ISUP grade 2 biopsy and 9 out of 50 (18%) had ISUP grade 3 biopsy. In the RARP group, 9 out of 50 patients (18%) had ISUP grade 1 biopsy, 31 out of 50 (62%) had ISUP grade 2 biopsy and 10 out of 50 (20%) had ISUP grade 3 biopsy. Median PSA was 5.9 micrograms/litre (IQR 3.3 to 7.3) for the IRE group and 6.3 micrograms/litre (IQR 4.3 to 7.7) for the RARP group.
Other issues: Study is also included in Guo (2021) systematic review.
Key efficacy findings
Number of patients analysed: 100 (50 IRE versus 50 RARP)
Oncological outcomes
Of the IRE patients who had biopsies at 12 months, 13 out of 44 (29.5%) had residual PCa. One patient was diagnosed with metastatic disease directly after IRE because of persisting elevated PSA (>10 nanograms/ml).
Median PSA after IRE: 2.8 nanograms/ml (IQR 0.9 to 4.5) – reduction of 51% (IQR 28% to 85%).
None of the RARP patients experienced biochemical failure (PSA ≥0.2 nanograms/mL) within the first 12 months of follow up.
IRE was superior to RARP in preserving ESI during the first 12 months of follow up. The absolute risk reduction to develop erectile dysfunction was 32%, 46%, 27% and 22% at 1.5, 3, 6, and 12 months, respectively.
Key safety findings
Rate of complications
Pad free continence
Follow up | Pad free continence % IRE (all) | Pad free continence % RARP (all) | Pad free continence % IRE (continent at baseline) | Pad free continence % RARP (continent at baseline) |
Baseline (n=100) | 98 | 98 | 100 | 100 |
6 weeks (n=93) | 87 | 44 | 89 | 45 |
3 months (n=97) | 96 | 75 | 98 | 77 |
6 months (n=94) | 98 | 85 | 100 | 87 |
12 months (n=71) | 96 | 84 | 100 | 86 |
IRE was superior to RARP in preserving pad-free UC during the first 12 months of follow up (p<0.01); The absolute risk reduction was 44%, 21%, 13% and 14% at 1.5, 3, 6, and 12 months, respectively.
ESI rate
Follow up | IRE ESI % (all) | RARP ESI % (all) | IRE ESI % (potent at baseline) | RARP % (potent at baseline) |
Baseline (n=100) | 69 | 68 | 100 | 100 |
6 weeks (n=93) | 40 | 20 | 57 | 25 |
3 months (n=97) | 54 | 22 | 74 | 28 |
6 months (n=94) | 49 | 28 | 65 | 38 |
12 months (n=71) | 56 | 36 | 72 | 50 |
Study 5 van den Bos (2018)
Study type | Case series |
|---|---|
Country | Australia |
Recruitment period | 2013 to 2016 |
Study population and number | n=63 patients with organ confined prostate cancer |
Age and sex | Median age 67 years (range 61 to 71 years) |
Patient selection criteria | Inclusion criteria: Low to intermediate-risk PCa according to D'Amico criteria; Gleason score ≤7 (ISUP Grade ≤3); Unilateral or single midline anterior/posterior index tumour, allowing single targeted ablative therapy; Life expectancy ≥10 years. Exclusion criteria: No previous treatment for PCa; No previous androgen suppression/hormone treatment for PCa; follow up of less than 6 months. |
Technique | All IRE procedures were done by a single urologist using an IRE device and 18-gauge electrodes (Nanoknife, AngioDynamics, Queensbury, NY, USA). All patients were given general anaesthesia with full-muscle paralysis and had prophylactic IV antibiotics at induction. An indwelling catheter was placed for urinary drainage. Safety margins of 5 or 10 mm from the targeted area were used to adjust for MRI lesion volume underestimation. The safety margin was increased to 10 mm after the first 10 cases. The number and active tip length of the electrodes was dependent on the size of the targeted lesion. |
Follow up | 6 to 24 months (outcomes reported up to 12 months) |
Conflict of interest/source of funding | No conflicts of interest reported. Funded by the Australian Commonwealth Department of Health and Ageing and the St Vincent's Prostate Cancer Centre. |
Analysis
Follow-up issues: Not all patients consented to have QoL evaluation during follow up (27% refused). 55/63 (87%) of primary patients had 6-month follow up with multiparametric MRI.45 out of 63 patients (71%) had had follow-up biopsy at the time of analysis, 3 refused follow-up biopsies and 15 patients were awaiting TTMB. Quality of life questionnaires were also completed at baseline, 6 weeks, and 3, 6 and 12 months postoperatively.
