VITUS Privatklinik

VITUS IRE – NanoKnife™ in prostate cancer

NanoKnife

A revolution in the treatment of prostate cancer

Men diagnosed with prostate cancer are usually given the choice by their urologist to have the prostate surgically removed(radical prostatectomy – RPE) or to undergo radiationtherapy (radio therapy – RT). Both procedures are fraught with significant side effects: Impotence and incontinence are the rule.

However, they by no means guarantee a cure: in most cases, prostate cancer comes back after surgery or radiation, because these so-called recurrences are very common in prostate cancer.

Irreversible
Electroporation (IRE) 

NanoKnife treatment:
High efficacy, few side effects 

This has changed since the successful introduction of Irreversible Electroporation (IRE) for the treatment of prostate cancer.

With IRE, prostate cancer can be focally destroyed, with a lower likelihood of side effects.

The wide range of
IRE treatments:

From focal therapy to problem solver in unresectable T4 carcinoma.

IRE – also known by the product name NanoKnife – enables the gentle treatment of prostate cancer while avoiding impotence and incontinence.

IRE can be used to treat the full range of prostate cancers – from small focal carcinomas to T4 tumors that have already infiltrated the bladder or rectum – in other words, inoperable, usually advanced cases1.

At the VITUS PRIVATKLINIK, we provide you with comprehensive information about all treatment options for prostate cancer and also inform you about possible alternatives.

Get in touch with us. We will be happy to advise you.

Our most important
Message: Don’t be pressured into treatment.

At VITUS we inform you in detail about all treatment options

Prostate cancer often progresses slowly. In most cases, you will have enough time to learn about all treatment methods. In addition, classical “radical” therapy (surgery and/or radiation treatment) rarely prolongs life expectancy in low-aggressive prostate carcinomas – and in highly aggressive carcinomas, according to available statistics, it does not do so in many men. The same applies to radiation therapy.

At the same time, the classical treatments mainly lead to serious side effects, rarely to cure: 70-80% of all men experience erectile dysfunction after surgery, and about 20-50% of patients experience urinary incontinence: about 20% of men experience severe incontinence requiring several diapers per day, and an additional 30% experience moderate incontinence where one diaper per day is sufficient (see Table 1).

Long-term consequences
2 years
5 years
15 years
Incontinence
RPE
RT
9,6%
3,2%
13,4%
4,4%
18,3%
9,4%
Impotence
RPE
RT
78,8%
60,8%
75,7%
71,9%
87,0%
93,9%
Disturbance of the
Intestinal function
RPE
RT
13,6%
34,0%
16,3%
31,3%
21,9%
35,8%

Table 1: Long-term sequelae of radical prostatectomy (RPE) and radiotherapy (RT) for prostate cancer regarding incontinence, impotence, and impaired bowel function. Table translated into German. Resnik MJ, Koyoma T, Fan K-H, et al. N Engl J Med 2013; 368:436-45.

Irreversible electroporation (IRE):
The NanoKnife process

The NanoKnife tissue ablation procedure is a novel, but now more than 10 years old, therapy that uses the Irreversible Electroporation (IRK) method to destroy cells. The surrounding tissue is not damaged in the process. Prostate cancer can be treated for the first time with this method in such a way that continence is preserved and there is only a low risk of impotence. In addition, the NanoKnife procedure has a very low likelihood of pain or scarring.

Here at VITUS, we are proud of the pioneering work we have done with the NanoKnife process. We are among the world’s leading experts in the use of IRE in the treatment of prostate cancer.

Through our close collaboration with the inventor of IRE for medical purposes, Prof. Boris Rubinsky of the University of Berkeley in the USA, we have had the opportunity to study and understand IRE at all stages of development, from the laboratory to animal studies to human application. Our physicists and physicians are thus among the pioneers and world’s leading experts in electroporation processes – both in the scientific-technical field and in clinical use.

