Prostate Cancer Treatment with Irreversible Electroporation (IRE): Safety, Efficacy and Clinical Experience in 471 Treatments – Beyond the Abstract

Prostate cancer (PCa) is with an estimated 174,650 new cases and 31,620 PCa-related deaths in 2019 the second most common cancer in men in the US. Standard therapies such as radical prostatectomy (RPE) and radiation therapy (RT) have high rates of undesirable side effects such as erectile impotence and urinary incontinence.

Focal therapies for the treatment of PCa have been on a rise, as their minimally invasive approach can significantly reduce side effects. Many of them, including Radiofrequency Ablation, Cryoablation or Microwave Ablation, are based on thermal tissue changes. The disadvantage of these modalities is that they can unselectively damage surrounding structures, making them an elegant alternative only in cases where cancerous lesions are not close to sensitive structures. In contrast to this, Irreversible Electroporation (IRE) is an image-guided tissue ablation technology that induces cell death non-thermally via very short and strong electric pulses. IRE has preserving properties towards vessels, nerves and the extracellular matrix, as its effect unfolds on a cellular level. This makes IRE an effective treatment modality in all cases of PCa, including high-grade cancers and cancers that have already infiltrated surrounding tissue.

In a recently published retrospective assessment, we report the outcome of 471 IRE treatments in 429 patients of all grades and stages of PCa with 6-year maximum follow-up time.

Toxicity Profile of IRE
Acute toxicity was recorded intra- and post-operatively in all cases and until the Foley catheter was removed. All patients had a control MRI 24 hours after treatment to confirm the congruence of the IRE-field with the extent of the tumor and to assess potential procedure-related side effects such as hemorrhage or rectal damage. Most adverse events were mild (in 19.7% of patients) to moderate (in 3.7% of patients). Dysuria and transient urinary retention were amongst the most common adverse events, both more frequent in large prostates and large ablation zones. Severe adverse events occurred in 1.4% of patients. Permanent urinary retention occurred in 4 patients, requiring TURP to restore normal urination. One of the first patients in this series developed a recto-prostatic fistula, which closed spontaneously after a few weeks, one patient experienced a bladder perforation by a faulty catheter, and one patient suffered from prolonged urogenital-tract infection.

Sexual Function After IRE
The overall occurrence of Erectile Dysfunction (ED) after IRE in this series was rare. Standard evaluation by IIEF5 revealed IRE-related severe ED in 11.3% of evaluated patients during the first 12 months, and in 3% of patients after 12 months. Figure 1 summarizes different aspects of the results. Figure 1A shows that smaller ablation volumes (less than half of the prostate) resulted in a mean IIEF5-Score reduction of 17.7% (-5.3 points), while it was twice as high in whole-gland ablations (37%, -11.1 points). Figure 1B displays the correlation between the involvement of the neurovascular bundle (NVB) with ED. Figure 1C illustrates a statistically significant improvement (p=0.045) of Erective Function (EF) over time: from a mean reduction of the IIEF5-Score of 33% (-8.72 points) during the first 18 months after IRE, to 15% (-3.88 points) beyond that time point. Thus, our data shows a recovery of EF after IRE. As assessment of EF is difficult due to co-factors such as the nocebo effect, we also used our own subjective assessment in interviews and with questionnaires. The results, which are shown in Figure 1D, confirm the transient nature of ED after IRE, with 45% of men experiencing transient ED (defined as up to 12 months), but only 3% patients experienced persistent severe ED, whilst 52% of patients experienced no ED at all.

BTA fig 1 overall occurance of ED

Figure 1: Overall occurrence of Erectile Dysfunction (ED) after IRE treatment. A: Reduction of IIEF5-Score dependent on ablation volume. Purple: 50% or less of the prostate was treated, green: 50-90% of the prostate volume was treated, red: whole gland ablations. B: Reduction of IIEF5-Score dependent on the involvement of the neurovascular bundles (NVB). Purple: no involvement, green: either left or right NVB, red: involvement of both NVB. C: Time-dependent mean reduction of the IIEF5-Score. Red: within the first 18 months post IRE, purple: after 18 months post IRE. D: Subjective assessment of ED.