Study design issues: Retrospective single centre analysis. The QoL and functional data were prospectively collected from all patients who provided consent using the EPIC, including urinary, sexual and bowel domains and the AUA symptom score (scored 0 to 35 where higher scores indicate increased severity). The SF-12 health survey physical component summary and mental component summary scores were used to assess overall health status.
Significant PCa on follow-up biopsy included high-volume Gleason sum score 6 (ISUP grade 1) with a core involvement of >5 mm/>50% maximum core volume or any core involvement with Gleason sum score of 7 to 10 (ISUP grades 2 to 5). A significant positive biopsy found within the targeted treatment area (or adjacent to the treatment area) was determined as in-field treatment failure and any found outside the target zone was designated as out-of-field treatment failure.
Wilcoxon's signed rank test and Wilcoxon's rank sum test (both 2-tailed) were used to assess statistically significant differences in paired continuous variables (all questionnaire outcomes at baseline and 6 months) and unpaired continuous variables (age, PSA, prostate volume, number of positive cores, biopsy ISUP grade, peri-operative treatment variables), respectively. p values <0.05 were taken to indicate statistical significance.
All AEs were recorded using the National Cancer Institute CTCAE version 4.0, graded 1 to 5, with 5 being the most severe.
Study population issues: According to D'Amico risk classification, 12.7% (8/63) of patients were low risk and 87.3% (55/63) were intermediate risk. Gleason scores were 3+3 (or ISUP Grade 1) for 9 out of 63 (14.2%) patients, 3+4 (ISUP Grade 2) for 38 out of 63 patients (60.3%), and 4+3 (ISUP grade 3) for 16 out of 63 patients (25.4%). Median serum PSA was 6 nanograms/ml (IQR 3.2 to 8.4).
Other issues: The safety margin was increased to 10 mm after the first 10 cases included in this analysis. Study also included in Guo (2021) systematic review.
Key efficacy findings
Number of patients analysed: 63
Outcome | |
Median (IQR) 6–12-month PSA (n=63) | 1.8 (0.96-4.8) |
MRI results at 6 months- Clear % (n=55) | 85.5 (47/55) |
MRI results at 6 months- In-field lesions % (n=55) | 7.3 (4/55) |
MRI results at 6 months- Out-of-field lesions % (n=55) | 3.6 (2/55) |
MRI results at 6 months- In- and out-of-field lesions % (n=55) | 3.6 (2/55) |
Biopsy outcome at 6-12 months (n=45) | |
Significant in-field disease, all patients, % (n=45) | 15.6 (7/45) |
Significant in-field disease, 5-mm safety margin, % (n=10) | 40 (4/10) |
Significant in-field disease, 10-mm safety margin, % (n=35) | 8.6 (3/35) |
Significant out-field disease n (%)* | 9.8 (4/41) |
All significant disease % (n=45) | 24.4 (11/45) |
Gleason score 3 + 3 (ISUP Grade 1), >5 mm/50% core involvement | 0 |
Gleason score 3 + 4 (ISUP Grade 2) | 15.6 (7/45) |
Gleason score 4 + 3 (ISUP Grade 3) | 4.4 (2/45) |
Gleason 4 + 4 (ISUP Grade 4) | 2.2 (1/45) |
Gleason 4 + 5 (ISUP Grade 5) | 0 |
High-grade | 1 (1/45) |
*: Patients who received follow up targeted biopsies were excluded from out-field analysis.
After patients treated with a narrow safety margin and system errors were excluded, in-field disease decreased to 2.6% (1/39) and total disease (in-field and out-field) decreased to 12.8% (34/39).