ADVANTAGES OF
NANOKNIFE TREATMENT
AT A GLANCE:

* Urinary incontinence, as it is called, is the lack or inability of the body to safely store and self-directly empty the contents of the bladder. This leads to involuntary loss of urine. While there are several possible definitions of incontinence, a long-term study of incontinence after prostatectomy** concludes that a reasonable definition of incontinence is when a patient requires 2 or more pads per day 12 months after prostate surgery.

** Sacco E, Prayer-Galetti T, Pinto F, et al. Urinary incontinence after radical prostatectomy: incidence by definition, risk factors, and temporal trend in a large series with a long-term follow-up. BJU Int. 2006;97:1234-41.

*** Syan, Raveen, and Victor W. Nitti. “Post-prostatectomy Incontinence Initial Evaluation.” Urinary Dysfunction in Prostate Cancer. Springer, Cham, 2016. 15-30.

NanoKnife technology – ideal for the treatment of prostate cancer

The NanoKnife process is based on ultra-short pulses that generate strong electric fields. The pulses are 100 microseconds long – i.e. 0.0001 seconds. Compared to standard procedures, this new technology has unique features that make it ideal for treating the prostate.

The precision is
crucial for the
Therapy success with NanoKnife

Since 2007, the IRE technique has been approved by the FDA in the USA and CE marking in Europe. This was done because corresponding studies prove that all cells within the treatment area can be killed with this method. In order to achieve this and carry out a successful IRE treatment, two factors are crucial:

The first condition is fulfilled by multiparameter MRI examination, 3D biopsy and, if necessary, other procedures. The second condition is fulfilled by a minimally invasive procedure under general anesthesia. Sterile needles with variable exposure length are inserted. “Exposure length” refers to the area of the needle that exposes the tissue to electrical current. We have experience with this procedure since 2011 and have performed the most prostate treatments worldwide. This makes us one of the leading experts worldwide, while other clinics are just getting started.

At the VITUS PRIVATKLINIK, we provide you with comprehensive information about all treatment options for prostate cancer and also inform you about possible alternatives.

Get in touch with us. We will be happy to advise you.

What is the procedure of a NanoKnife treatment?

Step 1: Planning

This step is perhaps the most important. NanoKnife is a focal, image-guided treatment whose results are only as good as the planning and diagnostics that precede it. This is because NanoKnife itself does not detect where the cancer is located.

As a patient, you should not compromise on diagnostics. All variants of ultrasound (including elastography and contrast-enhanced ultrasound) as well as rectal punch biopsies have alarmingly low detection rates. It is very unlikely that this will find (all) tumors.

At the present time, only multiparameter MRIs performed by specialized radiology institutes provide adequate imaging diagnostics – together with PSMA/choline PET/CT if required.

The 3D images from MRI are given yet another layer by a 3D saturation biopsy. We are specialized in both procedures. Both are required to achieve the diagnostic accuracy necessary to effectively deliver NanoKnife treatment.

Once our physicians and physicists have determined the target area using the MRI cross-sectional images and, if necessary, calculated it in advance using 3D simulations developed by us, the target area is saved and transferred to the surgical monitor on the day of the operation.

Step 2: Placing the electrodes

For prostate treatment, the needles are inserted transperineally, through the perineum (the area between the genitals and anus). An endorectal ultrasound helps with placement. Experience plays a decisive role here. Even two needles place high demands on the spatial imagination of the surgeon. Placements with many needles are extremely challenging. This is because the prostate is a relatively small organ with a complex geometry, surrounded by many sensitive anatomical structures. In addition, the positioning options of the needles are very limited. This process can sometimes take several hours, although here at the VITUS Prostate Center computer programs help us achieve the perfect placement.

Figure 1: Minimally invasive NanoKnife electrode

Step 3: Simulation

Once the needles are precisely placed, their position is measured by ultrasound and passed on to the NanoKnife software and other external software. The area to be treated can still be adjusted on the computer by various parameters such as voltage, pulse duration and number of pulses. When all settings match the geometry of the prostate and tumor (always allowing for a safety margin around the tumor), NanoKnife charges its capacitors.