Urinary Function After IRE
IPSS-Score analysis was used to determine urinary function after IRE. In patients fully continent before IRE, no urinary incontinence was observed 12 months post IRE or later during the observation period, despite the partial or total inclusion of the lower urinary sphincter in the treatment field. In 7.7% of the evaluated patients, scores increased temporarily from below 8 to above 19 (severe symptoms) after IRE. In one case, the last included data point still showed a score above 20. In terms of urinary symptoms, the majority of patients (72.8%) reported no change or an improvement in quality-of-life after IRE, while 27.2% reported a transient decrease. Until data analysis cut off, only one patient out of 429 who was initially satisfied reported dissatisfaction with regards to urinary function.

Treatment Efficacy After IRE: Recurrence-Free Survival Rate
Figure 2 and 3 illustrate the recurrence-free survival of patients with different Gleason Scores over time, and compare the results to outcomes after RPE . Figure 2 shows any tumor reoccurrence after IRE therapy, including those outside the IRE treatment field. Despite this conservative approach, the recurrence rates for high-grade (Gleason >7) cancers fall inside the corridor of the recurrence rates after RPE for comparable cancer stages and PSA-levels (blue and magenta dots, CI shown as bars for ease of perception). The Kaplan Meier Curve in Figure 3 only shows the recurrences which occurred inside or at the margin of the IRE treatment field, excluding the 20 cases where the recurrence was located within residual prostate tissue and thus classified as out-of-field recurrence. All recurrence rates are outside the corridor of the recurrence rates after RPE for comparable cancer stages and PSA-levels (blue and magenta dots, CI shown as bars for ease of perception).

BTA fig 2 after IRE

Figure 2: Kaplan-Meier-Curves, showing all tumor reoccurrences. The number of recurrences after IRE: Gleason 6: 3 patients, Gleason 7: 18 patients, Gleason > 7: 26 patients. Recurrence-free survival rates thus were: Gleason 6: 94%, Gleason 7: 85%, Gleason > 7: 60%.

BTA fig 3 survival after IRE

Figure 3: Kaplan-Meier-Curves, showing only the recurrences inside or at the margin of the IRE treatment field. The number of recurrences after IRE: Gleason 6: 1 patient, Gleason 7: 10 patients, Gleason > 7: 16 patients. Recurrence-free survival rates thus were: Gleason 6: 98%, Gleason 7: 93%, Gleason > 7: 75%.

Summary
The retrospective evaluation of our data allows the conclusion that Irreversible Electroporation (IRE) is a safe, effective and suitable modality for the treatment of prostate cancer at all clinical stages and for recurrent disease. Initial local tumor control was achieved in all patients. Treatment fields included the lower urinary sphincter, seminal vesicles, neurovascular bundles and in some cases partially the rectum and bladder, yet overall toxicity was low. Urinary continence was preserved in all cases. In terms of local tumor control, the comparison of IRE with radical prostatectomy (RPE) revealed similar recurrence rates over time, suggesting similar effectiveness of IRE to RPE. Thus the data illustrates the feasibility of IRE for prostate cancer treatments, with similar functional outcomes and short to midterm efficacy to RPE, but much lower toxicity profile.

Written by: Nina Klein, VITUS Prostate Center, Strahlenbergerstrasse 110, Offenbach, Germany

References:
1. Ezez. 2019. "Key Statistics for Prostate Cancer | Prostate Cancer Facts". Cancer.org.
2. Guenther, E., Klein, N., Zapf, S., Weil, S., Schlosser, C., Rubinsky, B., & Stehling, M. K. (2019). Prostate cancer treatment with Irreversible Electroporation (IRE): Safety, efficacy and clinical experience in 471 treatments. PloS one, 14(4), e0215093.
3.  Colloca, L., & Miller, F. G. (2011). The nocebo effect and its relevance for clinical practice. Psychosomatic Medicine, 73(7), 598.
4. Ezez. 2019. "Han Tables | Johns Hopkins Brady Urological Institute". Hopkinsmedicine.org.
5. Ezez. 2019. "Prostate Cancer Treatment You Can Trust | Vitus Prostate Center". Vitus EN.

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