Quality of life
Questionnaire | Baseline (n=46) | 3 months (n=46 for AUA and EPIC scores, n=45 for SF-12 physical, n=44 for SF-12 mental) | 6 months (n=40 for SF-12 scores, n=42 for all other scores) | 12 months (n=19) | P value for difference between baseline and 6 months | |
Median AUA score (IQR) | 5 (3 to 14) | 7 (3 to 10) | 5(3 to 10) | 4 (2 to 8) | 0.25 | |
Median EPIC urinary function summary score (IQR) | 92 (78 to 98) | 91 (77 to 98) | 93 (83 to 98) | 94 (92 to 98) | 0.41 | |
Median EPIC sexual function summary score (IQR) | 66 (47 to 85) | 50 (27 to 75) | 54 (29 to 72) | 48 (15 to 77) | <0.001 | |
Median EPIC bowel function summary score (IQR) | 96 (93 to 100) | 96 (91 to 100) | 96 (91 to 100) | 96 (93 to 100) | 0.83 | |
Median SF-12 physical component score (IQR) | 56 (51 to 57) | 55(49 to 57) | 55 (49 to 57) | 56 (53 to 57) | 0.81 | |
Median SF-12 mental component score (IQR) | 57 (48 to 58) | 57 (52 to 59) | 56 (47 to 58) | 57 (54 to 59) | 0.48 | |
Key safety findings
Rate of adverse events
Sexual dysfunction
Follow up | Erections sufficient for intercourse % | Impotence % |
Baseline | 70 (31/44) | - |
3 months | 55 (24/44) | - |
6 months | 46 (20/43) | 31 (8/26) |
12 months | 53 (10/19) | 23 (3/13) |
Study 6 Scheltema (2018b)
Study type | Case series |
|---|---|
Country | Australia |
Recruitment period | 2013 to 2016 |
Study population and number | n=60 patients with organ-confined prostate cancer |
Age and sex | Mean age 68±7.0 years |
Patient selection criteria | Patients treated with primary IRE for localised PCa; minimum of 6 months follow up. |
Technique | Single-surgeon IRE was done under general anaesthesia, antibiotic prophylaxis, and deep-muscle relaxation. An indwelling catheter was placed before the procedure. Using the Nanoknife® system (AngioDynamics), 4 to 6 needle electrodes were placed with a with a transperineal approach, encircling the tumour lesion. |
Follow up | 12 months |
Conflict of interest/source of funding | Three authors report receiving grants and one author receives consulting fees from AngioDynamics. Funded by the Australian Prostate Cancer Research Centre-NSW and the St. Vincent's Prostate Cancer Centre. |
Analysis
Follow-up issues: High loss to follow up; data available for 42% (25/60) of patients at 12 months. Genitourinary function and QoL data were prospectively evaluated using questionnaires at baseline, 3, 6, and 12 months.
Study design issues: Retrospective analysis of single centre data. The EPIC (graded 1 to 100 with 100 representing best QoL, AUA) symptom score (scored 0 to 35 with higher scores indicating increased severity of symptoms, SF-12 physical and mental component summary surveys were used to collect data on QoL and genitourinary function.
Differences in genitourinary function and QoL between segments was tested by the analysis of covariance model. In this model, the dependent variable was the measured value at month 6, the independent variable was the treatment group, and the covariate was the measured baseline value. All data were log-transformed before the analysis. Post-hoc comparison between groups was done with the Tukey's honest significant difference test within the R statistical environment. The level of significance was set at p<0.05.