Step 4: Treatment

A potential difference builds up between each set consisting of two needles each. This is normally 3000 volts (V). This means that there is +1500 V on needle 1 and -1500 V on needle 2. The patient remains at 0 V. These voltages may seem more life-threatening than gentle, but their duration of action is in the range of millionths of a second. This makes the procedure safe and side effects such as burns are avoided. For more on the technology and the theory behind it, read more about the theory of IRE here.

The number of needles may vary and depends largely on the area to be treated. The computer of the NanoKnife system takes over the appropriate control of the needles, according to the previous settings. The treatment itself usually takes only seconds, a few minutes at most.

Figure 2: Precise planning of IRE treatment

Step 5: Aftercare

Immediately after the needles are pulled out, the puncture sites close again. Most patients do not experience pain. However, some find the bladder catheter that is placed prior to treatment uncomfortable. It can be removed after 10 to 14 days. Small amounts of blood may still be found in the urine or seminal fluid several weeks later. This is because it takes up to six months for the body to move the tissue destroyed by NanoKnife ablation out of the body.

How good is the IRE
compared to the
radical prostatectomy (RPE):

Evaluation of results from 471 IRE treatments.

While we have successfully treated nearly 1300 men with prostate cancer at the VITUS Prostate Center in the meantime (as of March 2021), we have published the results of 471 IRE treatments over a maximum observation period of 7 years².

Table 2 shows that the majority of the patients we treated suffered from high-risk prostate cancer according to the D’Amico classification.

D’Amico Risk Classification
low risk
intermediate risk
high risk
other
25
88
312
4
Gleason Score
6
7(a/b)
7 (8/9/10)
N/A
82
225 (159/66)
113 (71/26/16)
9

Table 2

Most of the carcinomas were in stage T2a to T2c, i.e. within the prostate and had not yet (macroscopically) broken through the prostate capsule (“organ confined disease”). However, 84 patients with T3 and T4 carcinomas were also treated, i.e. carcinomas that had already penetrated the prostate capsule and spread outside the prostate (“non-organ confined disease”). Our treatment successes clearly show that IRE is not only suitable for the treatment of early, small carcinomas but also for the treatment of advanced carcinomas.

TNM stage
Number of Patients
T1a – T1c
32
T2a – T2c
281
T3a – T3b
54
T4 N0 M0
30
T4 N1 M0 /
T4 N0 M1 /
T4 N1 M1
31
N/A
1

Table 3

During the observation period of 70 months, only 4 recurrences occurred in patients with low-grade Gleason 6 carcinomas, 15 recurrences in patients with intermediate-grade Gleason 7 carcinomas, and 22 recurrences in the patient group with high-grade Gleason 8-10 carcinomas. Comparison with recurrence rates after radical prostatectomy (RPE) as specified in the Johns Hopkins University Han Tables shows that recurrence rates after IRE are comparable to those after RPE.

Recurrence rates after
IRE treatment
(NanoKnife)

Comparable to recurrence rates after radical prostatectomy

How can this be? After the radical removal of the prostate, the cancer should be completely removed from the body after all. But it is not so.

Looking more closely at the HAN Tables, one finds that recurrence rates after radical prostatectomy are high even when the tumor was completely removed along with the prostate (“organ-confined disease” category). So where do the recurrences in these cases come from? They originate from individual tumor cells that have migrated out of the prostate along connective tissue structures, lymphatic and blood vessels and have become embedded in the connective tissue surrounding the prostate. In fact, the tumor cells also circulate in the blood and can be detected there by means of a liquid biopsy.

This is because the prostate capsule is permeable to cells as it consists only of compacted connective tissue fibers. You can imagine it like the edge of a forest: from a distance of 1 km, the edge of the forest looks like a wall, but when you stand directly in front of it, you notice that it consists mainly of air, with a few branches and tree trunks in between. Accordingly, most recurrences after prostatectomy occur in the connective tissue that surrounded the prostate – and surrounds the prostate analogs after prostate removal.

So, strictly speaking, any prostate cancer treatment is just tumor mass reduction – the destruction or removal of the tumor mass IN the prostate. Tumor cells OUTSIDE the prostate remain in the body. This can be killed by the body’s own immune system. The patient is then cured – by his own immune system.