Study population issues: Gleason scores were 6 for 8 out of 60 (13%) patients, 3+4 for 40 out of 63 patients (67%), 4+3 for 10 out of 60 patients (17%) and 4+4 or higher for 2 out of 60 patients (3%). Mean serum PSA was 6±3.3 micrograms/litre
Key efficacy findings
Number of patients analysed: 58
Genitourinary function and QoL – anterior versus posterior
Outcome | Baseline (Anterior: n=18) (Posterior: n=39) | 3 months (Anterior n=17) (Posterior n=39) | 6 months (Anterior n=17) (Posterior n=35) | 12 months (Anterior n=4) (Posterior n=20) | Segment difference Baseline/6 months | Different treatment impact Anterior vs. Posterior |
AUA- Anterior | 6 (3 to 14) | 6 (3 to 11) | 4 (3 to 10) | 4 (2 to 5) | No (P = 0.55) | No (P = 0.97, E = E= -0.05, CI ±2.5) |
AUA-Posterior | 6 (3 to 12) | 7 (3 to 10) | 5 (2 to 11) | 4 (2 to 11) | No (P = 0.19) | - |
EPIC urinary -Anterior | 93 (72 to 98) | 89 (69 to 96) | 94 (79 to 98) | 92 (82 to 97) | No (P = 0.68) | No (P = 0.83, E= -0.71, CI ±6.6) |
EPIC urinary -Posterior | 89 (81 to 98) | 92 (81 to 98) | 92 (83 to 98) | 94 (85 to 98) | No (P = 0.24) | - |
EPIC sexual - Anterior | 60 (25 to 82) | 52 (29 to 71) | 46 (14 to 79) | 27 (2 to 79) | Yes (P = 0.03) | No (P = 0.41, E= -4.1, CI ±9.6) |
EPIC sexual - Posterior | 67 (48 to 81) | 47 (31 to 74) | 49 (29 to 69) | 42 (19 to 76) | Yes (P = 0.008) | - |
EPIC bowel - Anterior | 96 (92 to 100) | 96 (93 to 98) | 96 (91 to 99) | 93 (87 to 99) | No (P = 0.79) | No (P = 0.80, E= 0.51, CI ±3.9) |
EPIC bowel - Posterior | 96 (93 to 98) | 96 (89 to 100) | 96 (89 to 100) | 97 (92 to 100) | No (P = 0.70) | - |
SF-12 physical -Anterior | 55 (44 to 56) | 55 (48 to 56) | 55 (40 to 57) | 57 (43 to 58) | No (P = 0.64) | No (P = 0.74, E= -0.71, CI ±4.1) |
SF-12 physical -Posterior | 56 (52 to 56) | 55 (52 to 57) | 55 (52 to 57) | 55 (52 to 57) | No (P = 0.35) | - |
SF-12 mental -Anterior | 56 (39 to 58) | 56 (50 to 58) | 56 (40 to 60) | 53 (48 to 60) | No (P = 0.80) | No (P = 0.64, E= 1.1, CI ±4.4) |
SF-12 mental -Posterior | 56 (50 to 58) | 57 (53 to 59) | 56 (48 to 58) | 57 (56 to 59) | No (P = 0.45) |
Values reported as median (IQR). E=effect size
Genitourinary function and QoL – apex, base and apex to base
Outcome | Baseline (Apex n=18, Base n=14, Apex-to base n=26) | 3 months (Apex n=17, Base n=14, Apex-to base n=26) | 6 months (Apex n=17, Base n=13, Apex-to base n=24) | 12 months (Apex n=10, Base n=4, Apex-to base n=11) | Segment difference between baseline and 6 months | Difference in treatment impact, apex vs. base | Difference in treatment impact, apex vs. apex-to-base | Difference in treatment impact, base vs. apex-to-base |
AUA-Apex | 3 (2 to 16) | 7 (3 to 10) | 4 (2 to 12) | 4 (2 to 8) | No (P = 0.86) | No (P =0.79, E=0.43, CI±3.1) | No (P =0.28, E= -1.5, CI±2.7 | - |
AUA-Base | 10 (4 to 12) | 10 (4 to 13) | 7 (4 to 14) | 8 (2 to 23) | No (P = 0.89) | - | - | No (P = 0.41, E= 1.9, CI±3.0 |
AUA-Apex-to-Base | 6 (4 to 14) | 6 (3 to 11) | 5 (3 to 10) | 4 (3 to 5) | No (P = 0.19) | - | - | - |
EPIC urinary -Apex | 96 (81 to 98) | 94 (78 to 99) | 96 (77 to 98) | 94 (90 to 96) | No (P = 0.88) | No (P = 0.64, E= 2.0, CI ±8.2) | No (P = 0.34, E= 3.4, CI ±7.0) | - |
EPIC urinary -Base | 87 (78 to 94) | 89 (74 to 96) | 90 (84 to 97) | 85 (70 to 98) | No (P = 0.33) | - | - | No (P = 0.93, E= -1.5, CI±7.8) |
EPIC urinary -Apex-to-Base | 92 (77 to 98) | 89 (72 to 98) | 93 (84 to 98) | 95 (89 to 98) | No (P = 0.23 | - | - | - |
EPIC sexual -Apex | 67 (55 to 90) | 54 (39 to 75) | 53 (41 to 76) | 48 (26 to 87) | Yes (P = 0.008) | No (P = 0.53, E = -3.7,CI±11.6) | No (P = 0.91, E= 0.60, CI ±10.1) | - |
EPIC sexual -Base | 62 (49 to 76) | 51 (36 to 74) | 54 (23 to 73) | 50 (8 to 72) | Yes (P =0.046) | - | - | No (P = 0.72, E= -4.3, CI ±11.0) |
EPIC sexual -Apex-to-Base | 60 (27 to 85) | 42 (18 to 73) | 41 (21 to 69) | 35 (6 to 77) | Yes (P = 0.001) | - | - | - |
EPIC bowel -Apex | 96 (91 to 98) | 96 (94 to 100) | 98 (96 to 100) | 97 (94 to 100) | P = 0.055) | No (P = 0.08, E= -4.3, CI ±4.7) | No (P = 0.11, E= -3.5, CI ±4.1) | |
EPIC bowel -Base | 97 (91 to 100) | 93 (84 to 100) | 93 (85 to 100) | 86 (71 to 100) | No (P = 0.44) | - | - | No (P = 0.93, E= -0.87, CI ±4.6) |
EPIC bowel -Apex-to-Base | 96 (91 to 100) | 96 (91 to 99) | 96 (89 to 98) | 96 (91 to 100) | No (P = 0.44) | - | - | - |
SF-12 physical -Apex | 56 (53 to 56) | 55 (53 to 56) | 56 (53 to 57) | 55 (54 to 57) | No (P = 0.53) | No (P = 0.26, E= -2.9, CI ±5.0) | No (P = 0.63, E= -1.1, CI ±4.3) | - |
SF-12 physical -Base | 56 (52 to 58) | 56 (47 to 57) | 52 (40 to 57) | 47 (44 to 56) | No (P = 0.18) | - | - | No (P = 0.73, E= -1.9, CI ±4.8) |
SF-12 physical -Apex-to-Base | 54 (45 to 57) | 55 (46 to 57) | 56 (42 to 58) | 56 (53 to 58) | No (P = 0.71) | - | - | - |
SF-12 mental --Apex | 56 (52 to 58) | 7 (54 to 58) | 57 (54 to 58) | 58 (57 to 59) | No (P = 0.94) | No (P = 0.94,E= -0.23, CI ±5.6) | No (P = 0.77, E= 0.73, CI ±4.9) | - |
SF-12 mental -Base | 57 (48 to 58) | 56 (44 to 58) | 56 (41 to 57) | 48 (42 to 55) | No (P = 0.66) | - | - | No (P = 0.94, E= -0.96, CI ±5.4) |
SF-12 mental -Apex-to-Base | 57 (44 to 59) | 55/56* (50 to 59) | 54 (45 to 59) | 56 (49 to 60) | No (P = 0.62) | - | - | - |
Data are presented as median (interquartile range). E=effect size.