Therefore, it is not too surprising that recurrence rates after IRE treatment are comparable to recurrence rates after prostatectomy and radiotherapy.

Table 5 shows the number of recurrent tumors in the observation period of maximum 70 months in the different Gleason Score groups in 471 IRE treatments performed at VITUS Private Clinic. As expected, most recurrences occurred in the aggressive prostate cancer group (Gleason 8 -10). Fewer recurrences occurred in the Gleason 7 group and the fewest in the Gleason 6 group.

Number of recurrent tumors, total N = 41/429, at max. 70 months follow-up

Number of recurrent tumors, total N = 41/429, at max. 70 months follow-up
Stage
T1a-T2b = 11
T2c = 15
T3a-T4 = 15
Gleason score
Gl. 6 = 4
Gl. 7 = 15
Gl. > 7 = 22
Localization of the recurrence
inside the IRE field = 8
adjacent to the IRE field = 15
outside the IRE field = 16
3D biopsy preoperative
Yes = 16
No = 25

Table 4

Figure 1

The graph in Figure 1 shows the Kaplan-Meier curves of the 471 IRE treatments evaluated. The Kaplan Meier curves show the number of patients who developed prostate cancer recurrence in a given period after IRE treatment, again divided by prostate cancer aggressiveness: Gleason 6, Gleason 7, and Gleason 8-10. The maximum observation period was again 70 months.

It is interesting to compare the recurrence rates of the aggressive carcinomas (red curve) with the recurrence rates after radical prostatectomy (RPE) as obtained from the Han Tables of Johns Hopkins University, USA (blue and pink dashed lines). The comparison was made with data from patients with comparable tumor stage and Gleason score. Recurrence rates after IRE treatment (red curve) are in the “corridor” of recurrence rates after radical prostatectomy – i.e., they are comparably high.

The distinction between the different localizations of recurrences is also interesting: overall, only 8 of the 41 recurrences occurred within the IRE ablation field, and 15 occurred directly adjacent to the IRE field.

These can be assumed to have surviving tumor cells within or just outside the ablated tumor focus. However, 16 of 41 “recurrences” occurred in regions of the prostate that had been assessed as “tumor-free” prior to treatment and therefore had not been treated. Thus, these were small and minute carcinoma foci that had not attracted diagnostic attention, mainly in patients who had not undergone extensive diagnostic workup prior to IRE treatment: these patients refused 3D mapping biopsy (3DMB) and/or optimal endorectal MRI and/or PSMA-PET/CT with gallium68. In the strict sense, these “recurrences” are therefore not recurrences at all, but additional tumor foci in the prostate that were not known.

If these “pseudo-recurrences” are removed from the statistics and the Kaplan-Meyer curves are calculated based on the actual recurrences, even longer recurrence-free survival times are achieved. This can be seen in graph X: The Kaplan-Meyer curve for recurrence-free survival is shifted upward (gray arrows).

Figure 2 shows the treatment of a prostate carcinoma (stage T2b, N0, M0, Gleason 7b) in the left dorsal outer zone (arrow; radiological orientation, view from below, right and left interchanged) in a 53-year-old man. The treatment was performed with 3 electrodes whose positions are visible the day after the treatment (small red circles).
One ablation zone was generated per electrode pair (red ellipses). In the image after contrast administration, the ablation zone is clearly visible as an avascular area without blood supply. PSA levels decreased from 5.2 ng/ml before treatment to 2.3 ng/ml after IRE, rather than zero, because the right prostate lobe was preserved. This is typical of focal therapies.

IRE in prostate cancer:

High efficacy – low side effects

The table below shows side effects that occurred during the treatment of 471 prostate cancers at the VITUS Prostate Center.

First, it is noteworthy that due to the minimally invasive treatment, no life-threatening side effects and no deaths occurred.

Mild side effects occurred in approximately 1/5 of IRE-treated patients (green boxes), such as transient difficulty with urination (urine retention), so that a new urinary catheter had to be inserted after removal of the first bladder catheter and left in the bladder for a further 10-14 days. Mild discomfort and/or pain during urination (dysuria) and mild blood in the urine (hematuria) occurred in approximately 7% and 4% of patients, respectively.