*value given in study is 556 on a 1-100 scale – presumed error in paper (exact value not known)
Genitourinary function and QoL to bilateral versus unilateral
Unilateral Bilateral | Baseline (n=50) (n=10) | 3 months (n=49) (n=10) | 6 months (n=47) (n=8) | 12 months (n=21) (n=6) | Segment difference baseline/6 months | Different treatment impact Bilateral vs. Unilateral |
AUA | - | - | - | - | - | - |
Unilateral | 6 (3 to 13) | 7 (3 to 11) | 6 (2 to 11) | 4 (2 to 9) | No (P = 0.17) | No (P = 0.75,E= -0.71, CI ±6.6) |
Bilateral | 11 (4 to 13) | 5 (2 to 12) | 4 (3 to 14) | 5 (4 to 13) | No (P = 0.25) | - |
EPIC urinary | - | - | - | - | - | - |
Unilateral | 92 (80 to 98) | 91 (77 to 98) | 93 (81 to 98) | 94 (92 to 98) | No (P = 0.46) | No (P = 0.084, E= 7.4, CI ±8.3) |
Bilateral | 84 (76 to 95) | 88 (70 to 94) | 95 (90 to 99) | 88 (79 to 94) | No (P = 0.068) | - |
EPIC sexual | - | - | - | - | - | - |
Unilateral | 62 (45 to 79) | 47 (31 to 72) | 43 (26 to 69) | 38 (15 to 77) | Yes (P < 0.001) | No (P = 0.54, |
Bilateral | 83 (63 to 90) | 41 (21 to 76) | 63 (37 to 84) | 59 (28 to 77) | No (P = 0.16) | E= 3.8, CI ±12.0) |
EPIC bowel | - | - | - | - | - | - |
Unilateral | 96 (93 to 98) | 96 (91 to 100) | 96 (91 to 100) | 98 (93 to 100) | No (P = 0.67) | No (P = 0.62, E= -1.3, CI ±5.1) |
Bilateral | 95 (89 to 96) | 96 (90 to 98) | 93 (86 to 96) | 93 (82 to 97) | No (P = 0.31) | - |
SF-12 physical | - | - | - | - | - | - |
Unilateral | 56 (45 to 57) | 55 (50 to 57) | 56 (51 to 57) | 56 (53 to 57) | No (P = 0.63) | No (P = 0.31, E= 2.6, CI ±4.9) |
Bilateral | 55 (48 to 56) | 55 (49 to 57) | 54 (49 to 57) | 51 (44 to 56) | No (P = 0.40) | - |
SF-12 mental | - | - | - | - | - | - |
Unilateral | 57 (49 to 58) | 57 (51 to 58) | 56 (48 to 58) | 57 (55 to 59) | No (P = 0.46) | No (P = 0.94, E= 0.21, CI ±5.5) |
Bilateral | 58 (43 to 60) | 56 (46 to 59) | 56 (49 to 60) | 58 (49 to 61) | No (P = 0.61) | - |
Data are presented as median (interquartile range). E=effect size.
Key safety findings
No safety findings reported.
Study 7 Blazevski (2021)
Study type | Case series |
|---|---|
Country | Australia |
Recruitment period | 2013 to 2018 |
Study population and number | n=50 patients with apical prostate cancer |
Age and sex | Median age 68 years (IQR 63-71) |
Patient selection criteria | Patients with apical PCa; 12-month follow up; completion of QoL questionnaires; MRI lesion extended to within <3 mm of the apical capsule/border and so needed the IRE ablation to incorporate the distal 3 mm of the prostate |
Technique | IRE was done by a single urologist using an IRE device and 18-gauge electrodes (Nanoknife®; Angiodynamics, Queensbury, NY, USA). All patients were positioned in lithotomy position under general anaesthesia and deep-muscle paralysis. An indwelling catheter was placed to empty the bladder. 4 to 6 electrodes were placed through the perineum through the template grid to surround the PCa lesion. A 10 mm intra-prostatic margin was applied to prostate stroma surrounding the targeted area to allow for MRI volume underestimation. |
Follow up | Median 44 months – outcomes reported up to 24 months |
Conflict of interest/source of funding | Authors report receiving consultancy and proctor fees to AngioDynamics and other companies. Funding was provided by Australian Prostate Cancer Research Centre-NSW and St. Vincent's Prostate Cancer Centre |
Analysis
Follow-up issues: 40 out of 50 (80%) patients had had follow-up biopsy at the time of analysis. The remaining patients had either refused biopsy (against the urologist's recommendation) because of reassuring MRI and PSAs or were awaiting biopsy. All patients consented to have QoL evaluation and questionnaires were completed at baseline, 6 weeks and 3, 6, 12 and 24 months. Serial PSA levels were also measured every 3 months for the first 2 years and multiparametric MRI was done at 6 months.
Study design issues: Small retrospective analysis of prospective cohort registry. QoL and functional outcomes were measured using the EPIC score, including urinary, sexual and bowel domains (all measured 1 to 100 with 100 indicating the greatest QoL.
Follow-up biopsies were reported as follows: (1) negative, (2) in-field recurrence—defined as any PCa found within the intention-to-treat zone, or (3) out-of field—defined as any PCa found outside the intention-to-treat zone. Significant PCa on follow up was defined as Gleason score ≥ 3 + 4. Failure-free survival was defined as progression to whole-gland or systemic treatment or metastasis/death. FFS was reported at 3 years after initial treatment.
Wilcoxon's signed rank test and Wilcoxon's rank sum test (both 2-tailed) were used to assess statistically significant differences in paired continuous variables (all questionnaire outcomes at baseline and 12 months). A Chi-square test for differences between posterior and anterior ablation was performed for urinary incontinence, urinary leakage, and potency post treatment. P values<0.05 were taken to indicate statistical significance.
Study population issues: Median pre-operative PSA was 6.25 (IQR 4.35 to 8.9) nanograms/ml. A total of 43 out of 50 (86%) patients had intermediate-risk, 5 out of 50 (10%) had low-risk and 2 out of 50 (4%) had high-risk disease. A total of 5 out of 50 (10%) had ISUP grade 1 PCa, 37 out of 50 (74%) had ISUP grade 2 PCa, 6 out of 50 (12%) had ISUP grade 3 PCa and 2 out of 50 (4%) had ISUP grade 4 PCa (with higher numbers indicating greater severity).
Other issues: It is possible that patients included in this study may also be included in Blazevski (2020), which includes patients with patients with other locations of prostate cancer in addition to apical PCa.
Key efficacy findings
Number of patients analysed: 50
PSA and MRI outcomes
Outcome | |
Median (IQR) PSA at 12 months (n=50) | 1.7 nanograms/ml (0.84-3.35) |
MRI results at 6 months- Clear % (n=50) | 86 (43/50) |
MRI results at 6 months- In-field lesions % (n=50) | 14 (7/50) |
MRI results at 6 months- Out-of-field lesions % (n=50) | 0 |
Biopsy outcome (n=40) | |
Significant in-field disease at 12 months % | 2.5 (1/40) |
Significant out-field disease at 12 months (%) | 20 (8/40) |
Low volume Gleason 6 tumour % | 32.5 (13/40) |
Whole gland free of significant cancer at 12 months % | 77.5 (31/40) |
Failure-free survival
Of patients that had greater than 3-year follow up; the failure free survival at 3 years was 90% (36/40).
Clinical outcome | Median EPIC Urinary score* | Median EPIC Bowel score* | Median EPIC Sexual score* |
|---|---|---|---|
Baseline | 95 | 96 | 65 |
6 weeks | 65 | 97 | 46 |
3 months | 96 | 99 | 51 |
6 months | 97 | 100 | 57 |
12 months | 97 | 98 | 59 |
24 months | 99 | 100 | 76 |
*Results taken from graph
There was no statistically significant difference in urinary QoL at baseline and 12 months after treatment (p=0.063) or in bowel QoL(p=0.066).
There was a statistically significant difference in sexual QoL at baseline and 12 months after treatment (p=0.001). Of patients that were potent before IRE, 94% (30/32) remained potent sufficient for sexual intercourse after IRE ablation at 12-month after treatment.
Key safety findings
Complication grade | Listed complications | Incidence % |
Clavien-Dindo 1 | Dysuria, haematuria, urgency, and postoperative pain) | 20 (10/50) |
Clavien-Dindo 2 | Urinary tract infection, severe urgency/frequency, incontinence | 18 (9/50) |
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