Moderately severe adverse events occurred in only 2.5% of IRE-treated patients (yellow boxes). These were urinary tract infections due to the catheter, which had to be treated with antibiotics.

Medically relevant adverse events, but not life-threatening, occurred in only 1.3% of IRE-treated patients (pink boxes). These were persistent problems with urination caused by dead tumor tissue in the prostate, which had to be treated by removal of the tissue via the urethra (TURP), a fistula between the rectum and the prostate caused by the treatment, which healed spontaneously, and a perforation of the bladder caused by a urinary bladder catheter, which also closed spontaneously.

Side effects
Number of patients
Side effects due to IRE treatment
Number of patients
easy
Clinical or diagnostic monitoring only – no treatment required
93/477
(19,5%)
Temporary urine retention: bladder catheter longer than 14 days
43/477
(9,0%)
Dysuria
32/477
(6,7%)
Mild hematuria
18/477
(3,8%)
moderate
Minimal local or noninvasive treatment indicated; limitation of age-appropriate activities of daily living
12/477
(2,5%)
Urinary tract infection that must be treated with antibiotics
12/477
(2,5%)
Medically relevant and/or severe but not directly life-threatening; hospitalization or prolongation of hospital stay indicated; disabling; limitation of self-care in daily living
4/477
(0,8%)
Persistent urine retention: transurethral resection (TURP) required.
4/477
(0,8%)
Recto-prostatic fistula (misconnection); spontaneous healing/occlusion without surgery.
1/477
(0,2%)
Bladder perforation through catheter, self-healing
1/477
(0,2%)
life-threatening
Urgent medical measures required
0
Death by side effect
0

Table 5

Incontinence prevention  

Zero percent incontinence rate after IRE treatment in well over 1000 patients.

Incontinence is a common and serious side effect in approximately 50% of men who have undergone radical prostatectomy – with or without daVinci robots. Incontinence is difficult to avoid during surgical removal of the prostate, because the bladder sphincter (also called lower urinary sphincter – LUS) is located directly below the prostate and protrudes into the apex, the lower part of the prostate. If the prostate is removed, part of the sphincter is also removed. Further damage to the LUS occurs when the base of the bladder is sutured down after the prostate is removed and sutured to the sphincter muscle to ensure urine flow.

No incontinence occurred in the approximately 1300 patients treated with IRE to date. This fact was easy to ascertain because treated patients report it immediately, even with only minor involuntary urine loss. And indeed, immediately after IRE treatment, a small percentage of patients experience transient incontinence due to two mechanisms:

These types of incontinence are temporary and regress after a few days to a maximum of 3 months. They have nothing to do with the irreparable destruction of the sphincter muscle that occurs after surgery.

Table 6 shows our published data on urinary incontinence:

Subjective evaluation of urinary incontinence after IRE treatment. Patients were asked at the time of bladder catheter removal and during follow-up appointments and/or by telephone “whether their bladder function was normal or whether they were losing urine uncontrollably.” Minor “urge incontinence” within the first 3 months after IRE treatment was considered normal. Patients with urinary incontinence before IRE treatment were not included.
Number of patients
Urinary incontinence
0/385 (0%)

Table 6

Erectile dysfunction prevention

Zero to maximum 10% impotence after IRE treatment for prostate cancer.

The neurovascular bundle (NVB), a network of nerves and vessels, is responsible for the erketion function of the penis. It is mostly located inside and directly on the prostate capsule (see Figure 2) and therefore cannot be preserved during either radical prostatectomy or radiotherapy.

Therefore, the actual impotence rates after conventional prostate cancer treatment are very high at 60-90%, even after a so-called “nerve-sparing prostatectomy”. The result is the loss of erectile function: impotence.

Figure 2: On the left, a schematic representation of the prostate and its surrounding organs. The prostate is located deep in the pelvis. Posteriorly (dorsally) it lies directly against the rectum, superiorly (cranially) against the bladder, and inferiorly (caudally) against the sphincter. The neurovascular bundles (NVBs) are often depicted as “cable strands,” but this is incorrect. In the center, an anatomical preparation shows the actual neurovascular bundle – a complex network of nerves and vessels intimately connected to the prostate capsule. Free preparation, as shown here in the anatomical preparation, takes days and is not possible during surgery. Therefore, erectile dysfunction occurs in the majority of cases even after so-called “nerve-sparing” or “nerve-preserving” surgery. On the right, a schematic cross-section through the prostate (one half only) shows the exact location of the different parts of the NVB: intra- and interfascial (directly associated with the prostate) and extrafascial (located outside the prostate in the connective tissue).

Irreversible electroporation (IRE – NanoKnife) as a “problem solver” in inoperative prostate cancer: rectal infiltration, bladder floor infiltration, sphincter infiltration.

The treatment was performed with 5 electrodes whose positions are visible the day after the treatment (small black circles). One ablation zone was generated per electrode pair (red ellipses), for a total of 9 individual ablation zones. In the image after contrast administration, the total ablation zone is clearly visible as an avascular area without blood supply.

The prostate tissue was completely destroyed, only the prostate capsule is preserved, as it is largely composed of connective tissue, which is not destroyed by IRE. The PSA level decreased to 0 ng/ml, as after prostatectomy.

Before IRE treatment
PSA 11 ng/ml
1 day after IRE
3 months after IRE
PSA 0.0 ng/ml

The figures show the treatment of a prostate carcinoma stage T2c, N0, M0, Gleason score 8, in a 63-year-old man. The carcinoma has spread over both lobes of the prostate. In this case, focal therapy with preservation of substantial portions of healthy prostate tissue was no longer possible.

“Radical” therapy of prostatic carcinoma with Irreversible Electroporation (IRE – NanoKnife) – complete ablation of the prostate.

Figure 3 shows the treatment of a prostate carcinoma stage T4, N0, M0, Gleason score 8, in a 79-year-old man with infiltration of the rectum (rectal area; yellow arrows above). Radical prostatectomy would have been possible only with additional removal of the rectum and creation of an artificial anus praeter.

Infiltration of the rectum is shown on the MRI images in the top row of Figure Z: Left: lateral (sagittal) image; Middle: cross-sectional (axial image) with T2 weighting; Right: cross-sectional (axial image) after contrast administration.

The lower row of images shows the conditions 9 months after IRE treatment: The wall of the rectum appears normal, without injury and without fistula (malconnection) to the prostate: Left: lateral (sagittal) image; Middle: cross-section (axial image) with T2 weighting; Right: cross-section (axial image) after contrast administration.

Figure 3: A tumor recurrence outside the treatment field (red arrow) was successfully destroyed in a second IRE treatment, also without damage to the rectum.
Figure 4 shows the treatment of stage T4 prostate carcinoma with infiltration of the lower bladder sphincter. Radical prostatectomy would have been possible only with complete removal of the sphincter muscle and resulting complete loss of bladder control (incontinence, permanent involuntary loss of urine). IRE treatment allowed complete preservation of the bladder sphincter without any incontinence.

Inoperable prostate carcinomas:

Often not detected due to inadequate diagnostics

In the meantime, we have successfully treated dozens of patients with inoperable prostate carcinomas at the VITUS PRIVATKLINIK, preserving their function. If you suffer from advanced prostate cancer, let our experts advise you.

Unfortunately, inoperable tumor stages are often not detected before surgical intervention because sufficiently accurate diagnostics have not been performed.

This leads either to the abortion of the operation or to the incomplete removal of the tumor, in some cases also to the removal of the bladder and the rectum together with the prostate and, among other things, to the creation of an artificial outlet for the intestine and the bladder. In many cases, such a disaster can be avoided.

References
  1. OP nur möglich unter Entfernung der Blase und des Darmes mit künstlichem Blasen- und Darmausgang.
  2. Günther et al.
  3. Rosen RC, Cappelleri JC, Smith MD, et al. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res. 1999 Dec;11(6):319-26. © 1999